Dissertations / Theses on the topic 'Cellular Targeting, Imaging and Therapy'
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Nordberg, Erika. "EGFR and HER2 Targeting for Radionuclide-Based Imaging and Therapy : Preclinical Studies." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8721.
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Steyer, Grant J. "IMAGING OF CARDIOVASCULAR CELLULAR THERAPEUTICS WITH A CRYO-IMAGING SYSTEM." Case Western Reserve University School of Graduate Studies / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=case1271182554.
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Naik, Jay Dolatrai. "Cellular carriers of viral vectors for turmour selective targeting of cancer gene therapy." Thesis, University of Leeds, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.505080.
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Cancer gene therapy holds promise for patients, yet key issues involving the delivery of vector and achieving tumour selective cytotoxicity, has limited progress over recent years. In this thesis a combination of cell-based carriers, viral vectors and tumour selective promoters are assessed to tackle these two important issues directly. Initially two retroviral systems were considered: intracellular carriage of a rapamycin-inducible retrovirus and extracellular carriage ('hitchhiking') of a self-inactivating (SIN) retroviral vector. Both systems controlled transgene expression using the tumour selective human telomerase reverse transcriptase and telomerase RNA promoters (hTERTp & hTRp). Direct transduction of target cells with SIN marker virus, expressing enhanced Green Fluorescent Protein (eGFP) under the internal control of human telomerase reverse transcriptase promoter (hTERTp) demonstrated similar activity to a positive control virus, with some evidence of telomerase selectivity. Hitchhiking of the same SIN marker vectors also mediated eGFP expression in target cells. In contrast the therapeutic SIN vectors containing suicide transgenes did not achieve a reliable direct telomeraseltumour selective cytotoxic effect, with no discernible toxicity seen with hitchhiked vector. The rapamycin-inducible vectors in contrast to the SIN vectors only demonstrated retroviral genome expression following single cell cloning of a positive-control producer cell line. The retrovirus from this producer successfully mediated low-level target cell eGFP expression, however the data did not support development of therapeutic vectors in,corporating either telomerase promoter. Incorporating oncolytic viruses into the system allowed in vitro therapy. An eGFP expressing oncolytic vesicular stomatitis virus (VSV) and wild-type reovirus, showed direct cytotoxicity against a range of target cell lines. T-cell and non-T-cell peripheral blood mononuclear cell (PBMC) fractions were resistant to both viruses indicating their suitability as oncolytic viral carriers. Finally VSV was successfully hitchhiked on donor T-Iymphocytes leading to the release of VSV .and widespread replication within the malignant Molt-4 cell line.
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Rodrigues, Margret S. Tong Alex W. "Growth inhibition of human multiple myeloma cells by a conditional-replicative, oncolytic adenovirus armed with the CD154 (CD40-ligand) transgene." Waco, Tex. : Baylor University, 2006. http://hdl.handle.net/2104/5016.
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Liu, Jian. "POLYMER MODIFICATION OF FULLERENE FOR PHOTODYNAMIC TUMOR THERAPY AND TUMOR IMAGING." 京都大学 (Kyoto University), 2010. http://hdl.handle.net/2433/120886.
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Calì, Bianca. "Cellular communication and cancer therapy: targeting Ca2+and NO signalling within the tumour microenvironment." Doctoral thesis, Università degli studi di Padova, 2014. http://hdl.handle.net/11577/3423745.
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Cell death and bystander effect are crucial for both the efficacy of cancer therapy and the modulation of anti-tumour immune response. The ‘bystander effect’ refers to a process whereby untreated cells exhibit either the deleterious or beneficial indirect effects as a result of signals received from nearby targeted cells. Various molecular players and pathways have been suggested to mediate the bystander effects, nevertheless to date it is not known which are the key molecules and cellular mechanisms underpinning cell death signal propagation. Several reports suggest the involvement of both nitric oxide (NO) and reactive nitrogen species (RNS) in mediating the bystander effect. Nevertheless their role in the process has not been totally defined since these molecules can either inhibit or sustain tumour progression. Additionally, the methods conventionally applied for NO tracking do neither necessarily reflect real-time NO production nor allow studies into intact three-dimensional tumour mass.
The primary aim of this study was to investigate and characterize cell signals responsible for the bystander effect within the tumour microenvironment, paying particular attention to NO. To this purpose, we exploited intravital microscopy by taking advantage of the novel fluorecent probe for NO (CuFL) and the dorsal skinfold chamber model on living tumour-bearing mice subjected to photodynamic therapy (PDT).
Notably, the PDT-triggered bystander effect was associated to the generation of very fast NO and Ca2+ waves within the whole tumour mass, supported the hypothesis that constitutive NOS activity might be crucial for the beneficial spread of bystander response and death signals propagation. Additionally, we demonstrated that PDT triggered apoptosis in bystander cells, through gap junction intercellular communication.
Finally, our results, provide the first direct evidence of NO involvement in bystander responses within a three-dimensional tumour mass, and strikingly corroborate the notion that connexin gap junction are instrumental for mediating bystander death signals propagation.La morte cellulare e l’effetto bystander rappresentano degli elementi decisivi per l’efficacia della terapia antitumorale nonchè per la modulazione della risposta immunitaria contro il cancro. Per “effetto bystander” si intende il processo per il quale le cellule non soggette a determinati trattamenti farmacologici subiscono indirettamente gli effetti terapeutici, siano essi positivi o negativi, risultanti dal trattamento esclusivo delle cellule vicine. Nonostante siano state proposte diverse molecole e vie di segnalazione coinvolte nell’effetto bystander, i messaggeri molecolari essenziali ed i meccanismi che sottendono alla propagazione dei segnali di morte non sono ancora noti. Diversi studi suggeriscono un coinvolgimento dell’ossido nitrico (NO) e delle specie reattive dell’azoto (RNS) nell’effetto bystander tuttavia, il loro ruolo nel processo non è tuttora totalmente chiaro, considerato che essi possono sia inibire che sostenere la progressione del tumore. Inoltre, i metodi tradizionalmente usati per lo studio dell’ossido nitrico non riflettono necessariamente la produzione di NO in tempo reale nè consentono studi su complesse masse tumorali tridimensionali. L’obiettivo principale di questo studio è stato quello di individuare e caratterizzare i segnali cellulari responsabili dell’effetto bystander all’interno del microambiente tumorale, rivolgendo particolare attenzione all’NO. A questo scopo, abbiamo utilizzato delle tecniche di microscopia intravitale, avvalendoci di una nuova sonda fluorescente per l’NO (CuFL) e del modello sperimentale delle camerette dorsali impiantate su topi affetti da tumore e sottoposti a terapia fotodinamica (PDT). Da questo studio è emerso che l’effetto bystander indotto dalla terapia fotodinamica è associato alla generazione all’interno della massa neoplastica di onde molto rapide di segnali di NO e di Ca2+. Questi eventi avallano l’ipotesi che l’attività delle isoforme costitutive dell’enzima NOS possa esercitare un ruolo cruciale nella diffusione delle risposte bystander e nella trasmissione dei segnali di morte. Questo lavoro inoltre ci ha consentito di dimostrare che la terapia fotodinamica è in grado di indurre l’apoptosi delle cellule vicine non trattate (bystander) attraverso i meccanismi di comunicazione intercellulare mediati dalle giunzioni comunicanti. Infine, i risultati ottenuti hanno fornito la prima evidenza diretta della partecipazione dell’NO all’effetto bystander all’interno di una massa tumorale tridimensionale e corroborano efficacemente l’ipotesi che le giunzioni comunicanti formate da connesine siano essenziali per garantire la propagazione dei segnali di morte osservati nell’effetto bystander.
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Jing, Ying. "Magnetic nanoparticle tagging and application of magnetophoresis to cellular therapy and imaging." Columbus, Ohio : Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1153422245.
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Mickler, Frauke Martina. "Live-cell imaging elucidates cellular interactions of gene nanocarriers for cancer therapy." Diss., Ludwig-Maximilians-Universität München, 2013. http://nbn-resolving.de/urn:nbn:de:bvb:19-165829.
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Uttamapinant, Chayasith. "Cellular delivery and site-specific targeting of organic fluorophores for super-resolution imaging in living cells." Thesis, Massachusetts Institute of Technology, 2013. http://hdl.handle.net/1721.1/79263.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2013.Vita. Cataloged from PDF version of thesis.
Includes bibliographical references.
Recent advances in super-resolution fluorescence microscopy have pushed the spatial resolution of biological imaging down to a few nanometers. The key element to the development of such imaging modality is synthetic organic fluorophores with suitable brightness and photostability. However, organic fluorophores are very difficult to use in live cells because of their chemical compositions. Many excellent fluorophores, such as cyanine and Alexa Fluor dyes, are highly charged with sulfonate groups and do not cross the plasma membrane. Even if the fluorophores get inside cells, there exist few methods that can be used to target these nongenetically encoded probes to specific cellular proteins with high specificity and minimal interference. We describe herein the development of new methods for cellular delivery and sitespecific targeting of organic fluorophores to proteins in living cells. Building on our lab's previous work on engineering new substrate specificity for E. coli lipoic acid ligase (LplA), we created a mutant ligase that catalyzes covalent conjugation of a 7-hydroxycoumarin fluorophore onto a 13-amino acid peptide substrate, called LAP. We showed that enzymatic fluorophore ligation is compatible with the living cell interior and is highly specific for LAP fusion proteins. To extend the repertoire of fluorophores targetable by LplA inside cells, we devised a two-step labeling approach based on enzymatic azide ligation, followed by chemoselective derivatization with any membrane-permeable fluorophore via strain-promoted cycloaddition. As an auxiliary tool for enzymatic probe ligation, we also developed a very efficient and biocompatible variant of copper-catalyzed azide-alkyne cycloaddition that can be used for modification of cell-surface proteins. To overcome the lack of membrane permeability of sulfonated fluorophores, we identified a chemical reaction that efficiently masks charged sulfonate groups as esterase-labile sulfonate esters. Such masked sulfonated fluorophores enter cells readily and can be sitespecifically targeted to intracellular proteins. Our efforts in developing protein labeling and fluorophore delivery methods culminated in their application to super-resolution imaging of cellular proteins in living cells.
by Chayasith Uttamapinant.
Ph.D.
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Persson, Mikael. "Antibody Mediated Radionuclide Targeting of HER-2 for Cancer Diagnostics and Therapy : Preclinical Studies." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-6798.
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Spiegelberg, Diana. "Towards Personalized Cancer Therapy : New Diagnostic Biomarkers and Radiosensitization Strategies." Doctoral thesis, Uppsala universitet, Medicinsk strålningsvetenskap, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-247539.
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This thesis focuses on the evaluation of biomarkers for radio-immunodiagnostics and radio-immunotherapy and on radiosensitization strategies after HSP90 inhibition, as a step towards more personalized cancer medicine. There is a need to develop new tracers that target cancer-specific biomarkers to improve diagnostic imaging, as well as to combine treatment strategies to potentiate synergistic effects. Special focus has been on the cell surface molecule CD44 and its oncogenic variants, which were found to exhibit unique expression patterns in head and neck squamous cell carcinoma (HNSCC). The variant CD44v6 seems to be a promising target, because it is overexpressed in this cancer type and is associated with radioresistance. Two new radioconjugates that target CD44v6, namely, the Fab fragment AbD15179 and the bivalent fragment AbD19384, were investigated with regard to specificity, biodistribution and imaging performance. Both conjugates were able to efficiently target CD44v6-positive tumors in vitro and in vivo. PET imaging of CD44v6 with 124I-AbD19384 revealed many advantages compared with the clinical standard 18F-FDG. Furthermore, the efficacy of the novel HSP90 inhibitor AT13387 and its potential use in combination with radiation treatment were evaluated. AT13387 proved to be a potent new cancer drug with favorable pharmacokinetics. Synergistic combination effects at clinically relevant drug and radiation doses are promising for both radiation dose reduction and minimization of side effects, or for an improved therapeutic response. The AT13387 investigation indicated that CD44v6 is not dependent on the molecular chaperone HSP90, and therefore, radio-immunotargeting of CD44v6 in combination with the HSP90 inhibitor AT13387 might potentiate treatment outcomes. However, EGFR expression levels did correlate with HSP90 inhibition, and therefore, molecular imaging of EGFR-positive tumors may be used to assess the treatment response to HSP90 inhibitors. In conclusion, these results demonstrate how tumor targeting with radiolabeled vectors and chemotherapeutic compounds can provide more specific and sensitive diagnostic tools and treatment options, which can lead to customized treatment decisions and a functional diagnosis that provides more precise and safer drug prescribing, as well as a more effective treatment for each patient.
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ARMIJOS, RIVERA JORGE ISAAC. "Targeting cellular kinases and viral factors for molecular therapy of cancer, neurodegenerative diseases and viral infections." Doctoral thesis, Università degli studi di Pavia, 2018. http://hdl.handle.net/11571/1214796.
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Kato, Masashi. "The targeting of cyclophilin D by RNAi as a novel cardioprotective therapy : evidence from two-photon imaging." Kyoto University, 2009. http://hdl.handle.net/2433/126445.
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Doligalski, Michael Lawrence. "Design and Development of Peptidomimetic Ligands for Targeting Radiopharmaceuticals, Imaging Probes, and Immunotherapeutics in Oncologic Disease." Scholar Commons, 2016. http://scholarcommons.usf.edu/etd/6492.
