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Yung, Bryant Chinung. "NANOPARTICLE DRUG DELIVERY SYSTEMS FOR CANCER THERAPY". The Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1417614665.
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Zi, Hong. "Polymers for drug delivery in cancer therapy /". May be available electronically:, 2008. http://proquest.umi.com/login?COPT=REJTPTU1MTUmSU5UPTAmVkVSPTI=&clientId=12498.
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Liu, Yang. "Development of Novel Drug Delivery Systems for Cancer Therapy". The Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu153105342400785.
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Xu, Leyuan. "Engineering of Polyamidoamine Dendrimers for Cancer Therapy". VCU Scholars Compass, 2015. http://scholarscompass.vcu.edu/etd/3773.
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Dendrimers are a class of polymers with a highly branched, three-dimensional architecture comprised of an initiator core, several interior layers of repeating units, and multiple active surface terminal groups. Dendrimers have been recognized as the most versatile compositionally and structurally controlled nanoscale building blocks for drug and gene delivery. Polyamidoamine (PAMAM) dendrimers have been most investigated because of their unique structures and properties. Polycationic PAMAM dendrimers form compacted polyplexes with nucleic acids at physiological pH, holding great potential for gene delivery.
Folate receptor (FRα) is expressed at very low levels in normal tissues but expressed at high levels in cancers in order to meet the folate demand of rapidly dividing cells under low folate conditions. Our primary aim was to investigate folic acid (FA)-conjugated PAMAM dendrimer generation 4 (G4) conjugates (G4-FA) for targeted gene delivery. The in vitro cellular uptake and transfection efficiency of G4-FA conjugates and G4-FA/DNA polyplexes were investigated in Chapter 4. It was found the cellular uptake of G4-FA conjugates and G4-FA/DNA polyplexes was in a FR-dependent manner. Free FA competitively inhibited the cellular uptake of G4-FA conjugates and G4-FA/DNA polyplexes. G4-FA/DNA polyplexes were preferentially taken up by FR-positive HN12 cells but not FR-negative U87 cells. In contrast, the cellular uptake of G4 dendrimers and G4/DNA polyplexes was non-selective via absorptive endocytosis. G4-FA conjugates significantly enhanced cytocompatibility and transfection efficiency compared to G4 dendrimers. This work demonstrates that G4-FA conjugates allow FR-targeted gene delivery, reduce cytotoxicity, and enhance gene transfection efficiency.
The in vivo biodistribution of G4-FA conjugates and anticancer efficacy of G4-FA/siRNA polyplexes were investigated in Chapter 5. Vascular endothelial growth factor A (VEGFA) is one of the major regulators of angiogenesis, essential for the tumor development. It was found G4-FA/siVEGFA polyplexes significantly knocked down VEGFA mRNA expression and protein release in HN12 cells. In the HN12 tumor-bearing nude mice, G4-FA conjugates were preferentially taken up by the tumor and retained in the tumor for at least 21 days following intratumoral (i.t.) administration. Two-dose i.t. administration of G4-FA/siVEGFA polyplexes significantly inhibited tumor growth by lowering tumor angiogenesis. In contrast, two-dose i.t. administration of G4/siVEGFA polyplexes caused severe skin lesion, presumably as a result of local toxicity. Taken together, this work shows great potential for the use of G4-FA conjugates in targeted gene delivery and cancer gene therapy.
We also explored polyanionic PAMAM dendrimer G4.5 as the underlying carrier to carry camptothecin (CPT) for glioblastoma multiforme therapyin Chapter 6. "Click" chemistry was applied to improve polymer-drug coupling reaction efficiency. The CPT-conjugate displayed a dose-dependent toxicity with an IC50 of 5 μM, a 185-fold increase relative to free CPT, presumably as a result of slow release. The conjugated CPT resulted in G2/M arrest and cell death while the dendrimer itself had little to no toxicity. This work indicates highly efficient "click" chemistry allows for the synthesis of multifunctional dendrimers for sustained drug delivery.