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Cancer is a leading cause of morbidity and mortality in the developed world. While much has been learned about these diseases in the last few decades, one of the main barriers to widespread advancement is the heterogeneity of cancer biology. A growing body of evidence supports the idea that certain protein receptors are overexpressed on the surface of tumor cells as compared to normal tissues. These extracellular biomarkers provide a unique opportunity to selectively target the tumor with both imaging and therapeutic modalities. The research in this dissertation focuses on targeting proteins on the tumor cell surface with peptidomimetic ligands.
Following a description of various extracellular receptors, chapter one discusses targeting ligands designed to specifically and selectively bind these receptors. It reviews recent literature on targeted alpha-particle therapy and ends with an explanation of the advantages of peptide ligands. Three distinct approaches to imaging and therapeutic modalities are then discussed in subsequent chapters. First, a peptide ligand was designed to target radionuclides to malignant melanoma cells in an effort to develop companion radiotherapeutics and diagnostic imaging agents. The second research project describes the synthesis of a novel antagonist peptide ligand with conjugated near infrared dye, and its utility for real-time intraoperative guidance during pancreatic adenocarcinoma resection. Finally, the last chapter describes how the relatively new field of immunomodulatory effectors may be enhanced by their derivatization with peptide targeting ligands.
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Mickler, Frauke Martina [Verfasser], and CHRISTOPH [Akademischer Betreuer] BRAEUCHLE. "Live-cell imaging elucidates cellular interactions of gene nanocarriers for cancer therapy / Frauke Martina Mickler. Betreuer: Christoph Bräuchle." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2013. http://d-nb.info/1047300516/34.
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Phyu, Su Myat. "Targeting of the PI3K/AKT/mTOR signalling pathway and associated kinases in breast and colon cancer cells and response evaluation by molecular imaging techniques." Thesis, University of Aberdeen, 2018. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=238576.
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The phosphatidylinositol-3-kinase/AKT (Protein Kinase B)/mammalian target of rapamycin (PI3K/AKT/mTOR) signalling pathway, downstream of tyrosine kinase receptors, is upregulated in human cancers including breast and colon cancers. Glycogen synthase kinase 3 (GSK 3) is a serine/threonine protein kinase plays important role in various cellular processes including glycogen synthesis mediated by insulin signalling pathway. Moreover, 5' adenosine monophosphate activated protein kinase (AMPK), a crucial cellular energy sensor, has regulatory role in cell growth and proliferation through mTOR pathway. Phosphatidylcholine (PtdCho) is the major phospholipid in the mammalian cell membranes and is mainly synthesized by the CDP-choline pathway. Malignant transformation has been reported to be associated with altered choline metabolism. Hyperactivation of the PI3K/AKT signalling pathway upregulates the key enzymes of phospholipid metabolism. The first line antidiabetic drug, metformin, modulates glucose and concomitant lipid metabolism through AMPK activation. Studies suggest phosphatidylcholine biosynthesis and breakdown through CDP-choline pathway are modulated by glucose metabolism and de novo fatty acid synthesis. Cancer cell growth inhibitory effect of PI3K/AKT/mTOR/GSK3 pathway inhibitors and metformin were investigated by cytotoxic assay, western blot and cell cycle analysis in breast and colon cancer cells. IC50 values of anticancer drugs and combination indices between drug combinations were determined. 31P-NMR was carried out on cell extracts after drug treatments. [14C (U)] glucose and [3H] choline incorporation into lipids were also determined. All inhibitors targeting PI3K/AKT/mTOR signaling pathway, GSK3 and metformin have cancer cell growth inhibition. By 31P-NMR, PI3K/AKT/mTOR pathway inhibition induced agent-specific changes in PCho intensity. Increased UDP-sugars observed in breast and colon cancer cell extracts treated with LY294002 and AZD8055, an effect abrogated by inclusion of a GSK3 inhibitor. A link between glycolytic intermediates and phosphatidylcholine biosynthesis was investigated by metformin and GSK3 inhibitor in breast and colon cancer cells.
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Zangoni, Elena. "Synthesis, quality control and pharmacological studies of 99mTc- and 188Re- radiopharmaceuticals for imaging and therapy." Doctoral thesis, Università degli studi di Padova, 2009. http://hdl.handle.net/11577/3426623.
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The most important goal of the research in the radiopharmaceutical field is the development of radioactive isotopes containing drugs, suitable for the application in diagnosis and therapy.
Technetium-99m is a gamma-emitter with optimal characteristics widely employed in Nuclear Medicine for imaging, and it is readily available as pertechnetate from the 99Mo/99mTc generator.
Rhenium-188 appears to be promising as a candidate for the treatment of neoplasia for its beta(-)- emission, available as perrhenate from a 188W/188Re generator, facility that makes it suitable for clinical use.
For the development of site-directed diagnostic and therapeutic radiopharmaceuticals, a biomolecule (hormones, peptides i.e.) with high affinity for a receptor-target should be labelled to deliver the radionuclide in a specific body region.
Labelled biomolecules must exhibit in vivo stability and retain receptor affinity after administration. The labelling protocol is therefore optimised depending on the structure of the desired biomolecule, then receptor binding studies and in vivo biodistribution studies on the labelled species must be performed to confirm the ability to accumulate on target cells or organs.
This work relates on the production of target-specific radiopharmaceuticals focusing on two types of biomolecules, somatostatin analogues and hyaluronic acid.
The first part of this work involves the indirect labelling of two somatostatin dicarba-analogues, named CIF and CIN, conjugated to the chelating agent PN2S. Chapter 2 describes the adopted labelling protocols, which were carried out using two different metal cores: 99mTc-oxo for the CIN-PN2S peptide, and 99mTc–tricarbonyl for the CIF-PN2S peptide. Afterwards, stability studies and biodistribution studies in animal models were performed on the obtained complexes, which results are debated in chapter 3. In particular, [CIF-PN2S-99mTc(CO)3-DMTC] complex demonstrated to maintain its specificity for somatostatin-receptor expressing organs.
The second part of this work is focused on the direct labelling with 188Re of the liver targeting agent hyaluronic acid. In order to evaluate the possible therapeutic use of the obtained complex, stability studies and pharmacokinetics of 188Re-HA were carried out, as reported in chapter 4. Afterwards, toxicity and dosimetry of the radiolabelled compound were evaluated, and finally therapeutic effect on animal models with induced liver cancer was studied. The encouraging results obtained, reported in chapter 5, prompted us to consider hyaluronic acids with different molecular weights (5, 10, 200 and 500 kDa), in order to determine if they can provide some advantages in liver uptake with respect to the HA previously studied. As reported in chapter 6, high molecular weight HAs were directly labelled with 188Re and tested to evaluate their stability. Biodistribution studies in healthy mice showed that liver uptake was higher with respect to the 70 kDa HA used in the previous chapter. Therefore these high molecular weights 188Re HAs seem to be promising agents for the treatment of liver cancer, since they enable a further reduction on the exposition of non target tissues to radiation damage.La ricerca nella disciplina radiofarmaceutica ha come obiettivo primario lo sviluppo di composti contenenti isotopi radioattivi per applicazioni di tipo diagnostico e/o terapeutico. Il tecnezio-99m è gamma emettitore dotato di ottime proprietà sia chimiche che nucleari, che ne giustificano l’enorme impiego nella diagnostica per “imaging” in medicina nucleare. E’ inoltre disponibile nella specie pertecnetato grazie al generatore 99Mo/99mTc, che per la sua reperibilità ed economicità è presente in quasi tutti gli ospedali. Il renio-188 invece è un radionuclide beta-meno emettitore, particolarmente interessante per il potenziale trattamento radioterapico dei tumori. Anch’esso viene prodotto mediante un generatore, rendendo dunque possibile un suo impiego nei reparti di medicina nucleare. La marcatura con un tracciante radioattivo di biomolecole con affinità recettoriale si inserisce nel settore della produzione di radiofarmaci target-specifici. In particolare questa strategia deve portare all’ottenimento di specie stabili in vivo e non deve alterare la loro biospecificità. Il metodo di marcatura deve quindi essere studiato in funzione della biomolecola in esame, e successivamente devono essere effettuati studi di binding recettoriale e di biodistribuzione in vivo per confermare la capacità della specie marcata di accumularsi a livello dell’organo o delle cellule bersaglio. Questo lavoro di tesi affronta la produzione di radiofarmaci recettore-specifici attraverso lo studio di due biomolecole, derivati della somatostatina e acido ialuronico. La prima parte del lavoro riguarda la marcatura indiretta di due dicarba-analoghi della somatostatina, CIF e CIN, derivatizzati con il set chelante PN2S. Nel capitolo 2 vengono riportati i due protocolli di marcatura adottati, che prevedono l’impiego di due diversi centri metallici: 99mTc-oxo per il peptide CIN-PN2S e 99mTc –tricarbonile per il peptide CIF-PN2S. Successivamente sui complessi ottenuti sono stati eseguiti gli studi di stabilità e biodistribuzione in animali, i cui risultati sono discussi nel capitolo 3. Il complesso [CIF-PN2S-99mTc(CO)3-DMTC] ha dimostrato mantenere la specificità per gli organi esprimenti recettori per la somatostatina. La seconda parte di questo lavoro invece si è concentrata sulla marcatura diretta con 188Re di acido ialuronico quale agente direzionante per il fegato. Al fine di valutare il possibile impiego terapeutico del complesso ottenuto, sono stati eseguiti studi di stabilità e farmacocinetiche di 188Re-HA riportate nel capitolo 4. Successivamente, sono state prese in esame la tossicità e la dosimetria legate alla somministrazione del composto marcato, per poi studiarne l’effetto terapeutico su modelli animali con tumore epatico. I risultati incoraggianti di questo studio, riportati nel capitolo 5, ci hanno indotto a prendere in esame acidi ialuronici a diversi pesi molecolari (5, 10, 200 e 500 kDa), per verificare se potessero offrire dei vantaggi rispetto all’HA precedentemente utilizzato dal punto di vista dell’accumulo nell’organo bersaglio. Come riportato nel capitolo 6, i derivati ad elevato peso molecolare una volta marcati direttamente con 188Re, sottoposti ai successivi studi di stabilità e di biodistribuzione in animali sani, hanno evidenziato come l’accumulo di HA a livello epatico sia maggiore rispetto all’acido ialuronico (70 kDa) utilizzato nei trattamenti terapeutici, risultando così vantaggiosi poiché permettono di ridurre ulteriormente l’esposizione dei tessuti non target al danno da radiazione.
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Hoover, Brett A. "Smart Cellector: A Proposal for the Development and Commercialization of a Cellular Imaging, Analysis and Processing Technology for Application in Regenerative Medicine." Case Western Reserve University School of Graduate Studies / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=case1295655205.
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Wen, Amy M. "Engineering Virus-Based Nanoparticles for Applications in Drug Delivery, Imaging, and Biotechnology." Case Western Reserve University School of Graduate Studies / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=case1452954511.
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Shokouhimehr, Mohammadreza. "Prussian Blue Nanoparticles and its Analogues as New-Generation T1-Weighted MRI Contrast Agents for Cellular Imaging." Kent State University / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=kent1275612500.
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Ferrer, Font Laura. "Tuning response to therapy in preclinical GL261 glioblastoma through CK2 targeting and temozolomide metronomic approaches: non-invasive assessment with MRI and MRSI-based molecular imaging strategies." Doctoral thesis, Universitat Autònoma de Barcelona, 2017. http://hdl.handle.net/10803/402400.
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El treball descrit en aquesta tesi fa referència al tractaments de glioblastomes (GBM) GL261 preclínics que creixen en ratolins C57BL/6, també al seguiment no invasiu de la resposta a la teràpia, usant tècniques de ressonància magnètica (RM). El model immunocompetent GL261 GBM s’indueix per injecció estereotàctica de cèl·lules GL261 a l’estriat de ratolins WT C57BL/6. Tres agents terapèutics s’han provat en aquest model: el CX-4945®, inhibidor de la proteïna kinasa II (CK2), i dos agents alquilants d’administració oral usats habitualment en pràctica clínica pel tractament de GBM: la temozolamida (TMZ) i la ciclofosfamida (CPA). La CK2 ha estat descrita com a diana potencial pel tractament del càncer, ja que contribueix en el desenvolupament tumoral, proliferació i supressió de l’apoptosi. A més, nivells elevats d’expressió s’han demostrat en varis tipus de càncer. Malgrat això, el CX-4945, el qual està en fase clínica I/II, no va produir l’efecte beneficiós desitjat descrit per altres autors quan es va usar amb el nostre model de GBM GL261. A més, el tractament d’aquest model amb 3 cicles de TMZ, ja ha estat descrit en el nostre grup amb un augment significatiu de la supervivència. Per contra, la teràpia combinada de 3 cicles TMZ amb CX-4945, inesperadament, va revertir l’efecte beneficiós de la TMZ, el que va suggerir una interferència amb el sistema immunitari relacionat amb el desenvolupament i tractament del càncer. Això ens va portar a considerar l’ús d’un esquema de teràpia metronòmic (administració de dosis baixes separades per períodes iguals i sense llargs períodes de repòs entremig) descrit amb resultats prometedors a la literatura. La CPA, la TMZ i el CX-4945 van ser analitzats en un esquema de teràpia metronòmic a dosis diferents. Dins les diferents estratègies analitzades, els millors resultats es van obtenir amb el protocol metronòmic de teràpia combinada, cada 6 dies, de TMZ i CX-4945, mostrant un increment significatiu en la supervivència. Aquests resultats també van apuntar cap a la probable participació del sistema immunitari en resposta a la teràpia, tot i que es necessitaran futurs estudis d’histopatologia per confirmar aquesta hipòtesis.