Immobilizing PAMAM dendrimers to the cell surface may represent an innovative method of enhancing cell surface loading capacity to deliver therapeutic and imaging agents. In Chapter 7, macrophage RAW264.7 (RAW) was hybridized with PAMAM dendrimer G4.0 (DEN) on the basis of bioorthogonal chemistry. Efficient and selective cell surface immobilization of dendrimers was confirmed by confocal microscopy. It was found the viability and motility of RAW-DEN hybrids remained the same as untreated RAW cells. Furthermore, azido sugar and dendrimer treatment showed no effect on intracellular AKT, p38, and NFκB (p65) signaling, indicating that the hybridization process neither induced cell stress response nor altered normal signaling. This work shows the feasibility of applying bioorthogonal chemistry to create cell-nanoparticle hybrids and demonstrates the noninvasiveness of this cell surface engineering approach.
In summary, these studies indicate surface-modification of PAMAM dendrimer G4 with FA can effectively target at FR-positive cells and subsequently enhance in vitro transfection efficiency and in vivo gene delivery. G4-FA conjugates may serve as a versatile targeted gene delivery carrier potentially for cancer gene therapy. PAMAM dendrimers G4.5 may serve as a drug delivery carrier for the controlled release of chemotherapeutics. The immune cell-dendrimer hybrids via bioorthogonal chemistry may serve as an innovative drug and gene delivery carrier potentially for cancer chemotherapy. Taken together, engineering of PAMAM dendrimers may advance anticancer drug and gene delivery.
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Qin, Yiru. "Graphene Quantum Dots-Based Drug Delivery for Ovarian Cancer Therapy". Scholar Commons, 2016. http://scholarcommons.usf.edu/etd/6358.
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Ovarian cancer, one of the most dreadful malignancies of the female reproductive system, poses a lethal threat to women worldwide. In this dissertation, the objective was to introduce a novel type of graphene quantum dots (GQDs) based nano-sized drug delivery systems (DDS) for ovarian cancer treatment. As a starting point, the facile synthesis method of the GQDs was established. Subsequently, the targeting ligand,folic acid (FA), was conjugated to GQDs. Next, a FDA approved chemotherapeutic drug, Doxorubicin (DOX), was loaded to form the GQDs-FA-DOX nano-conjugation as the DDS. Moreover, the uptake profile and anti-cancer effect of the GQDs-FA-DOX were validated in ovarian cancer cells. Finally, the immunotoxicity of GQDs and its mechanism were investigated and elucidated. Taken together, the findings described in this dissertation provide a novel and powerful strategy of targeted treatment for ovarian cancer.
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Man, Kwun-wai Dede, i 文冠慧. "Oleanolic acid delivery using biodegradable nanoparticles for cancer therapy". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2015. http://hdl.handle.net/10722/208550.
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Escolà, Jané Anna. "Somatostatin analogues as drug delivery systems for receptor-targeted cancer therapy". Doctoral thesis, Universitat de Barcelona, 2018. http://hdl.handle.net/10803/663804.
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Somatostatin (SST or SRIF14) is a peptidic hormone secreted throughout the central nervous system and in the gastrointestinal tract which has anti-secretory, anti-proliferative and anti-angiogenic effects. Although its administration as a drug is effective in certain conditions, its therapeutic use is limited by its short plasma half-life (< 3 min), the broad spectrum of biological responses and the lack of selectivity over its receptors (SSTRs).
In order to obtain more stable and selective analogues we have incorporated both non-natural electron-rich and electron-poor aromatic amino acids at key positions of the native sequence to overcome the above-mentioned drawbacks. In this regard, we have obtained different analogues which have been studied by NMR obtaining the structures of the major set of conformations. Their binding profile and half-lives have also been determined. Among all the analogues, one stood out due to its half-life of around 40 h, the highest one known for a SRIF14 analogue. Furthermore, it displayed a major set of conformations in solution and high selectivity towards SSTR2.