Altres resultats interessants addicionals van ser: en primer lloc, l’aparició d’un clar edema peritumoral durant moments concrets del tractament quimioterapèutic. En segon lloc, que la metodologia no-invasiva per determinar la resposta a la teràpia basat en l’anàlisi semi-supervisat de fonts d’imatge espectroscòpica de ressonància magnètica (MRSI), prèviament desenvolupat en el nostre grup amb ratolins tractats amb TMZ, també va demostrar ser viable per detectar la resposta induïda pel CPA en el nostre model preclínic. Això suggeriria que es pot observar un “patró metabolòmic de resposta” comú sota diferents estratègies terapèutiques. I en tercer lloc, l’aparició de limfomes trobats en les necròpsies de ratolins curats després de dosis cumulatives elevades de TMZ (480-1400 mg/Kg), suggerint que cal investigar estratègies per disminuir la dosi administrada d’agents alquilants per evitar efectes perjudicials en els ratolins tractats.Work described in this thesis deals with the treatment of GL261 preclinical glioblastoma (GBM) growing in C57BL/6 mice, as well as with the non-invasive assessment of response to therapy using magnetic resonance (MR) techniques. The GL261 GBM is an immunocompetent model induced by stereotactic injection of GL261 cells into the striatum of C57BL/6 WT mice. Three different therapeutic agents have been tested in this model: CX-4945®, a protein kinase II (CK2) inhibitor, and two oral alkylating agents commonly used in the clinic for GBM treatment, temozolomide (TMZ) and cyclophosphamide (CPA). CK2 has been described as a potential suitable target for cancer treatment because it contributes to tumour development, proliferation, and apoptosis suppression in cancer. In addition, elevated CK2 expression levels have been demonstrated in several cancer types. Nevertheless, CX-4945, which already reached phase I/II clinical trials, did not produce the expected beneficial effect described by others when applied to our GL261 GBM model. Moreover, the GL261 GBM treatment with 3 TMZ cycles had been already described by our group with significant survival improvement. Nevertheless, the combined therapy 3 cycle-TMZ+CX-4945, unexpectedly, reverted the beneficial effect of TMZ, which suggested an interference with the immune cycle related with cancer development and treatment. This lead us to consider the use of a metronomic schedule (administration of low and equally spaced doses of drugs without long rest periods in between) described with promising results in the literature. CPA, TMZ and CX-4945 were assessed in a 6-day schedule metronomic schedule at different doses. Among the different strategies evaluated, best results were obtained with the combined metronomic administration, every 6 days, of TMZ and CX-4945 drugs, showing significant improved survival. This also pointed to the probable paticipation of the host mice immune system in therapy response, although further histopathological studies will be needed to fully confirm this hypothesis. Additional interesting findings were: firstly, a clear peritumoral brain edema appearance during certain stages of chemotherapeutic treatment. Secondly, that the non-invasive method for therapy response assessment based in semi-supervised source analysis of Magnetic Resonance Spectroscopy Imaging (MRSI) data, previously developed in our group with TMZ-treated mice, also proved useful for detecting CPA-induced response in our preclinical model. This would suggest that a common “metabolomics responding pattern” can be observed under different therapeutic strategies. And thirdly, the necropsy findings in mice cured from GL261 GBM after high TMZ cumulative dosage (480-1400 mg/Kg), which presented relevant lymphoma incidence, suggesting that strategies to decrease the administered dose should be investigated to avoid harmful effects in mice treated with alkylating agents.
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Marusak, Charles. "MT1-MMP: TARGETING THE CENTER OF MELANOMA METASTASIS, GROWTH AND TREATMENT RESISTANCE." Case Western Reserve University School of Graduate Studies / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=case1548327646756039.
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Kujanpää, K. (Kirsi). "Mechanisms behind stem cell therapy in acute myocardial infarction." Doctoral thesis, Oulun yliopisto, 2016. http://urn.fi/urn:isbn:9789526212920.
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Abstract Ischemic heart disease is one of the leading cause of death in the Western world. There is convincing evidence that stem cell therapy improves cardiac function and reduces the scar formation following an acute myocardial infarction (AMI). The mechanisms involved in the recovery remain partly unknown. Direct injection of stem cells into myocardium is a widely used transplantation technique though there are few details available about the behavior of cells after transplantation. A cardiac explant culture model simulating tissue stress was developed in this study to examine in detail the properties of the stem cells after their transplantation. The migration range in myocardium and the number of adherent stem cells increased with time. In vitro and in vivo studies revealed that after their administration, the stem cells became localized in the slit-like spaces, such as in the capillaries. Even though the study outcomes regarding the impact of stem cell therapy in recovery after AMI have been largely promising, the results of the clinical studies have proved to be more controversial. If one wishes to evaluate the true contribution of the stem cell therapy to the recovery, it is essential to devise a reliable study method for cell targeting. Here, iron labeled stem cells in combination with magnetic resonance imaging (MRI) were used. The MRI data corresponded to the histological results. Thus, it is concluded that MRI is a feasible method for monitoring the effectiveness of cell targeting. Stem cell treatment was shown to increase cardiac function at three weeks after AMI. If there was a high number of stem cells in cardiac tissue after transplantation, this predicted a greater improvement in cardiac function. Improper stem cell injection may lead to leakage of the stem cells out of the myocardium, leading to unreproducible study results. Inflammation modulating factors secreted by the stem cells are considered as key mechanisms in the recovery after AMI. There were differences in the cytokine levels between the stem cell treated and control groups in a clinical and in vivo animal study i.e. stem cell therapy exerted a balancing effect on the inflammatory process, a crucial component in the optimal recovery after AMI. The present study reveals many properties of stem cells, importance of cell targeting and the influence of stem cell therapy on cytokine levels after AMITiivistelmä Iskeeminen sydänsairaus on yksi yleisimmistä kuolinsyistä länsimaissa. Tutkimusten mukaan kantasoluterapia parantaa sydämen toimintakykyä ja pienentää akuutin sydäninfarktin jälkeen sydämeen muodostuvan arpikudoksen määrää. Paranemiseen liittyvät mekanismit ovat edelleen osittain tuntemattomia. Kantasolujen ruiskutus suoraan sydämeen on paljon käytetty menetelmä, vaikka solujen käyttäytymistä ei tunneta tarkkaan.Tutkimuksessa kehitetyn kudoksen stressitilaa simuloivan sydänkudoksen kasvatusmenetelmän avulla tutkittiin siirrettyjen kantasolujen toimintaa yksityiskohtaisesti. Kantasolujen vaeltaman matkan sydänkudoksessa ja kiinnittyneiden kantasolujen lukumäärä havaittiin kasvavan ajan kuluessa. In vitro ja in vivo tutkimuksissa havaittiin kantasolujen sijaitsevan ruiskutuksen jälkeen rakomaisissa paikoissa kuten pienissä verisuonissa. Vaikka tutkimustulokset kantasoluterapian hyödyistä paranemisen suhteen ovat pääosin lupaavia, kliinisten tutkimusten tulokset ovat ristiriitaisia. Todellisen kantasoluhoidon vaikutuksen arvioimiseksi tarvitaan luotettava menetelmä varmistamaan kantasolujen hakeutuminen vaurioalueelle. Tässä tutkimuksessa rautaleimattujen kantasolujen paikantamisessa käytetty magneettikuvantaminen vastasi histologisia löydöksiä. Magneettikuvantaminen todettiin käyttökelpoiseksi menetelmäksi solujen paikallistamisessa. Kantasoluhoidon osoitettiin parantavan sydämen toimintakykyä kolme viikkoa akuutin sydäninfarktin jälkeen. Suuri kantasolumäärä sydänkudoksessa siirron jälkeen ennusti parempaa toipumista. Puutteellisesti suoritettu kantasoluruiskutus voi johtaa kantasolujen vuotamiseen pois sydänkudoksesta aiheuttaen vaihtelevuutta tutkimustuloksiin. Kantasolujen erittämiä tulehdusta sääteleviä tekijöitä pidetään tärkeimpänä mekanismina paranemisprosessissa. Tutkimus osoitti eroavaisuuksia kantasoluhoidetun ja kontrolliryhmän välillä. Kliinisessä ja koe-eläintutkimuksessa kantasolusiirrolla todettiin tulehdusreaktiota tasapainottava vaikutus, mikä on tärkeää optimaalisen sydänlihaskudoksen paranemisen kannalta akuutin sydäninfarktin jälkeen. Tutkimus toi esiin monia kantasolujen ominaisuuksia, solujen paikantamisen tärkeyden ja kantasoluhoidon vaikutuksen sytokiinipitoisuuksiin akuutin sydäninfarktin jälkeen
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Chaix, Arnaud. "Nanoparticules de silicium poreux pour la thérapie photodynamique et la thérapie génique." Thesis, Montpellier, Ecole nationale supérieure de chimie, 2015. http://www.theses.fr/2015ENCM0008.
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L'utilisation de nanoparticules comme vecteurs d'anticancéreux est de plus en plus étudiée afin de résoudre certains problèmes inhérents aux traitements conventionnels, tels que la faible spécificité des agents anticancéreux pour la tumeur, et le risque de provoquer des effets secondaires irréversibles. L'objectif de cette thèse a été d'étudier l'utilisation de nanoparticules de silicium poreux fonctionnalisées (pSiNP), biorésorbables et non toxiques in vivo, pour l'imagerie et la délivrance ciblée d'agents photosensibilisateurs pour la thérapie photodynamique (PDT) et pour la délivrance contrôlée d'acides nucléiques. Dans une première étude, différentes formulations à base de pSiNP, comportant une porphyrine et/ou un agent de ciblage des cellules cancéreuses, le mannose, ont été préparées. L'imagerie de fluorescence à 2-photon a montré que les nanoparticules étaient internalisées par les cellules plus efficacement lorsqu'elles étaient fonctionnalisées avec le mannose. L'efficacité photodynamique de ces systèmes a été démontrée in vitro sur plusieurs lignées cellulaires (cancer du sein (MCF-7) et cancer de la prostate (LNCaP)) sous irradiation biphotonique. Nous avons déterminé que l'effet PDT observé se produit par excitation des pSiNP, qui ensuite transfèrent leur énergie à la porphyrine greffée. En comparaison, une irradiation monophotonique entraîne une excitation directe de la porphyrine. Par ailleurs, des formulations encapsulant d'autres photosensibilisateurs tels que des complexes de ruthénium (II), ou des nanoparticules d'or ont été préparées et leur efficacité photodynamique a été également testée. Dans une deuxième étude, des pSiNP ont été préparées et fonctionnalisées avec des acides aminés (histidine, lysine et poly-L-Lysine) pour la complexation et la délivrance d'acides nucléiques (pDNA, siRNA). Les différentes formulations ont été testées en transfection cellulaire sur différentes lignées cellulaires (HEK, MCF-7). La délivrance photocontrôlée de siRNA sous irradiation biphotonique a été montrée pour des formulations fonctionnalisées via un ligand azobenzene photosensibleThe use of nanoparticles as anticancer nanovectors is intensively studied in order to solve some inherent problems with conventional treatments, such as the low specificity of the anticancer agents for the tumor, and the risk of causing irreversible side effects. The goal of this thesis was to study the potential of functionalized bioresorbable and non-toxic porous silicon nanoparticles (pSiNP) for both, the imaging and the targeted release of photosensitizing agents for photodynamic therapy, as well as for the release of nucleic acids for gene therapy. In a first study, several pSiNP based formulations containing a porphyrin and/or a cancer cells targenting agent (mannose) were prepared. Two-photon fluorescence imaging showed that the nanoparticles were more efficiently internalized by the cells when they were functionalized with mannose. The photodynamic efficiency of these systems was demonstrated in vitro in several cell lines (breast cancer cell (MCF-7) and prostate cancer cell (LNCaP)) under 2-photons irradiation. We determined that the observed PDT effect occurs by exciting the pSiNP which then transfer their energy to the grafted porphyrin. In comparison, a 1-photon irradiation causes a direct excitation of the porphyrin. Furthermore, formulations encapsulating other photosensitizers such as ruthenium (II) complexes, or gold nanoparticles were prepared and their photodynamic efficiency was also tested. In a second study, pSiNP were prepared and functionalized with amino acids (histidine, lysine and poly-L-lysine) for the complexation and release of nucleic acid (pDNA, siRNA). The different formulations were tested in cellular transfection on different cell lines (HEK, MCF-7). The photo-controlled release of the siRNA under 2-photons irradiation was demonstrated for functionalized formulations via a photosensitive azobenzene ligand
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Stojanovic, Vanja. "Nanoparticules de silicium poreux (pSiNPs) pour l'imagerie et la thérapie photodynamique des cancers solides de petite taille." Thesis, Montpellier, 2016. http://www.theses.fr/2016MONTT091/document.