In recent years, receptor-targeted cancer therapy has gained interest as certain receptors are overexpressed in cancer cells. This is the case of SSTRs in endocrine tumours. On this subject, we have coupled different molecules at the N-terminal part of the previously mentioned analogue. The first one was a chromophore which enabled us to follow the internalisation of the analogue inside CHO-K1 wild type (WT) and CHO-K1 SSTR2-overexpressing (ST) cell lines which turned to be far more better in ST than in WT. In light of these findings, we decided to go one step further and test this analogue as a drug delivery system thus coupling it to a colour-changing chromophore (green: bonded to the peptide, blue: when released). As before, both the internalisation and the drug release was better in ST than in WT. Last step was to test the analogue as a p38α inhibitor by coupling the inhibitor directly at the N-terminal part. As for the other assays, the inhibition of p-Hsp27 (p38α downstream target) was better in ST than in WT which was attributed to a better internalisation of the analogue.La somatostatina (SST o SRIF14) es una hormona peptídica secretada por el sistema nervioso central y el tracto gastrointestinal que tiene efectos anti-secretores, anti-proliferativos y anti-angiogénicos. Aunque su administración como fármaco es eficaz en ciertas condiciones, su uso terapéutico está limitado por su corta vida media plasmática (<3 min), el amplio espectro de respuestas biológicas y la falta de selectividad entre sus receptores. Con el fin de obtener análogos más estables y selectivos, hemos incorporado aminoácidos aromáticos no naturales ricos y pobres en electrones en posiciones clave de la secuencia nativa para superar dichos inconvenientes. Así, se obtuvieron diferentes análogos que fueron estudiados por RMN obteniendo la estructura de sus conformaciones mayoritarias. También se determinó su perfil de unión a los receptores y sus vidas medias. Entre los análogos, uno destacó por tener una vida media de 40 h, la más alta conocida para un análogo de 14 aminoácidos. Además, mostró un conjunto de conformaciones en solución parecido y una gran selectividad para SSTR2. Recientemente, la terapia contra el cáncer dirigida a receptores ha ganado interés ya que ciertos receptores están sobre-expresados en las células cancerosas. Este es el caso de los receptores de somatostatina en tumores endocrinos. Así, acoplamos diferentes moléculas en la parte N-terminal del análogo mencionado anteriormente. La primera fue un cromóforo que nos permitió seguir la internalización del análogo en dos líneas celulares: CHO-K1 de tipo salvaje (WT) y CHO-K1 con SSTR2 sobre-expresado (ST); dicha internalización fue mucho mejor en ST que en WT. Al ver estos resultados prometedores, fuimos un paso más allá y probamos el análogo cómo sistema de liberación de fármacos, acoplándolo a un cromóforo que cambia de color (verde: unido al péptido, azul: cuando se libera). Cómo antes, tanto la internalización como la liberación fueron mejores en ST que en WT. El último paso fue probar el análogo como inhibidor de p38α acoplando el inhibidor directamente en la parte N-terminal. Cómo en los ensayos anteriores, la inhibición de p-Hsp27 (diana downstream de p38α) fue mejor en ST que en WT, lo que se atribuyó a una mejor internalización del análogo en ST.
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Riaz, Muhammad Kashif. "Peptide functionalized drug delivery system for an efficient lung cancer therapy". HKBU Institutional Repository, 2019. https://repository.hkbu.edu.hk/etd_oa/609.
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Lung cancer has a high incidence rate globally and the leading cause of cancer related mortalities. In 2018, lung cancer has been estimated to cause 1.76 million deaths worldwide (18.33% of total cancer mortalities). In Hong Kong lung cancer has been a leading cause of cancer related deaths, and in 2016 caused 3780 deaths (26.6% of total cancer mortalities). Non-small cell lung cancer (NSCLC) is the major (~85%) lung cancer type, and five-year survival rate for lung cancer has estimated to be 18%. Thus, an efficient lung cancer treatment with lesser adverse effects is need of the hour. In this connection, active targeting of overexpressed receptors at lung tumor site with a ligand functionalized drug delivery system is the current approach, and pulmonary administration could augment chemotherapeutic effect of the drug through localized administration, minimizing the off-target effects by retention of the drug in lungs.Quercetin (QR), a natural flavonoid present in edible fruits and vegetables possess anticancer activity i.e. inhibits lung cancer growth. However, the application of QR in lung cancer therapy has been restricted by various factors i.e. low water solubility (2.15 µg/ml at room temperature), low bioavailability and rapid plasma clearance. To overcome the issues, we have formulated various QR-loaded liposomes surface functionalized with transferrin receptor (TFR) targeting peptides i.e. T7 (HAIYPRH) and T12 (THRPPMWSPVWP) in two research projects with active targeting ability, prolonged circulation time, and sustained release behavior for lung cancer specific QR delivery. In first research project, T7 targeted liposomes with different peptide densities i.e. 0.5%, 1% and 2% and QR-lip (non-targeted) were formulated. TFRs are over expressed (~100 folds) in various cancers including lung cancer and have low expression in most normal cells. T7 surface-functionalized liposomes (2% T7-QR-lip) demonstrated significantly enhanced cytotoxicity (~3-folds), cellular-uptake, S-phase cell cycle arrest and apoptosis in A549 cells. However, in MRC-5 (normal-lung fibroblast) cells no significant difference was observed after treatment with T7-QR-lip and QR-lip in cytotoxicity and cellular uptake studies. In tumor spheroid penetration and inhibition studies, T7 targeted liposomes showed deeper penetration and pronounced inhibition. In vivo biodistribution study via pulmonary administration of T7-DiR-lip has demonstrated liposomes accumulation in the lungs and sustained-release behavior upto 96h. Further, T7-QR-lip significantly enhanced anticancer activity of QR and life-span of orthotopic lung-tumor bearing mice (**p < 0.01, compared with control) via pulmonary administration. In second research project, T12 surface-functionalized liposomes with 0.5%, 1% and 2% T12 peptide densities and QR-lip have been formulated with ~95 % encapsulation efficiency. In vitro drug release study showed sustained release of QR from T12-QR-lip and QR-lip. In vitro experiments showed A549 cells treatment with 2% T12-QR-lip enhanced cellular-uptake, in vitro cytotoxicity, induced apoptosis and S-phase cell cycle arrest due to TFR mediated endocytosis. No significant variation has been observed in cellular-uptake and cytotoxicity after MRC-5 cells were treated with T12-QR-lip and QR-lip. Further, T12-Cou6-lip showed significantly deeper penetration i.e. 120 µm in 3D lung tumor-spheroids. Biodistribution study showed retention of T12-DiR-lip and DiR-lip mainly in the lungs upto 96h after pulmonary administration, as compared to free DiR. Pulmonary administration of T12-QR-lip showed the strongest tumor growth inhibition and survival time of orthotopic lung tumor implanted mice without any systemic toxicity as compared to QR-lip and free-QR. In summary, in vitro and in vivo results of the two research projects suggest that surface functionalization of the liposomes with TFR targeting peptides i.e. T7 and T12 is a promising approach for lung cancer therapy through active targeting and receptor mediated endocytosis of QR at lung tumor site. Moreover, T7 and T12 functionalized liposomes provides a potential drug delivery system for a range of anticancer drugs to enhance their therapeutic efficacy by localized i.e. pulmonary administration and targeted delivery.
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KALAJA, ODETA. "Nanoparticles based delivery System of Flavonoids for Cancer Therapy". Doctoral thesis, Università degli Studi di Trieste, 2018. http://hdl.handle.net/11368/2917683.
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Nowadays, cancer remains one of the major public health problem. Although chemotherapeutic drugs efficiently kill cancer cells, these cells can defend themselves from such toxic compounds with a process called cancer multidrug resistance (MDR). Because of unsatisfactory treatment scenario there has been growing interest in the health advantages of using plant-derived compounds for cancer prevention or in the treatment of chemo-resistant cells.
Anthocyanidins are a group of pigments belonging to the family of flavonoids present in red-blue fruits and vegetables. Several studies demonstrated that, together with their glycosylated forms, they exert intense biological activity towards normal and cancer cells, including selective cytotoxicity, capability to interact with extrusion pumps, cell cycle perturbation, anti-proliferation and apoptosis.
Usually, the concentrations used to prove the biological effects of such compounds are far from those obtained when the assumption passes only through the ingestion of food rich of phytochemicals, and there is a lack of information on the possible long term toxic effects.
Beyond proven biological effect, anthocyanins have low stability and bioavailability. Moreover, when ingested, their bioavailability is drastically reduced by their poor chemical stability in the weak alkaline conditions of the small intestine, thus challenging the possibility to translate their proven biological effects into therapeutic applications.
Nanotechnologies has been widely applied in pharmaceutical field to improve the absorption of bioactive compounds.
Delphinidin, one of the major anthocyanidins naturally found in red-blue fruits and vegetable, is a compound that exhibits a wide range of biological activities such as anti-tumor and anti-inflammatory and exert great effect on oxidative stress.