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Ce projet vise à développer et à analyser de nouveaux nanovecteurs pour des applications biomédicales. Nous travaillons en étroite collaboration avec des chimistes pour mettre au point des nanoparticules hautement efficaces (principalement des nanoparticules de silicium poreux - pSiNPs). Mon travail consiste à évaluer la toxicité des nano-objets développés et à établir leur potentiel en terme de thérapie photodynamique et d'imagerie. Les nanovecteurs sont recouverts de sucres reconnus par les lectines surexprimées par les cellules cancéreuses. Cette interaction permet le ciblage spécifique des cellules cancéreuses par les nanovecteurs. Lors des études in vitro, nous sélectionnerons les nano-objets les plus prometteurs pour réaliser des études préliminaires in vivoThe focus of this project concerns the development and the analysis of new nanocarriers for biomedical applications. We work in collaboration with chemists to design efficient nanoparticles (mainly porous silicon nanoparticles - pSiNPs). Then, I evaluate their cytotoxic activity and their photodynamic therapeutic effect as well as their imaging potential. Nanovectors are coated with sugar recognized by lectins overexpressed on the surface of cancer cells. This interaction permits the specific targeting of cancer cells by nanovectors synthesized. During the study in vitro, we will select the most promising nanotools for preliminary studies in vivo
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Garrier, Julie. "Optimisation de la dosimétrie appliquée en thérapie photodynamique pour l'évaluation et la prédiction de l'efficacité du traitement de tumeurs." Phd thesis, Université Henri Poincaré - Nancy I, 2011. http://tel.archives-ouvertes.fr/tel-00655408.
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La thérapie photodynamique (PDT) est une modalité de traitement des petites tumeurs accessibles à la lumière. Elle repose sur l'action combinée d'un photosensibilisateur qui, en présence d'oxygène et sous l'effet d'une irradiation lumineuse, induit la synthèse d'espèces réactives de l'oxygène cytotoxiques. L'effet tumoricide de la PDT se traduit par des dommages directs sur les cellules ainsi que des dommages indirects de la néovascularisation tumorale et une activation du système immunitaire. Dans cette étude, nous avons démontré dans une première partie l'intérêt de se baser sur la distribution intratumorale de la mTHPC et non pas sur les études de biodistribution pour l'optimisation des conditions de traitement par PDT et en particulier de l'intervalle drogue-lumière (IDL). Un co-ciblage des vaisseaux et du parenchyme tumoral via un fractionnement de l'administration de la mTHPC a permis d'obtenir un taux de guérisons de 100%. Cette efficacité a été corrélée à la potentialisation de la mort des cellules par apoptose et valorisée par son association à des dommages secondaires cutanés restreints. La stratégie de fractionnement de l'administration s'avère donc être très prometteuse dans un contexte clinique. Dans la seconde partie de cette étude, nous avons établi la redistribution de la mTHPC in vivo dans le modèle de la membrane chorioallantoïdienne de poulet (CAM) à partir de formulations liposomales (Foslip®, Fospeg®) et son impact sur les dommages vasculaires photoinduits par la PDT.
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Faye, Nathalie. "Thérapie cellulaire de l’angiogenèse tumorale : évaluation par imagerie morphologique et fonctionnelle en IRM et vidéomicroscopie de fluorescence." Thesis, Paris 11, 2011. http://www.theses.fr/2011PA112248/document.
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Introduction : L’angiogenèse tumorale conduit au développement de nouveaux vaisseaux destinés à permettre la croissance de la tumeur. Les vaisseaux tumoraux sont caractérisés notamment par des anomalies des cellules murales (cellules musculaires périvasculaires), responsables d’anomalies de la fonctionnalité et de la maturation. Dans ce travail de thèse, nous avons étudié un modèle tumoral de thérapie cellulaire par injection de cellules murales en IRM et vidéomicroscopie de fluorescence. Matériels et méthodes : Notre étude a porté sur un modèle sous cutané de carcinome épidermoïde chez la souris nude. Les animaux étaient divisés en trois groupes : contrôle (n=17), contrôle négatif (n=16) et « traité » avec injection locale de cellules murales humaines (n=17). Les animaux bénéficiaient d’une IRM et d’une exploration par vidéomicroscopie avant (J7) et après traitement (J14). Les paramètres mesurés étaient la taille tumorale (pied-à-coulisse et IRM), la densité microvasculaire (DMV par IRM, vidéomicroscopie et histologie), l’ADC, f, Dr et D* (IRM de diffusion), les variations de R2* sous air, oxygène et carbogène (IRM par effet BOLD) et « l’index leakage » (reflétant la perméabilité capillaire, en vidéomicroscopie). Résultats : Lors de la croissance tumorale, le groupe contrôle a montré une diminution des vaisseaux circulants (ou fonctionnels) qui se reflétait par une diminution du D* et du R2* sous air, une perte de la capacité à répondre au carbogène qui se reflétait par une augmentation du delta R2* sous carbogène, et une augmentation de la perméabilité capillaire qui se traduisait par un « index leakage » plus élevé. Dans le groupe traité par injection de cellules murales, nous avons observé un ralentissement de la croissance tumorale et une stabilisation de ces paramètres de microcirculation et maturation vasculaire. Conclusion : Nous avons montré un effet biologique de notre thérapie cellulaire par injection locale de cellules murales qui se traduisait par un ralentissement de la croissance tumorale, une stabilisation de l’hémodynamique microcirculatoire et de la maturation, et une perméabilité capillaire diminuée, concordants avec l’effet présumé stabilisateur et normalisateur des cellules murales sur les microvaisseauxIntroduction : Tumor angiogenesis leads to the development of new vessels enabling the growth of the tumor. Tumor vessels are characterized by abnormalities including mural cells (perivascular muscular cells) responsible for abnormal vessel function and maturation. In this thesis, we studied cellular therapy in a tumor model by injection of mural cells using MRI and fluorescence videomicroscopy. Materiels and methods: Nude mice were injected with squamous cell TC1 tumors and animals were divided in three groups: control (n=17), sham control (n=16) and treated by local injection of human mural cells (n=17). Animals underwent MRI and videomicroscopy before (D7) and after (D14) treatment. Measured parameters included tumor size (caliper and MRI), microvessels density (MVD using MRI, videomicroscopy and pathology), ADC, f, Dr, D* (diffusion MRI), R2* variations under air, oxygen and carbogen (BOLD MRI), and ‘index leakage’ (reflecting capillary permeability, using videomicroscopy). Results: During tumor growth, the control group showed a decrease in circulating (or functional) vessels reflected by a decrease in D* and R2* under air, the loss of vessel ability to respond to carbogen reflected by an increase of the delta R2* under carbogen, and increased capillary permeability resulting in a higher ”index leakage”. In the group treated by injection of mural cells, we observed a slowing of tumor growth and stabilization of these parameters of microcirculation and vessel maturation. Conclusion : Therapy by local injection of mural cells was effective resulting in slower tumor growth, stabilization of microcirculatory hemodynamics and maturation, and decreased capillary permeability, consistent with the alleged ‘stabilizing’ and ‘normalizing’ effects of mural cells on microvessels
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詹偉翔. "Multifunctional Mixed Micelles for Cancer Targeting Imaging and Therapy." Thesis, 2008. http://ndltd.ncl.edu.tw/handle/00045461519835355006.
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Ganai, Sabha. "Targeting bacteriolytic therapy of solid tumors with attenuated Salmonella typhimurium." 2007. https://scholarworks.umass.edu/dissertations/AAI3289263.
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Attenuated Salmonella typhimurium, a motile, nonpathogenic facultative anaerobic bacterium, has been demonstrated experimentally as a novel anticancer agent because of its favored growth within tumors. Specificity towards tumors allows for its potential use as an adjunctive approach to pharmacologic, radiation, and ablative therapies in the treatment of solid malignancies. However, limitations in its use as a tumor-specific vector may be present due to preferential colonization within nutrient-rich and hypoxic microenvironments of necrosis. Using a syngeneic murine model of mammary carcinoma, experiments were designed to study the spatiotemporal dynamics of bacterial proliferation within tumor microenvironments. With time, bacteria accumulate in the tumor transition zone, a region of quiescence between viable tumor and necrosis. An increase in tumor apoptosis and a decrease in tumor growth were noted at two days aftera single systemic treatment; this response was abrogated by four days after treatment. Bacterial specificity in colonization was noted towards subcutaneous tumors compared to liver, as well as hepatic metastases compared to normal liver. Using knowledge of observed patterns in bacterial accumulation it was determined that by two days adequate colonization in viable tumor and optimal effect in tumor apoptosis was achieved. Subsequently, strains were electroporated with radiation-inducible prokaryotic-expression plasmids to allow for tumor-specific production of either a green fluorescent protein (control) or murine tumor necrosis factor related apoptosis-inducing ligand (TRAIL). The effect of systemic infection of mice with subcutaneous mammary tumors was examined, comparing the administration of bacterial vectors with or without addition of 2Gy gamma radiation at two days after colonization. The combination of systemic infection with attenuated S. typhimurium and gamma-irradiation conferred a significant increase in tumor doubling time. The expression vector for TRAIL under a radiation-inducible promoter conferred a significant improvement in survival, with flattening of tumor growth curves after induction by radiation. Repeated dosing and irradiation after one week limited tumor growth from baseline, with a significant survival benefit. By capitalizing on the intrinsic motility of bacteria and their preferred microenvironments within tumors in time, the therapeutic utility of targeted therapy using attenuated Salmonella typhimurium as a TRAIL expression vector has been demonstrated in vivo.
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Badolato, Mariateresa, Sebastiano Andò, Antonio Garofalo, and Francesca Aiello. "Preclinical and mechanistic studies of small-molecule drugs targeting stat3." Thesis, 2018. http://hdl.handle.net/10955/1838.
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Liu, Tracy Wei-Bin. "Porphyrin-based Agents and Their Applications in Cancer Imaging and Therapy." Thesis, 2013. http://hdl.handle.net/1807/35884.
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Porphyrins represent one of the oldest, most widely studied chemical structures, both in nature and in biomedical applications. Due to their tumor avidity and favorable photophysical properties, such as long wavelength absorption and emission, easy derivatization, high singlet oxygen quantum yield and low in vivo toxicity, porphyrins have found particular success for photodynamic therapy and fluorescence imaging of cancer. Additionally, they are excellent metal chelators, forming highly stable metallo-complexes, making porphyrins an efficient delivery vehicle for radioisotopes. Thus, there is great potential in the applications of these multi-modal porphyrin-based agents for cancer imaging and therapy. I have investigated the characteristics of various porphyrin-based probes and their potential application in different clinically relevant models. Here, I will discuss three types of porphyrin-based agents: 1) photodynamic molecular beacons (PPMMPB), 2) targeted peptide porphyrins (PPF) and 3) porphyrin-lipid nanovesicles, porphysomes. I will demonstrate that all of these porphyrin-based agents have potential clinical applications in various fields of cancer imaging and therapy. Although these three agents differ greatly, they all aim to increase the signal-to-background ratio of tumor to healthy tissue uptake of porphyrins, thereby increasing our ability to detect tumor tissue and better preserve healthy tissue during therapy.
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Behzadi, Fernanda. "Therapeutic potential of targeting the oncofetal antigen ROR1." Thesis, 2019. https://hdl.handle.net/2144/36249.
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The increasing prevalence of drug resistant cancers to conventional therapies remains a major challenge in oncology, emphasizing the need for further research and treatment development. The receptor tyrosine kinase-like orphan receptor 1 (ROR1) presents as a particularly suitable target for cancer therapy, as this type I transmembrane protein is expressed during embryogenesis and up-regulated in various solid and hematological malignancies, but generally repressed in normal adult tissues. A growing cancer literature has established ROR1 as a contributor to cell metastasis and a survival factor for malignant cells, suggesting the therapeutic potential in targeting ROR1 for cancer therapy. The tumor-selective expression of ROR1 has encouraged investigation of novel ROR1-targeted therapies including monoclonal antibodies, small molecule inhibitors, and chimeric antigen receptor T-cells, and preclinical trials have supported their safety and efficacy in inducing tumor growth suppression. Despite these advances in therapeutics, the role of ROR1 in oncogenic signaling is not yet fully understood. Through a comprehensive examination of ROR1 literature, this review will examine the biology of ROR1 as it relates to tumor progression, and demonstrate the viability of current ROR1-targeted therapies.
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Bhattacharyya, Arnab. "Studies on BODIPY-conjugates of Copper and Zinc for Cellular Imaging and Photodynamic Therapy." Thesis, 2021. https://etd.iisc.ac.in/handle/2005/5669.