In this study, we aimed to:
a) Evaluate the effects of a non-toxic long-term treatment with delphinidin on LoVo/Dx cells (metastatic human colorectal adenocarcinoma cell line, doxorubicin resistant). Precisely, we studied the interferences with cell cycle, the expression of specific membrane transporters responsible for drug resistance, the accumulation of the drug in the cells, its cytotoxicity and the cellular ATP levels after treatment. Significant results, like cell cycle arrest and increase of doxorubicin accumulation were reported, but they were not linked to a down regulation of protein and ATP levels. Since these effects were not maintained in time, we hypothesized that the failure in chronic treatment with delphinidin could be attributable to adaptive metabolic response. Moreover, the low stability of the molecule in aqueous solution, such as culture media, suggested a higher suitability of action in acute conditions.
b) Produce and assess different chemical and biological properties of Delphinidin-nanoparticles (DNPs) on biological samples. In particular, Transmission Electron Microscopy (TEM) and Dynamic Light Scattering (DLS) were used to measure size, dispersity and morphology. The encapsulation of delphinidin within chitosan nanoparticles was investigated through UV Resonant Raman Spectroscopy. The encapsulation efficiency of the nanoparticles was determined to be 73%, and their stability was strongly increased in comparison to the free compound. Results indicated that the DNPs are positively charged and are, therefore, an ideal carrier on targeting the colon mucosa. On different colon cancer cell lines, the DNPs treatment showed a dramatic increase of doxorubicin uptake in doxorubicin-resistant colon cells (LoVo/DX). In addition, preliminary results showed even a combined reduction of the expression of inflammatory biomarkers.
In conclusion, these results show the higher performance of DNPs for applications in cancer drug development and might give rise to a new antitumor therapeutic approach avoiding cancer multidrug resistance.
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Cheng, Yu. "Gold Nanoparticles as Drug Delivery Vectors for Photodynamic Therapy of Cancers". Case Western Reserve University School of Graduate Studies / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=case1301503263.
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Yin, Hongran. "RNA nanoparticles for anti-oncogenic miRNA and drug delivery for cancer therapy". The Ohio State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu1589836157141191.
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Madadi, Ardekani Sara. "CARBON NANOMATERIALS DERIVED FROM ORGANIC SOURCES FOR DRUG DELIVERY AND THERAPY". Thesis, The University of Sydney, 2019. http://hdl.handle.net/2123/20998.
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Remotely triggered drug delivery using nanoparticles is an area of great interest for targeted therapy to fight cancer. We developed photoresponsive nanoparticles to remotely initiate the release of doxorubicin (DOX) to 3D cultured human breast cancer cells (MCF-7) via NIR two-photon excitation (TPE) using carbon nanomaterials (CNMs). The drug loading capacity of CND-P was measured to be 0.98 w/w with the ability to release DOX via two-photon excitation (TPE). The biocompatible CNMs showed 88% cell viability at concentrations as high as 1100 μg/mL. The combined chemo and photothermal therapeutic effect of the DOX-loaded CNMs resulted in the death of 78% of the MCF-7 cells compared to 59% with DOX alone. Apart from extracellular pathogens, a common theme in the persistence of microbial infections involves intracellular survival of microbial pathogens within their host cells. To destroy such a recalcitrant pathogen, an intracellular infection of the cultured epithelial cell-line H413 with the periodontal pathogen Porphyromonas gingivalis (P. gingivalis) was used. The conjugated CNMs were rapidly internalized into the cultured cells, reaching almost 90% uptake within 3 hours of the challenge, resulting in significantly increased inhibition of intracellular P. gingivalis compared to metronidazole alone. Conjugated CNMs and the drug doxorubicin (DOX) developed to release DOX from the surface of CNMs into cell nuclei with the use of ultrasound (ULS) as a trigger. The amino-acid derived green-emitting CNMs with high quantum yield (40%) showed excellent drug loading efficiency (97% w/w). The on-demand drug release was validated by taking advantage of the fluorescent properties of the CNMs using both confocal laser scanning microscopy and time-correlated single-photon counting techniques. Exposure of conjugated CNMs to 180 s of ULS enhanced its efficiency by 26.32 % compared to DOX alone.
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Heister, Elena. "Functionalized carbon nanotubes as a multimodal drug delivery system for target cancer therapy". Thesis, University of Surrey, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.529424.
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Guo, Sijin. "RNA Nanoparticle as A Safe and Effective Drug Delivery Platform for Cancer Therapy". The Ohio State University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1561719043509709.
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Stolzoff, Michelle L. "Designing the surface properties of expansile nanoparticles for targeted cancer therapy". Thesis, Boston University, 2013. https://hdl.handle.net/2144/21256.
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Thesis (M.Sc.Eng.) PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.Nanoparticle-based drug delivery has been explored to circumvent the often-toxic chemotherapy treatments used today by providing a more efficient and specific delivery to diseased tissues. Recently we have developed polymeric pH-responsive expansile nanoparticles (eNPs) for intracellular delivery of paclitaxel (Pax) as an improvement upon the traditional methods of delivery of Pax with using Cremophor/ethanol. As eNPs are internalized by the cell, the hydrophobic protecting groups found on side chains along the polymer backbone are hydrolyzed, leaving behind hydrophilic moieties that cause the eNPs to slowly swell with water. In this manner, the encapsulation and controlled release of a hydrophobic drug can be achieved. By altering the surface characteristics of the eNPs, one can change the behavior of the delivery vehicle as well as the biological response. To explore this approach, two surfactant strategies were employed. Specifically, the original sodium dodecyl sulfate (SDS) surfactant has been substituted with PEGylated surfactants (either lipids or poloxamer) to improve circulation and in vivo stability. In addition, these surfactants were functionalized to target the folate receptor (FR), which is overexpressed in several cancers, in order to increase cancer cell-specific localization and uptake. The resulting eNPs retained their swelling characteristics while demonstrating improved cellular uptake in folate receptor-expressing KB and MDA-MB-231 carcinoma cells with no change in uptake in A549 cells, which do not express the folate receptor.
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García, Díaz María. "Drug delivery in photodynamic therapy: From pharmaceutics to animal testing". Doctoral thesis, Universitat Ramon Llull, 2012. http://hdl.handle.net/10803/81987.
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S'ha estudiat el desenvolupament de fotosensibilitzadors i la seva formulació en teràpia fotodinàmica. S'han caracteritzat les propietats fotofísiques dels fotosensibilitzadors porficènics. S'han proposat diferents estratègies tals com la introducció de grups carboxilat en la perifèria o ions de metalls pesants en el nucli, per millorar el disseny de nous fotosensibilitzadors basats en el macrocicle porficènic.
Entre ells, el temocè (m-THPPo), el porficè anàleg a la temoporfina, mostra excel•lents propietats fotofísiques, fotoestabilitat i alta eficàcia fotodinàmica. A causa de la seva alta hidrofobicitat, s'ha desenvolupat una formulació liposomal per a l'administració in vitro i in vivo del temocè. m-THPPo/DPPC/DMPG (1:67.5:7.5 relació molar) té alta eficiència d'encapsulació mantenint les seves propietats tant fotofísiques com a biològiques. El temocè liposomal va exhibir l'eficàcia fotodinàmica in vitro més alta per molècula internalitzada, sent un sistema d'administració de fàrmacs eficaç per a una estratègia in vivo dirigida a les cèl•lules tumorals. El temocè encapsulat en micel•les de Cremophor EL va mostrar una mínima internalització cel•lular. Consistentment, la formulació micel•lar va mostrar millor la resposta in vivo quan s'utilitza en un règim vascular.
Amb la finalitat de minimitzar la internalització del fotosensibilitzador en les cèl•lules normals, es van proposar liposomes decorats amb lligands folat. Aquesta estratègia resulta en una internalització dues vegades major dels liposomes dirigits al receptor folat respecte a la corresponent formulació no específica.