Full textAbstract:
Cancer is a dreadful disease that occurs due to the uncontrolled division of abnormal cells. Though there are different therapeutic modalities available for cancer, chemotherapy is considered as the most practiced method. It is also well established that the transition metal-based chemotherapeutic agents provide several medicinal benefits in comparison to the purely organic counterparts. However, the efficacy of metal-based anticancer agents, especially the commercial platinum-based drugs is greatly reduced due to the dose-limiting toxicity and associated adverse effects. Shifting to photodynamic therapeutic treatment modality (PDT) may provide better spatio-temporal control on drug action but the clinically approved porphyrinic photosensitizers also show limited success owing to their hydrophobic nature and aggregation-induced photobiological deactivation-related issues under physiological conditions. Though Photofrin®, the FDA approved PDT drug, is found to be useful against a vast group of cancers, it suffers from additional drawbacks like skin photosensitivity and hepatotoxicity. It has been documented that the insertion of selective transition metals inside the porphyrinic core could result significant improvement in their photophysical and photobiological activities but even with the development of metallo-porphyrins, the challenges regarding the hydrophobic and aggregative-nature of these macrocyclic photosensitizers could not be addressed successfully. One possible way is the introduction of non-porphyrinic photosenstizers that should contain only the positive attributes of porphyrin or phthalocyanine-based classical PDT agents. BODIPY or boron-dipyrromethene-based dyes have recently emerged as the preferred alternatives, which are also known as ‘half of porphyrin’ or ‘porphyrin’s little sisters’ due to their close structural proximity with porphyrin unit. However, despite several promises, quite surprisingly, none of the BODIPY-based molecules have received clinical approval yet for the treatment of PDT. The limited success of BODIPY-based photosensitizers in clinical level could be attributed to their aqueous insolubility and limited physiological stability leading to poor pharmacokinetic behaviour under physiological conditions, especially applicable for the heavy atom (I, Br)-tethered BODIPY-based photosensitizers. Present thesis focuses to address these challenges alongside establishing the virtually unexplored chemistry of metallo-BODIPY conjugates as PDT photosensitizers. With the objective to explore the medicinal aspects of BODIPY dyes as the cellular imaging and photosensitizing unit inserted within the ligand system of transition metal complexes, we selected copper and zinc as our preferred choices since these cost-effective metals are essential for our survival and their usage can also circumvent the problem related with heavy-metal toxicity. Current work thus focuses on the design, synthesis, physicochemical and photobiological aspects of multiple Cu(II)-BODIPY and Zn(II)-BODIPY conjugates and evaluates their suitability as next-generation replacements of existing metallo-porphyrinoids as PDT agents, both from the therapeutic as well as diagnostic point of view. Taking the advantage of variable coordination number of copper and zinc and the flexible coordination geometry of Cu and Zn-based complexes, mixed ligand metallo-BODIPY conjugates are also developed to achieve additional benefits such as drug selectivity, intracellular organelle targeting, modulation of metal-centered redox activity and regulation in dark toxicity, simultaneous activation of multiple photodynamic pathways and augmented imaging-cum-photosensitizing activities.
References: A. Bhattacharyya and A. R. Chakravarty et al., Med. Chem. Commun., 2015, 6, 846-851; RSC Adv., 2016, 6, 104474-104482; Dalton Trans., 2018, 47, 5019-5030; Dalton Trans., 2021, 50, 103-115; Eur. J. Med. Chem., 2021, 220, 113438.CSIR, DST-SERB, IISc
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MUZI, LAURA. "Carbon nanotube and graphene cellular impact towards their possible use as nanovectors for anticancer therapy and cell targeting." Doctoral thesis, 2015. http://hdl.handle.net/11573/1013955.
Full textAbstract:
In the last two decades, lots of progresses have been made in the application of nanomaterials in biology, giving rise to a new revolutionary field of the biomedical research that is called nanomedicine. Carbon nanotubes (CNTs) and graphene are among the most attractive candidates under investigation in this context. Such carbon-based nanomaterials possess outstanding chemico-physical properties and their high surface area provides multiple attachment sites for almost all the molecules of biological interest. In fact, chemical strategies allow for their conjugation with DNA, proteins, peptides and small drugs. The so-functionalized materials have shown great promises in several biomedical contexts, from diagnosis to tissue regeneration. In addition, the ability of CNTs and graphene to enter and accumulate inside the cells makes them good candidates as nanovectors for drugs. In vitro and in vivo studies showed how these nanomaterials could enhance the drug accumulation inside the cells and its bioavailability. CNTs and graphene are also able to passively target tumor tissues exploiting the so-called enhanced permeability and retention effect, and actively, following the conjugation with targeting moieties.
On the other hand, the use of these materials in nanomedicine will be approved only after the demonstration of their safety in terms of tissue damage, carcinogenicity and proinflammatory response. Different approaches have been used to make these materials biocompatible and recently, it has been demonstrated that functionalized CNTs and graphene oxide can be degraded by oxidative enzymes. However, the results obtained on CNT and graphene toxicity are often conflicting; thus, further investigations are needed.
In the first introductive chapter of this thesis, an overview of the general features of nanomaterials is given. The focus goes then on CNTs and graphene. First, we will see how their biocompatibility, biodegradability and in vivo fate strictly depend on several factors. The mechanisms by which the two nanomaterials are able to enter the cells are also illustrated. In the second part of the introduction, the potential of CNTs and graphene in targeted drug delivery is described, focusing on anticancer therapy.
The three following chapters illustrate the results obtained by three related studies carried out during my PhD internship.
Results described in the second chapter shed more light on the impact of CNTs on living cells. CNTs having single walls (SWCNTs) were dispersed with the biocompatible protein bovine serum albumin (BSA). BSA protein showed to be a good dispersant agent for the CNTs and was able to enhance their biocompatibility. The impact of the protein-coated materials on cell vital parameters, such as viability, activation and interaction/internalization mechanisms, is described. In addition the effect of nanotubes on the plasma membrane dielectric characteristics and ion flux, very poorly
2 Abstract
investigated up to date, is presented.
In the following chapter, a cisplatin prodrug was encapsulated within the inner cavity of two types of multi-walled CNTs (MWCNTs) having different diameters, in order to allow a controlled release inside the cells. The efficacy of the complexes was investigated on human cervix cancer cells and compared to murine macrophages. The latter were also used to evaluate the possibility of a proinflammatory effect. Results on cell viability, cell activation and cell uptake show that CNTs are promising nanocarriers to improve the accumulation of a chemotherapeutic drug inside the cells, without inducing a high proinflammatory response. In addition, by tuning CNT diameter it is possible to control the time of release of the drug prolonging its anticancer efficacy.
The fourth chapter gives more insights about the impact of different types of graphene on cells, focusing on macrophages. Results evidenced a specific cytotoxic effect of graphene oxide (GO) towards this cell population among the other murine immune cells. The mechanisms by which macrophages internalize GO are also elucidated. In addition, GO was conjugated with lysozyme protein and was tested for its ability to selectively target a B cell model overexpressing a lysozyme-specific B cell receptor. Results showed that graphene is able to target B cells in a selective manner, thus suggesting its possible application in therapies where the specific elimination of B lymphocytes is required.
Finally, a conclusive chapter summarizes the main findings obtained during my doctoral work, focusing, in particular, on future perspectives.
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DURANTI, CLAUDIA. "Novel molecular tools in cancer therapy: diagnostic and therapeutic applications of antibodies targeting ion channels and receptors." Doctoral thesis, 2017. http://hdl.handle.net/2158/1077157.
Full textAbstract:
Immunotherapy has had a revolutionary impact on cancer treatment, providing valuable
tools to be used in combination or as an alternative to chemotherapy (Weiner G.J.,
2015).
Such wide success has been demonstrated by the fact that, since 1997, twelve
monoclonal antibodies have been approved by the FDA for the treatment of a variety of
solid tumors and haematological malignancies, along with an increasing number of new
antibodies that are now being tested at different stages of clinical trials
(ClinicalTrials.gov). Nevertheless, there are limitations to the use of monoclonal
antibodies mainly due to their big size, which is detrimental especially for their
applications in clinics and diagnostics. For these reasons, the arise of recombinant
antibodies, which conjugate small size with antigen specificity has represented a big
achievement in the oncological setting.
Another crucial point is the identification of cell antigens, which can be exploited to
target cancer cells. To this purpose, we have focused on inotropic Glutamate Receptor 4
(iGluR4), which is involved in many CNS pathological conditions and, moreover, has
recently emerged to be implicated in many aspects of cancer progression (Stepulak A. et
al., 2011; Stepulak A. et al., 2014; Ribeiro MP et al., 2016). We have also focused on
hERG1 voltage-gated ion channel, that it is known to be a role player in cancer
progression (Bianchi L. et al., 1998; Lastraioli E. et al., 2015). More recently, it has
emerged as a novel target for cancer therapy and as a marker for patients’ stratification
(Arcangeli A. et al., 2009; Pointer KB et al., 2016). Moreover, it has been demonstrated
that hERG1 forms complexes in particular with β1 subunit of integrin receptors, thus
mediating its effects in cancer cell behavior (Crociani et al. 2013).
The present work has focused on developing new antibodies, that have demonstrated
their potential from a diagnostic or a therapeutic point of view.
We have produced two clones B5 and C4 of a monoclonal antibody directed against
ionotropic Glutamate Receptor 4 (iGluR4), providing evidences that this molecule is
able to recognize the antigen, also in a pathological scenario such as that of tuberous
sclerosis complex (TSC) disease. Moreover, C4 anti-iGluR4 clone has emerged as a
Abstract
possible positive allosteric modulator of the receptor; such behavior will be better
characterized in the future, to exploit its potential application as a channel regulator
(Stepulak A. et al., 2014).
We are also assembling a construct for the production of a scFv-iGluR4 directed against
the same antigen as the monoclonal antibody, to overcome the problems related to the
passage of the blood brain barrier (BBB). In fact, it is known that recombinant protein
therapeutics are too large to cross the BBB, however, recombinant proteins can be
reengineered as BBB-penetrating IgG fusion proteins, where the IgG part is a
genetically engineered monoclonal antibody (MAb) (Pardridge WM and Boado RJ,
2012). The recombinant antibody we have produced will be conjugated with NPs
(already capable to cross an in vitro model of BBB), to set up a drug-delivery system.
In parallel, we have developed a single-chain variable fragment antibody, scFv-hERG1-
G3 (scFv-hERG1 construct), that has already been validated, after labelling with Alexa
488 fluorophore, as a tool for optical in vivo imaging (Lastraioli E. et al., 2016).
Moreover, we have produced a new antibody scFv-hERG1-D8-Cys (scFv-hERG1-Cys
construct) (via mutagenesis of the scFv-hERG1 construct), in which we have
reintroduced one of the cysteine that is in a fundamental position for the formation of
the disulfide bonds, within the VH chain of the scFv antibody. In fact, scFv-hERG1-G3
antibody, in this position, showed a phenylalanine amino acid. We have given evidence
that the restoration of the Cys deeply affects the protein yield, without affecting the
antibody binding capacities. scFv-hERG1-D8-Cys has also demonstrated to have effects
on cell growth and invasiveness, as demonstrated by the viability experiments
performed on 2D tumour cell lines and on 3D spheroid tumour cell cultures (patent in
preparation).
In the third part of this work, we have focused on the expression and characterization of
a scDb bispecific antibody directed against hERG1-β1 oncogenic unit. The antibody has
been also characterized with IF experiments performed on different substrates, showing
the capacity to recognize hERG1-β1complex.
These evidences allow us to conclude that both scFv-hERG1-D8-Cys and anti-scDbhERG1-
β1, after a proper validation, will represent valuable tools for cancer therapy.
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(8771426), Saeed Salehin Akhand. "PHARMACOLOGICAL TARGETING OF FGFR SIGNALING TO INHIBIT BREAST CANCER RECURRENCE AND METASTASIS." Thesis, 2020.
Find full textAbstract:
Breast cancer (BC) is one of the deadliest forms of cancers with high incidence and mortality rates, especially in women. Encouragingly, targeted therapies have improved the overallsurvival and quality of life in patients with various subtypes of BC. Unfortunately, these first-line therapies often fail due to inherent as well as acquired resistance of cancer cells. Treatment evading cancer cells can exhibit systemic dormancy in patients over a long period of time without manifesting any symptoms. In a suitable environment, these undetected disseminated tumor cells can relapse in the form of metastasis. Therefore, it is essential to understand the mechanisms of
BC recurrence and to develop durable therapeutic interventions to improve patient’s survival. In this dissertation work, we studied fibroblast growth factor receptors (FGFR), as therapeutic targets to treat the recurrence of drug-resistant and immune-dormant BC metastasis.
The HER2 subtype of BC is characterized by the overexpression of human epidermal growth factor receptor 2 (HER2), which drives elevated downstream signaling promoting tumorigenesis. Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate in which an anti-HER2 antibody targets HER2 overexpressing tumor cells and delivers a highly potent microtubule inhibitor. Using novel models of minimal residual disease (MRD) following T-DM1 treatments, we found that epithelial to mesenchymal transition is a critical process for cells to persist the TDM1 treatments. The upregulation of FGFR1 may facilitate insensitivity to T-DM1. Our data also showed that FGFR1 overexpression in HER2+ tumors leads to a higher incidence of recurrence, and these recurrent tumors show sensitivity towards covalent inhibition of FGFR.
In addition to drug-induced MRD in the primary tumor sites, disseminated tumor cells (DTCs) can demonstrate dormant phenotype via maintaining an equilibrium with immunemediated tumor clearance. Factors affecting such equilibrium may contribute to the recurrence of breast cancers metastasis. We show that such immune-mediated dormancy can be modeled with the 4T07 tumors. These tumors display immune-exclusion phenotypes in metastatic pulmonary organs. The inhibition of FGFR modulates the immune cell compositions of pulmonary organs favoring anti-tumor immunity. However, inhibition of FGFR may also affect T cell receptor downstream signaling, resulting in the inhibition of cytolytic T cell’s function. Finally, we report that combination therapy using the FGFR kinase inhibitor and an immune checkpoint blockade showed effective targeting of metastatic 4T07 tumors.