Finalment, han estat explorats nous models cel•lulars in vitro per a l'optimització dels processos amb oxigen singlet. Els cultius cel•lulars en 3D reprodueixen l'heterogeneïtat d'oxigen i fotosensibilitzador que està present en els teixits reals, proporcionant informació molt útil per interpretar i predir el resultat de la teràpia fotodinàmica. També s'ha demostrat la capacitat de desactivació de l'oxigen singlet d'antioxidants en un model ex vivo de pell porcina.Se ha estudiado el desarrollo de fotosensibilizadores y su formulación en terapia fotodinámica. Se han caracterizado las propiedades fotofísicas de los fotosensibilizadores porficénicos. Se han propuesto diferentes estrategias tales como la introducción de grupos carboxilato en la periferia o iones de metales pesados en el núcleo, para mejorar el diseño de nuevos fotosensibilizadores basados en el macrociclo porficénico. Entre ellos, el temoceno (m-THPPo), el porficeno análogo a la temoporfina, muestra excelentes propiedades fotofísicas, fotoestabilidad y alta eficacia fotodinámica. Debido a su alta hidrofobicidad, se ha desarrollado una formulación liposomal para la administración in vitro e in vivo del temoceno. m-THPPo/DPPC/DMPG (1:67.5:7.5 relación molar) tiene alta eficiencia de encapsulación manteniendo sus propiedades tanto fotofísicas como biológicas. El temoceno liposomal exhibió la eficacia fotodinámica in vitro más alta por molécula internalizada, siendo un sistema de administración de fármacos eficaz para una estrategia in vivo dirigida a las células tumorales. El temoceno encapsulado en micelas de Cremophor EL mostró una mínima internalización celular. Consistentemente, la formulación micelar mostró mejor la respuesta in vivo cuando se utiliza en un régimen vascular. Con el fin de minimizar la internalización del fotosensibilizador en las células normales, se propusieron liposomas decorados con ligandos folato. Esta estrategia resulta en una internalización dos veces mayor de los liposomas dirigidos al receptor folato respecto a la correspondiente formulación no específica. Por último, han sido explorados nuevos modelos celulares in vitro para la optimización de los procesos con oxígeno singlete. Los cultivos celulares en 3D reproducen la heterogeneidad de oxígeno y fotosensibilizador que está presente en los tejidos reales, proporcionando información muy útil para interpretar y predecir el resultado de la terapia fotodinámica. También se ha demostrado la capacidad de desactivación del oxígeno singlete de antioxidantes en un modelo ex vivo de piel porcina.
The photosensitizer and formulation development in photodynamic therapy have been studied. They have been characterized the photophysical properties of new porphycene-based photosensitizers. Different strategies such as the introduction of carboxylate groups in the periphery or heavy metal ions in the core have been proposed for improving the design of novel photosensitizers based on the porphycene macrocycle. Among them, temocene (m-THPPo), the porphycene analogue to temoporfin, shows excellent photophysical properties, superior photostability and high photodynamic efficiency. Owing to its high hydrophobicity, a liposomal formulation has been developed for in vitro and in vivo administration of temocene. m-THPPo/DPPC/DMPG (1:67.5:7.5 molar ratio) yielded high encapsulation efficiency maintaining its photophysical and biological properties. Liposomal temocene exhibited the highest in vitro killing efficacy per uptaken molecule and they were an efficient drug delivery system for in vivo tumor cell targeting strategy. Temocene encapsulated in Cremophor EL micelles showed minimal cell internalization. Consistently, micellar formulation showed the best in vivo response when used in a vascular regime. In order to minimize the internalization of the photosensitizer in normal cells, liposomes decorated with folic acid ligands were proposed. This strategy leads to a 2-fold higher uptake of folate-targeted liposomes than the corresponding non-targeted formulation. Finally, new in vitro cellular models for a better optimization of singlet oxygen-involved processes were explored. 3D cellular cultures reproduced the oxygen and photosensitizer heterogeneity found in real tissues, providing useful information to interpret and predict the photodynamic therapy outcome. The singlet oxygen quenching ability of antioxidants in ex vivo porcine skin model has also been demonstrated.
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Adjei, Isaac Morris. "Nanoparticle-mediated cancer therapy for primary and metastasized tumors". Case Western Reserve University School of Graduate Studies / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=case1386342707.
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Gade, Terence Peter Ferrante. "Integrated imaging of drug delivery : a molecular imaging approach to the optimization of cancer therapy /". Access full-text from WCMC:, 2007. http://proquest.umi.com/pqdweb?did=1432803381&sid=12&Fmt=2&clientId=8424&RQT=309&VName=PQD.
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Gubbins, James. "Engineering theranostic liposomes for image guided drug delivery as a novel nanomedicine for cancer therapy". Thesis, University of Manchester, 2016. https://www.research.manchester.ac.uk/portal/en/theses/engineering-theranostic-liposomes-forimage-guided-drug-delivery-as-a-novelnanomedicine-for-cancer-therapy(ce8381bb-84ee-4b9a-a96c-d09b21956c73).html.