FGFR signaling as a therapeutic target in various tumors has been an active focus of cancer research. In this dissertation work, we have expanded our understanding of the role of FGFR in the recurrence of drug-resistant breast cancers as well as in the maintenance of an immune evasive microenvironment promoting pulmonary growth of tumors. Moreover, we presented evidence that it is possible to repurpose FGFR targeted therapy alone or in combination with checkpoint blockades to target recurrent metastatic BCs. In the future, our novel models of minimal residual diseases and systemic immune dormancy may act as valuable biological tools to expand our understanding of the minimal residual disease and dormant tumor cells.
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Koslowsky, Ingrid L. "Synthesis and evaluation of an [18F]-labelled antisense oligonucleotide as an imaging probe to measure cellular response to radiation therapy." Phd thesis, 2010. http://hdl.handle.net/10048/1267.
Full textAbstract:
Antisense oligodeoxynucleotides (asODNs) show strong binding and high selectivity and can be constructed to recognize specific cellular targets such as gene regulated mRNA. Radiolabelled asODNs have the potential to image gene expression through mRNA targeting and could be a valuable tool in the early assessment of outcome to cancer treatment. We have explored the potential of in vivo imaging of p21 gene expression, using fluorine-18 labelled asODNs ([18F]asODNs) and in vitro techniques, recognizing the relationship between the expression of this gene and resistance of cancer cells to radiation therapy. Radiolabelling of fully phosphorothioated, 20-mer ODNs was performed using the [18F]-labelled prosthetic group, 4-N-[18F]fluorobenzyl-2-bromoacetamide ([18F]FBBA). [18F]FBBA was first synthesized in an automated synthesis unit, resulting in a modest radiochemical yield. Methods to improve the yield were investigated using a metal catalyst-assisted borohydride exchange resin. Alkylation of [18F]FBBA to ODN resulted in radiochemical yields of 40%. Cellular uptake and retention studies were performed in human carcinoma cells expressing p21+/+ (HCT116) and the p21 knock-out cell line, 80S4, using both [18F]-labelled antisense and random sequence ODNs. Nonradioactive FBBA-labelled ODNs were used to evaluate the antisense effectiveness and distribution of the FBBA-modified ODNs. In vitro studies demonstrated that FBBA did not interfere with the antisense effect of ODNs against p21 mRNA; however, the probes required a transfection agent to observe an antisense effect. Cell fractionation studies with [18F]ODNs revealed increasing accumulation of liposome-transfected [18F]asODN in the cytoplasm of HCT116 cells over time. A biocompatible spermine-grafted block copolymer (SP) was subsequently evaluated as a potential vector to improve the delivery of [18F]asODN into cells. SP was shown to direct [F]-labelled ODNs to the cytoplasm, whereas naked [F]ODNs remained sequestered in vesicles, and liposome-transfected [F]ODNs localized mostly in the nucleus. Selective uptake and retention of [18F]asODN was observed in p21+/+ cells only when the probe was transfected with SP. Based on these studies, it can be concluded that [18F]asODNs have the potential to image gene expression, however the focus may need to be directed to find an appropriate vector which can rapidly deliver [18F]-labelled asODNs to the target tissue in vivo.
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Mishra, Akaash K. "Developing small molecule inhibitors targeting Replication Protein A for platinum-based combination therapy." Thesis, 2014. http://hdl.handle.net/1805/6466.
Full textAbstract:
Indiana University-Purdue University Indianapolis (IUPUI)All platinum (Pt)-based chemotherapeutics exert their efficacy primarily via the formation of DNA adducts which interfere with DNA replication, transcription and cell division and ultimately induce cell death. Repair and tolerance of Pt-DNA lesions by nucleotide excision repair and homologous recombination (HR) can substantially reduce the effectiveness of the Pt therapy. Inhibition of these repair pathways, therefore, holds the potential to sensitize cancer cells to Pt treatment and increase clinical efficacy. Replication Protein A (RPA) plays essential roles in both NER and HR, along with its role in DNA replication and DNA damage checkpoint activation. Each of these functions requires RPA binding to single-stranded DNA (ssDNA). We synthesized structural analogs of our previously reported RPA inhibitor TDRL-505, determined the structure activity relationships and evaluated their efficacy in tissue culture models of epithelial ovarian cancer (EOC) and non-small cell lung cancer (NSCLC). These data led us to the identification of TDRL-551, which exhibited a greater than 2-fold increase in in vitro and cellular activity. TDRL-551 showed synergy with Pt in tissue culture models of EOC and in vivo efficacy, as a single agent and in combination with platinum, in a NSCLC xenograft model. These data demonstrate the utility of RPA inhibition in EOC and NSCLC and the potential in developing novel anticancer therapeutics that target RPA-DNA interactions.
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Paul, Subhadeep. "Studies on BODIPY Appended Ruthenium(II) Complexes for Bioimaging and Photodynamic Therapy Applications." Thesis, 2022. https://etd.iisc.ac.in/handle/2005/5894.
Full textAbstract:
Photodynamic therapy (PDT) is a medical technique that utilizes light, oxygen, and a photosensitizer to treat several medical conditions, including cancer. Because of the limitations and side effects of traditional anticancer therapies like surgery, chemotherapy, and radiation therapy, PDT has been recognized as an adjuvant and, in some cases, a mainstream alternative. Currently, clinical PDT utilizes tetrapyrrolic photosensitizers that possess several drawbacks. Even worldwide approved gold standard photosensitizer Photofrin® requires a high dose for the therapeutic effect that results in undesirable side effects like skin sensitivity and hepatotoxicity. In recent years, transition metal complexes are gaining interest as new photosensitizers with their fine-tuned photophysical and biological properties. This thesis work presents the results from a systematic study on the design and synthesis of new boron-dipyrromethene (BODIPY) appended ruthenium(II)complexes to study their photoinduced reactive oxygen species (ROS) generation ability, light-induced cytotoxicity and cellular imaging ability.
Here, a wide range of ruthenium coordination units are connected to BODIPY chromophore with various linkers, and their effect on photophysical and photobiological properties investigated. New ruthenium(II) complexes with formulations [Ru(L1/2)(L3/4)Cl]Cl where L1, L2 (having biotin) are NN-donor bidentate phenanthroline derivatives and L3, L4 (contain BODIPY) are NNN-donor tridentate dipicolylamine derivative, were synthesized, characterized and their photocytotoxicity evaluated. The complex having both BODIPY and cancer targeting biotin showed cancer cells elective PDT effect giving respective IC50 value of 0.98±0.04 and 3.9±0.4 μM in A549 (lung cancer) and HPL1D (noncancerous) cell lines in visible light of 400-700 nm, while being non-toxic in the dark. Analogous complexes containing di-styryl BODIPY were prepared and their PDT activity with redlight activation was evaluated. The active complex produced a remarkable photocytotoxicity index (PI, ratio of IC50 in dark and with light exposure) of >5000 with red light (600- 720 nm) activation. Next, a series of bichromophoric systems having a heteroleptic [Ru(tpy)2] (tpy = terpyridine) moiety covalently linked to a BODIPY pendant were prepared, characterized and their photophysical and photobiological properties were evaluated. In a following study, a series of biotin-conjugated compounds containing BODIPY or Ru(II)-bis-tpy or both chromophoric units were developed and the difference of multichromophoric Ru-BODIPY conjugates with structurally similar compounds having a single chromophore were investigated highlighting the importance of constructing such bichromophoric systems. These bichromophoric systems produced both superoxide and singlet oxygen via dual type-I/II photosensitization processes and exerted potent apoptotic PDT effect with visible light activation. Finally, two homoleptic complexes with formulation [Ru(tpy-BODIPY)2]Cl2,where the connection between the BODIPY unit and the Ru(II)-bis-tpy scaffold differs by a phenylacetylene spacer, were prepared as PDT agents with simple molecular design and the effect of the spacer was studied in terms of structure-activity relationship. In summary, this thesis work presents systematic developments of Ru(II)-BODIPY conjugates as novel photosensitizers and photodetection agents for phototherapeutic applications.
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Basu, Uttara. "Insights into the Chemistry of Iron Complexes as Imaging and Photocytotoxic Agents." Thesis, 2015. http://etd.iisc.ac.in/handle/2005/3753.
Full textAbstract:
The current thesis addresses the various facets of the chemistry of photocytotoxic iron complexes including their syntheses, characterization, evaluation of the anti-proliferative activities in various cancer cell lines upon photo-exposure, mechanism of cell death, the cellular uptake, localization inside cells, the interaction with double stranded DNA and their ability to induce DNA photocleavage.
Chapter I presents a general introduction to cancer and the anticancer agents. It covers various procedures available for cancer treatment and different aspects of chemotherapy are discussed in details. The mechanism of action of several chemotherapeutic agents, the DNA cleavage pathways and the anticancer activity of bleomycins are delineated. Photo-chemotherapy or photodynamic therapy which has emerged as an alternative treatment modality is described. It also contains a brief description of ideal photosensitizers and the ones that are currently approved. The potential of transition metal complexes as photo-chemotherapeutic agents is discussed based on the recent literature reports on the prospective photocytotoxic metal complexes, the photo-release of cytotoxic molecules from metal complexes, the DNA cleavage activities and their cytotoxicities. The biochemistry of iron and its medical utility which prompted the development of iron based cytotoxins has been presented. The objective of the present investigation is also defined in this chapter.
Chapter II describes the syntheses, characterization, evaluation of visible light induced cytotoxicity and interaction with DNA of a series of iron(II) bis-terpyridine complexes. Some interesting redox behaviour observed for two of the complexes has been described in details and rationalized from theoretical calculations. The DNA binding affinities of the complexes and their ability to induce DNA photocleavage in green light are discussed. The importance of this work lies in the remarkable photocytotoxic behaviour of the iron(II) complexes with visible light which was not reported earlier.
Chapter III addresses the syntheses of a series of iron(III) catecholate complexes which upon irradiation with red light can initiate photoreactions to generate cytotoxic species and induce death in HeLa, HaCaT, MCF-7 and A549 cells. The mechanisms of cell death, effect of the complexes on the cell cycle under various conditions, the uptake inside cells and the cellular localization of the complexes are studied. The DNA binding affinities of the five complexes and their ability to induce DNA photocleavage in red light are also presented here. These are the first iron based complexes to show red light induced photocytotoxicity.
Chapter IV addresses the drawbacks associated with the aforementioned iron(III) catecholates and their modification with a mitochondria targeting triphenylphosphonium unit. The synthesis, characterization, photocytotoxicities in HeLa, HaCaT, MCF-7 and A549, cell death mechanisms and cellular uptake and localization of four iron(III) complexes are discussed.
Chapter V describes the syntheses, characterization and the biological activities of carbohydrate appended iron(III) complexes and their non-glucose analogues. The selective and faster internalization of the glyco-conjugated complexes in HeLa cells has been studied using various spectroscopic and microscopic techniques. The red light induced cytotoxicities of the complexes, their effect on the progression of the cell cycle with and without irradiation and the mechanisms of cell death are explored. DNA binding abilities and photocleavage of DNA are also discussed.
Chapter VI presents the syntheses, characterization of a series of iron(III) complexes of a pyridoxal derivative and their salicyldehyde analogues for exploring their differential photocytotoxicity and cellular uptake in cancer cells compared to
normal cells. The visible light induced cytotoxicities of the complexes in HeLa, HaCaT, MCF-7 A549 cells and HPL1D cells, their effect on the progression of the cell cycle in dark and light, the mechanisms of cell death and the localization of the complexes inside the cells are explored.
The references have been compiled at the end of each chapter and given as superscripts in the text. The complexes presented in this thesis are indicated by bold-faced numbers. Crystallography data of the complexes that are structurally characterized by single crystal X-ray crystallography are given in CIF format in the enclosed CD (Appendix-I). Due acknowledgements have been made wherever the work described is based on the findings of other investigators. Any unintentional omission that might have happened due to oversight is regretted.
INDEX WORDS: Iron complexes • Crystal structure • Red light induced cytotoxicity
• Cellular imaging • DNA binding • DNA photocleavage.
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Basu, Uttara. "Insights into the Chemistry of Iron Complexes as Imaging and Photocytotoxic Agents." Thesis, 2015. http://etd.iisc.ernet.in/2005/3753.
Full textAbstract:
The current thesis addresses the various facets of the chemistry of photocytotoxic iron complexes including their syntheses, characterization, evaluation of the anti-proliferative activities in various cancer cell lines upon photo-exposure, mechanism of cell death, the cellular uptake, localization inside cells, the interaction with double stranded DNA and their ability to induce DNA photocleavage.
Chapter I presents a general introduction to cancer and the anticancer agents. It covers various procedures available for cancer treatment and different aspects of chemotherapy are discussed in details. The mechanism of action of several chemotherapeutic agents, the DNA cleavage pathways and the anticancer activity of bleomycins are delineated. Photo-chemotherapy or photodynamic therapy which has emerged as an alternative treatment modality is described. It also contains a brief description of ideal photosensitizers and the ones that are currently approved. The potential of transition metal complexes as photo-chemotherapeutic agents is discussed based on the recent literature reports on the prospective photocytotoxic metal complexes, the photo-release of cytotoxic molecules from metal complexes, the DNA cleavage activities and their cytotoxicities. The biochemistry of iron and its medical utility which prompted the development of iron based cytotoxins has been presented. The objective of the present investigation is also defined in this chapter.
Chapter II describes the syntheses, characterization, evaluation of visible light induced cytotoxicity and interaction with DNA of a series of iron(II) bis-terpyridine complexes. Some interesting redox behaviour observed for two of the complexes has been described in details and rationalized from theoretical calculations. The DNA binding affinities of the complexes and their ability to induce DNA photocleavage in green light are discussed. The importance of this work lies in the remarkable photocytotoxic behaviour of the iron(II) complexes with visible light which was not reported earlier.
Chapter III addresses the syntheses of a series of iron(III) catecholate complexes which upon irradiation with red light can initiate photoreactions to generate cytotoxic species and induce death in HeLa, HaCaT, MCF-7 and A549 cells. The mechanisms of cell death, effect of the complexes on the cell cycle under various conditions, the uptake inside cells and the cellular localization of the complexes are studied. The DNA binding affinities of the five complexes and their ability to induce DNA photocleavage in red light are also presented here. These are the first iron based complexes to show red light induced photocytotoxicity.
Chapter IV addresses the drawbacks associated with the aforementioned iron(III) catecholates and their modification with a mitochondria targeting triphenylphosphonium unit. The synthesis, characterization, photocytotoxicities in HeLa, HaCaT, MCF-7 and A549, cell death mechanisms and cellular uptake and localization of four iron(III) complexes are discussed.
Chapter V describes the syntheses, characterization and the biological activities of carbohydrate appended iron(III) complexes and their non-glucose analogues. The selective and faster internalization of the glyco-conjugated complexes in HeLa cells has been studied using various spectroscopic and microscopic techniques. The red light induced cytotoxicities of the complexes, their effect on the progression of the cell cycle with and without irradiation and the mechanisms of cell death are explored. DNA binding abilities and photocleavage of DNA are also discussed.
Chapter VI presents the syntheses, characterization of a series of iron(III) complexes of a pyridoxal derivative and their salicyldehyde analogues for exploring their differential photocytotoxicity and cellular uptake in cancer cells compared to
normal cells. The visible light induced cytotoxicities of the complexes in HeLa, HaCaT, MCF-7 A549 cells and HPL1D cells, their effect on the progression of the cell cycle in dark and light, the mechanisms of cell death and the localization of the complexes inside the cells are explored.
The references have been compiled at the end of each chapter and given as superscripts in the text. The complexes presented in this thesis are indicated by bold-faced numbers. Crystallography data of the complexes that are structurally characterized by single crystal X-ray crystallography are given in CIF format in the enclosed CD (Appendix-I). Due acknowledgements have been made wherever the work described is based on the findings of other investigators. Any unintentional omission that might have happened due to oversight is regretted.
INDEX WORDS: Iron complexes • Crystal structure • Red light induced cytotoxicity
• Cellular imaging • DNA binding • DNA photocleavage.
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Chattopadhyay, Niladri. "Development, Characterization and Validation of Trastuzumab-Modified Gold Nanoparticles for Molecularly Targeted Radiosensitization of Breast Cance." Thesis, 2012. http://hdl.handle.net/1807/43379.
Full textAbstract:
The overexpression of the human epidermal growth factor receptor-2 (HER-2) in 20-25% of human breast cancers was investigated as a target for development of a gold nanoparticle (AuNP) based radiosensitizer for improving the efficacy of neoadjuvant X-radiation therapy of the disease. HER-2 targeted AuNPs were developed by covalently conjugating trastuzumab, a Health Canada approved monoclonal antibody for the treatment of HER-2-overexpressing breast cancer, to 30 nm AuNPs. Trastuzumab conjugated AuNPs were efficiently internalized by HER-2-overexpressing breast cancer cells (as assessed by darkfield microscopy and transmission electron microscopy) and increased DNA damage from X-radiation in these cells by more than 5-fold. To optimize delivery of AuNPs to HER-2-overexpressing tumors, high resolution microSPECT/CT imaging was used to track the in vivo fate of 111In-labelled non-targeted and HER-2 targeted AuNPs following intravenous (i.v.) or intratumoral (i.t.) injection. For i.v. injection, the effects of GdCl3 (for deactivation of macrophages) and non-specific (anti-CD20) antibody rituximab (for blocking of Fc mediated liver and spleen uptake) were studied. It was found that HER-2 targeting via attachment of trastuzumab paradoxically decreased tumor uptake as a result of faster elimination of the targeted AuNPs from the blood while improving internalization in HER-2-positive tumor cells as compared to non-targeted AuNPs. This phenomenon could be attributed to Fc-mediated recognition and subsequent sequestration of trastuzumab conjugated AuNP by the reticuloendothelial system (RES). Blocking of the RES did not increase tumor uptake of either HER-2 targeted or non-targeted AuNPs. Following i.t. injection, our results suggest that Au-NTs redistribute over time and traffick to the liver via the ipsilateral axillary lymph node leading to comparable exposure as seen with i.v. administration. In contrast, targeted AuNPs are bound and internalized by HER-2-overexpressing tumor cells following i.t. injection, with a lower proportion of AuNPs redistributing to normal tissues. In vivo, the combination of HER-2 targeted AuNPs injected i.t. and X-radiation (11 Gy) yielded a 46% decrease in tumor size over a 4 month period in contrast to an 11.5% increase in tumor size for X-radiation treatment alone. Toxicology studies (evaluated through complete blood cell counts, by serum transaminase and creatinine measurements and by monitoring the body weight) demonstrated no apparent normal organ toxicity from the combination of HER-2 targeted AuNPs and X-radiation. These results are promising for the clinical translation of HER-2-targeted AuNPs for radiosensitization of tumors to X-radiation.
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Baldo, Silvia. "Synthesis of Therapeutically Useful Multivalent Boronated Complexes." Doctoral thesis, 2020. http://hdl.handle.net/10451/45274.
Full textAbstract:
Bioconjugates are among other biomolecules, derived from proteins, peptides, carbohydrates and/or nucleic acids, that upon connection with specific payloads (e.g., cytotoxic drugs, small vitamins, fluorophores) via a linker, have gained biological activity, a therapeutic effect and/or fluorescence. In the area of unmet medical needs, these hybrid materials achieved relevant success because of their ability to deliver the payload of choice to specific targets inside a biological environment, thanks to the recognition ability of the targeting biomolecule. Although conceptually simple, the construction of bioconjugates still struggles with the lack of suitable chemical functions to directly install the payloads onto biomolecules, and with the complexity of the synthetic introduction of the linker unit. Such limitations have been the reason why, despite the prominent success that antibody drug conjugates readily exhibited in the clinic, alternative strategies for targeted delivery such as small-molecule drug conjugates (SMDCs) have been explored.
Boronic acids are organic functionality having a strong Lewis acid character that allows them to form reversible covalent ligations with nucleophiles, including in biocompatible conditions, and therefore good candidates for successful application in the development of stimulus-responsive bioconjugates.
Herein is presented an innovative construction of SMDCs based on iminoboronate complexes (B-complexes). Their assembly, promoted by boronic acid simplifies the linker system and yields compact conjugates to selectively release bortezomib (BTZ). These Bcomplexes were found to be more stable than their counterpart of first generation, under biocompatible conditions (e.g. degradation < of 20 % in human plasma and no hydrolysis in the presence of glutathione). B-complex 54, a bombesin-conjugate and B-complex 57, a di-bombesin conjugate showed in HT-29 cancer cell IC50 values in the nanomolar range.
Moreover, this modular technology was employed in the construction of fluorescent boronic acid salicylidenehydrazone (BASHY) complexes, which exhibited suitable structural and photophysical properties for live cell bioimaging applications. BASHY 67 was selected to vectorise BTZ into lipid droplets (LDs), and this led us to study the drugtreatment resistance of cells, caused by LDs drugs sequestration. In vitro test of BTZ, BASHY-BTZ and bombesin-BASHY-BTZ were carried out in HT-29, HeLa and MCF-7 cancer cells lines, and the cell viability was found to be dependent of the drug complexation state.Os bioconjugados são entidades formadas por biomoléculas tais como proteínas, péptidos, carboidratos ou ácidos nucleicos, que devido à sua ligação com cargas úteis específicas (por exemplo, drogas citotóxicas, pequenas vitaminas, fluoróforos) através de um linker, exercem atividade biológica, terapêutica ou de imagiológica. Entre as novas terapias médicas, os bioconjugados constituídos por uma biomolécula que promova um direcionamento terapêutico selectivo para alvos específicos obtiveram um sucesso relevante devido à selectividade daentrega seletiva, nomeadamente dede fármacos citotóxicos em ambiente biológico, permitindo quer uma maior atividade terapêutica, quer.uma maior segurança Embora conceptualmente simples, a construção de bioconjugados é desafiante não só devido à falta de funções químicas adequadas para instalar diretamente os fármacos nas biomoléculas mas também dada a complexidade do processo sintético para preparar o linker. Estas limitações têm fomentado a procura de novas estratégias alternativas para a entrega seletiva de fármacos. Por exemplo, apesar do sucesso proeminente que os bioconjugados do tipo anticorpo conjugado com fármacos exibiram na clínica, a dificuldade e o custo da sua preparação foram pontos cruciais que levaram à procura de alternativas , sendo uma das mais relevantes odesenvolvimento da conjugação de fármacos com moléculas pequenas capazes de direcionamento (SMDCs). Os ácidos borónicos são entidades orgânicas com forte caráter de ácido de Lewis que permitem formar ligações covalentes reversíveis com nucleófilos em condições biocompatíveis. O caracter reversível destas ligações covalentes permite o desenvolvimento de bioconjugados sensíveis a estímulos, tais como a alteração de pH ou presença de outras biomoléculas. Neste trabalho é apresentada uma construção inovadora de SMDCs baseadas em complexos de iminoboronato (complexos B), cuja estabilização promovida pelo ácido borónico produz conjugadosrobustos e sinteticamente acessíveis ,simplificando a tecnologia dos linker para a libertação seletiva do bortezomib (BTZ), mas ainda capaz de libertar o fármaco na resposta a um estímulo. Os complexos B de segunda geração são mais estáveis em condições biocompatíveis que os respectivos complexos B de primeira geração, apresentando por exemplo, degradação inferior a 20% em plasma humano e resistência à degradação na presença de glutationa. O SMDC 54 conjugado com uma unidade do péptido bombesina e o SMDC 57 conjugado com duas unidades do peptido bombesina demonstraram valores de IC50 na gama de nanomolar para a linha de células cancerígenas HT-29. 4 Esta tecnologia modular foi ainda utilizada na construção de complexos de boro fluorescentes (BASHY), que exibem propriedades estruturais e fotofísicas adequadas para aplicações de bioimagem em células vivas. O BASHY 67 foi selecionado para vetorizar o BTZ em gotículas lipídicas (LDs), abordando assim a nossa intenção de estudar a resistência das células ao tratamento medicamentoso, devido ao sequestro de fármacos pelas LDs. Testes in vitro de BTZ na forma livre e conjugado como BASHY (BASHY-BTZ) e testes in vitro de BASHY-BTZ conjugado com o peptide bombesina foram realizados nas linhas de células cancerígenas HT-29, HeLa e MCF-7, e demonstram que a viabilidade celular é dependente do estado de complexação da droga.
Marie Sklodowska-Curie Actions ITN ProteinConjugates (MSCA-ITN-2015-ETN-675007)
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Babu, Balaji. "Studies on Photocytotoxic Ferrocenyl Conjugates." Thesis, 2014. http://etd.iisc.ac.in/handle/2005/3028.
Full textAbstract:
The present thesis deals with different aspects of the chemistry and photo-biology of various ferrocene-conjugates, their interaction with double helical DNA, DNA photocleavage and photo-enhanced cytotoxicity in visible light, localization and cellular uptake to study the mechanism of cell death. Phenyl analogues of the active complexes have been synthesized and used for comparison in biological assays.
Chapter I presents an overview of cancer and its types, various treatments for cancer. A general overview on the Photodynamic Therapy, a new modality of light activated cancer treatment and its various possible mechanism of action, has been made. The promise of photoactivated chemotherapy is discussed with recently developed metal based antitumor agents. Biological applications of few ferrocene conjugates as anticancer and anti-malarial agents are discussed. The objective of the present investigation is also presented in this chapter.
Chapter II presents the synthesis, characterization, structure, DNA binding, DNA photocleavage, photocytotoxicity and cellular localization of ferrocene-conjugated dipicolylamine oxovanadium(IV) complexes of curcumin. To explore the role of the ferrocenyl moiety the phenyl analogue of the ferrocenyl complexes is synthesized and used as a control for comparison purpose.
Chapter III deals with the photo-induced DNA cleavage and photo-enhanced cytotoxicity of ferrocene-conjugated oxovanadium(IV) complexes of heterocyclic bases. The synthesis, characterization, structural comparisons, DNA binding, DNA photocleavage and photocytotoxic activity in visible light are discussed in detail.
Chapter IV describes the synthesis, characterization and structure of ferrocene-conjugated oxovanadium(IV) complexes of acetylacetonate derivatives. The complexes are evaluated for DNA binding, DNA photocleavage and photocytotoxic activity in HeLa, MCF-7, 3T3 cells in visible light. The fluorescent nature of the complexes is used to study the cellular localization of the complexes and the mechanism of cell death induced by the complexes is also discussed.
Chapter V presents the photocytotoxic effect of ferrocene-conjugated oxovanadium(IV) complexes of different curcuminoids in HeLa , HepG2 and 3T3 cells. Curcumin based fluorescence has been successfully used to study the cellular uptake and localization behavior of the complexes. The positive role of the ferrocenyl complex is evident from the ~4 fold increase in its photocytotoxicity compared to the phenyl analogue. The apoptotic mode of cell death is evident from nuclear co-staining using Hoechst dye.
Chapter VI describes the synthesis, characterization and photochemotherapeutic efficacy of ferrocene conjugates of N-alkyl pyridinium salts. Mitochondria targeting property of ferrocene compound having n-butyltriphenylphosphonium group has been studied by JC-1 assay. FACS analysis showed significant sub G1/G0 phase cell-cycle arrest in cancer cells on visible light treatment.
Finally, the summary of the dissertation and conclusions drawn from the present investigations are presented.
The references in the text have been indicated as superscript numbers and compiled at the end of each chapter. The complexes presented in this thesis are represented by bold-faced numbers. Crystallographic data of the structurally characterized complexes are given in CIF format in the enclosed CD (Appendix-I). Due acknowledgements have been made wherever the work described is based on the findings of other investigators. Any unintentional omission that might have happened due to oversight or mistake is regretted.
INDEX WORDS: Ferrocene conjugates Crystal structure DNA binding DNA photocleavage Photocytotoxicity Vanadium Cellular Imaging
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Babu, Balaji. "Studies on Photocytotoxic Ferrocenyl Conjugates." Thesis, 2014. http://hdl.handle.net/2005/3028.
Full textAbstract:
The present thesis deals with different aspects of the chemistry and photo-biology of various ferrocene-conjugates, their interaction with double helical DNA, DNA photocleavage and photo-enhanced cytotoxicity in visible light, localization and cellular uptake to study the mechanism of cell death. Phenyl analogues of the active complexes have been synthesized and used for comparison in biological assays.
Chapter I presents an overview of cancer and its types, various treatments for cancer. A general overview on the Photodynamic Therapy, a new modality of light activated cancer treatment and its various possible mechanism of action, has been made. The promise of photoactivated chemotherapy is discussed with recently developed metal based antitumor agents. Biological applications of few ferrocene conjugates as anticancer and anti-malarial agents are discussed. The objective of the present investigation is also presented in this chapter.
Chapter II presents the synthesis, characterization, structure, DNA binding, DNA photocleavage, photocytotoxicity and cellular localization of ferrocene-conjugated dipicolylamine oxovanadium(IV) complexes of curcumin. To explore the role of the ferrocenyl moiety the phenyl analogue of the ferrocenyl complexes is synthesized and used as a control for comparison purpose.
Chapter III deals with the photo-induced DNA cleavage and photo-enhanced cytotoxicity of ferrocene-conjugated oxovanadium(IV) complexes of heterocyclic bases. The synthesis, characterization, structural comparisons, DNA binding, DNA photocleavage and photocytotoxic activity in visible light are discussed in detail.
Chapter IV describes the synthesis, characterization and structure of ferrocene-conjugated oxovanadium(IV) complexes of acetylacetonate derivatives. The complexes are evaluated for DNA binding, DNA photocleavage and photocytotoxic activity in HeLa, MCF-7, 3T3 cells in visible light. The fluorescent nature of the complexes is used to study the cellular localization of the complexes and the mechanism of cell death induced by the complexes is also discussed.
Chapter V presents the photocytotoxic effect of ferrocene-conjugated oxovanadium(IV) complexes of different curcuminoids in HeLa , HepG2 and 3T3 cells. Curcumin based fluorescence has been successfully used to study the cellular uptake and localization behavior of the complexes. The positive role of the ferrocenyl complex is evident from the ~4 fold increase in its photocytotoxicity compared to the phenyl analogue. The apoptotic mode of cell death is evident from nuclear co-staining using Hoechst dye.
Chapter VI describes the synthesis, characterization and photochemotherapeutic efficacy of ferrocene conjugates of N-alkyl pyridinium salts. Mitochondria targeting property of ferrocene compound having n-butyltriphenylphosphonium group has been studied by JC-1 assay. FACS analysis showed significant sub G1/G0 phase cell-cycle arrest in cancer cells on visible light treatment.
Finally, the summary of the dissertation and conclusions drawn from the present investigations are presented.
The references in the text have been indicated as superscript numbers and compiled at the end of each chapter. The complexes presented in this thesis are represented by bold-faced numbers. Crystallographic data of the structurally characterized complexes are given in CIF format in the enclosed CD (Appendix-I). Due acknowledgements have been made wherever the work described is based on the findings of other investigators. Any unintentional omission that might have happened due to oversight or mistake is regretted.
INDEX WORDS: Ferrocene conjugates Crystal structure DNA binding DNA photocleavage Photocytotoxicity Vanadium Cellular Imaging
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Hussain, Akhtar. "Studies On Lanthanide Complexes Showing Photo-activated DNA Cleavage And Anticancer Activity." Thesis, 2011. https://etd.iisc.ac.in/handle/2005/2428.
Full textAbstract:
This thesis work deals with different aspects of the chemistry of La(III) and Gd(III) complexes, their interaction with DNA and proteins, photo-induced cleavage of double-stranded DNA, photocytotoxic effect on cancer cells, cell death mechanism and cellular localization behaviour.
Chapter I gives an introduction to the metal-based anticancer agents with special emphasis on clinically used drugs and the growing field of lanthanide therapeutics. An overview of the current strategies of cancer treatment, especially photodynamic therapy (PDT), is presented. Mode of small molecule-DNA interactions and the mechanistic aspects associated with DNA photodamage reactions and PDT effect are discussed with selected examples of compounds that are known to photocleave DNA on exposure to light of different wavelengths. A brief discussion on the various therapeutic applications of the lanthanide compounds is also made.
Chapter II presents the synthesis, characterization, DNA binding, BSA binding, photo-induced DNA cleavage activity and photocytotoxicity of La(III) and Gd(III) complexes of phenanthroline bases to explore the UV-A light-induced DNA cleavage activity and photocytotoxicity of the complexes.
Chapter III describes the synthesis, characterization, DNA binding, photo-induced DNA cleavage activity and photocytotoxicity of La(III) and Gd(III) complexes of phenanthroline bases with an aim to improve the design of the complexes to achieve better solution stability and DNA binding of the complexes.
Chapter IV presents the synthesis, characterization, DNA binding, and UV-A light-induced DNA photocleavage activity and photocytotoxicity of La(III) and Gd(III) complexes of pyridyl phenanthroline bases with an objective to improve the photoactivity of the complexes by introducing an additional pyridyl group. Cell death mechanism and confocal microscopic studies are also carried out to gain more insight into the PDT effect caused by light in the presence of the complex.
Chapter V describes the synthesis and characterization of La(III) and Gd(III) complexes of terpyridine bases and acetylacetonate to study the complexes as a new class of photosensitizers to explore their DNA photocleavage activity and photocytotoxicity in HeLa cells. Effect of attaching a glucose moiety to the acetyl acetone (Hacac) ligand has been studied. The cellular uptake behaviour of the La(III) pyrenyl-terpyridine complexes has also been investigated.
Finally, Chapter VI presents the synthesis and characterization of curcumin and glycosylated curcumin La(III) and Gd(III) complexes having terpyridine base with an objective to study the photoactivated anticancer activity of the complexes in visible light. This chapter describes the visible light-induced DNA cleavage activity and photocytotoxicity of the complexes by exploiting curcumin and glycosylated curcumin as the photosensitizer ligands. Study on the cellular uptake behavior of curcumin La(III) complexes having pyrenyl terpyridine ligand is also presented.
The references have been assembled at the end of each chapter and indicated as superscript numbers in the text. The complexes presented in this thesis are represented by bold-faced numbers. Crystallographic data of the complexes which are characterized structurally by single crystal X-ray crystallography are provided in CIF format in the enclosed CD (Appendix-I). Due acknowledgements have been made wherever the work described is based on the findings of other investigators. Any unintentional omission that might have happened due to oversight or mistake is sincerely regretted.
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Hussain, Akhtar. "Studies On Lanthanide Complexes Showing Photo-activated DNA Cleavage And Anticancer Activity." Thesis, 2011. http://etd.iisc.ernet.in/handle/2005/2428.
Full textAbstract:
This thesis work deals with different aspects of the chemistry of La(III) and Gd(III) complexes, their interaction with DNA and proteins, photo-induced cleavage of double-stranded DNA, photocytotoxic effect on cancer cells, cell death mechanism and cellular localization behaviour.
Chapter I gives an introduction to the metal-based anticancer agents with special emphasis on clinically used drugs and the growing field of lanthanide therapeutics. An overview of the current strategies of cancer treatment, especially photodynamic therapy (PDT), is presented. Mode of small molecule-DNA interactions and the mechanistic aspects associated with DNA photodamage reactions and PDT effect are discussed with selected examples of compounds that are known to photocleave DNA on exposure to light of different wavelengths. A brief discussion on the various therapeutic applications of the lanthanide compounds is also made.
Chapter II presents the synthesis, characterization, DNA binding, BSA binding, photo-induced DNA cleavage activity and photocytotoxicity of La(III) and Gd(III) complexes of phenanthroline bases to explore the UV-A light-induced DNA cleavage activity and photocytotoxicity of the complexes.
Chapter III describes the synthesis, characterization, DNA binding, photo-induced DNA cleavage activity and photocytotoxicity of La(III) and Gd(III) complexes of phenanthroline bases with an aim to improve the design of the complexes to achieve better solution stability and DNA binding of the complexes.
Chapter IV presents the synthesis, characterization, DNA binding, and UV-A light-induced DNA photocleavage activity and photocytotoxicity of La(III) and Gd(III) complexes of pyridyl phenanthroline bases with an objective to improve the photoactivity of the complexes by introducing an additional pyridyl group. Cell death mechanism and confocal microscopic studies are also carried out to gain more insight into the PDT effect caused by light in the presence of the complex.
Chapter V describes the synthesis and characterization of La(III) and Gd(III) complexes of terpyridine bases and acetylacetonate to study the complexes as a new class of photosensitizers to explore their DNA photocleavage activity and photocytotoxicity in HeLa cells. Effect of attaching a glucose moiety to the acetyl acetone (Hacac) ligand has been studied. The cellular uptake behaviour of the La(III) pyrenyl-terpyridine complexes has also been investigated.
Finally, Chapter VI presents the synthesis and characterization of curcumin and glycosylated curcumin La(III) and Gd(III) complexes having terpyridine base with an objective to study the photoactivated anticancer activity of the complexes in visible light. This chapter describes the visible light-induced DNA cleavage activity and photocytotoxicity of the complexes by exploiting curcumin and glycosylated curcumin as the photosensitizer ligands. Study on the cellular uptake behavior of curcumin La(III) complexes having pyrenyl terpyridine ligand is also presented.
The references have been assembled at the end of each chapter and indicated as superscript numbers in the text. The complexes presented in this thesis are represented by bold-faced numbers. Crystallographic data of the complexes which are characterized structurally by single crystal X-ray crystallography are provided in CIF format in the enclosed CD (Appendix-I). Due acknowledgements have been made wherever the work described is based on the findings of other investigators. Any unintentional omission that might have happened due to oversight or mistake is sincerely regretted.
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Corridon, Peter R. "Hydrodynamic delivery for the study, treatment and prevention of acute kidney injury." Thesis, 2014. http://hdl.handle.net/1805/4603.
Full textAbstract:
Indiana University-Purdue University Indianapolis (IUPUI)Advancements in human genomics have simultaneously enhanced our basic understanding of the human body and ability to combat debilitating diseases. Historically, research has shown that there have been many hindrances to realizing this medicinal revolution. One hindrance, with particular regard to the kidney, has been our inability to effectively and routinely delivery genes to various loci, without inducing significant injury. However, we have recently developed a method using hydrodynamic fluid delivery that has shown substantial promise in addressing aforesaid issues. We optimized our approach and designed a method that utilizes retrograde renal vein injections to facilitate widespread and persistent plasmid and adenoviral based transgene expression in rat kidneys. Exogenous gene expression extended throughout the cortex and medulla, lasting over 1 month within comparable expression profiles, in various renal cell types without considerably impacting normal organ function. As a proof of its utility we by attempted to prevent ischemic acute kidney injury (AKI), which is a leading cause of morbidity and mortality across among global populations, by altering the mitochondrial proteome. Specifically, our hydrodynamic delivery process facilitated an upregulated expression of mitochondrial enzymes that have been suggested to provide mediation from renal ischemic injury. Remarkably, this protein upregulation significantly enhanced mitochondrial membrane potential activity, comparable to that observed from ischemic preconditioning, and provided protection against moderate ischemia-reperfusion injury, based on serum creatinine and histology analyses. Strikingly, we also determined that hydrodynamic delivery of isotonic fluid alone, given as long as 24 hours after AKI is induced, is similarly capable of blunting the extent of injury. Altogether, these results indicate the development of novel and exciting platform for the future study and management of renal injury.
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Behrendt, Frank. "Synthese und biologische Evaluierung von fluorezenzmarkierten Duocarmycin-Analoga." Doctoral thesis, 2011. http://hdl.handle.net/11858/00-1735-0000-0006-B093-D.
Full text