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Cancer mortality is progression-dependent thus its treatment relies on effective therapy and monitoring of responses. Nanoparticles have long been used to improve the therapeutic index of drugs by facilitating their transit to the target site at higher concentrations than free drugs, whilst protecting healthy tissues from an often potent and cytotoxic payload. Through the EPR (enhanced permeability and retention) effect, injected, PEGylated nanoparticles preferentially accumulate in tumour tissue deeming them eminently suitable for cancer intervention for delivery of both therapeutic and contrast agents The development of theranostic liposomal systems comprising both imaging and therapeutic capabilities exploits the facets of liposomes, and forms an elegant strategy to address major problems which hinder effective cancer therapy. Liposomes can be tailored to be thermosensitive in a low hyperthermic range of ~42°C, above physiological temperature but below that which can induce tissue damage. This allows the use of heating as an external triggering modality to induce targeted drug release. Throughout the course of this work, the photoacoustic contrast agent ICG was successfully incorporated into PEGylated doxorubicin-encapsulating liposomes, marrying two FDA approved entities. The project commenced with the development of the basic liposomal-DOX. Differing lipid compositions of varying fluidities were tested against those which have been previously established. These compositions carried a range of phase transition temperatures, above which the liposomes release the encapsulated DOX. This study concluded with the generation of a library of liposomes with differing release kinetics at 42°C in simulated physiological conditions. The second section of the project investigated the methodology behind the incorporation of ICG into the liposomal bilayers. The lipid composition used for the study was based on the DOXIL® formulation, due to its robust structure and establishment in the field of cancer therapy. The protocols used varied on the basis of chronology in regards to the liposome preparation protocol. The film insertion method incorporated the ICG in initial lipid film generation. The freeze fracture protocol introduced the ICG during lipid film hydration. The post insertion protocol introduced ICG in the final stages of DOX loading. The downsizing protocol was also varied between extrusion and sonication. Through varying of the protocols and downsizing methodology, it was possible to incorporate differing ICG concentrations and attain differing levels of structural stability. The most successful liposome was then tested for its imaging potential in vivo through a photoacoustic imaging modality namely multispectral optoacoustic tomography. This validated accumulation of the liposomes at the tumour site along with co-localisation of both drug and dye. The project culminated in the combination of the two studies, producing a thermosensitive theranostic ICG labelled liposomal doxorubicin system. The system showed improved blood stability than the current clinical systems, and demonstrated imaging potential through IVIS based fluorescence imaging. Through exploitation of the photothermal effects of ICG within a thermosensitive lipid vesicle, it was also possible to induce drug release through irradiation with a non-thermal near-infrared laser. This shows promise for future therapy, allowing simultaneous imaging, optimum release induction and monitoring response to therapy, in a cheap, effective and time-efficient manner.
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Yu, Bo. "Oligonucleotide Based Liposomal Nanoparticles for Leukemia and Liver Cancer Therapy". The Ohio State University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=osu1275490450.
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Shao, Huimin. "Development of an advanced drug delivery system to prevent and treat breast cancer bone metastasis". Thesis, The University of Sydney, 2021. https://hdl.handle.net/2123/28640.
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Metastastic breast cancer is one of the leading causes of cancer death among women worldwide. Bone metastases occur most frequently among breast cancer patients that significantly influence the patients’ quality of life and reduce their survival rate. Among all types of breast cancer, triple negative breast cancer (TNBC) is more aggressive and more likely to develop metastasis. Thus, a targeted preventative modality is highly demanded for this unmet challenge. Nanoparticles have been under investigation for a few decades and have shown ample potential for the treatment of challenging types of cancer. The utilisation of nanoparticles can alter the drugs’ pharmacokinetics via different mechanisms, including improvement of the poor solubility of hydrophobic drugs and reduction of the metabolism. Curcumin, an active ingredient of the herb Curcuma longa rhizome, has been proven to have anticancer activity in various cancers. However, due to its low aqueous solubility and poor stability, the clinical application of curcumin in cancer treatment has been limited.
In this research, in order to overcome the challenges associated with the poor druggability of curcumin, we designed and fabricated two different types of nanoparticles: Pluronic® F127-based micelles (with/without D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS)) and poly (lactic-co-glycolic acid) (PLGA) -based polymeric nanoparticles (NPs) aiming at preventing and treating breast cancer bone metastasis.
A main focus of this study was the development of hybrid untargeted, mono- and dual-targeted delivery systems for curcumin. With Pluronic® F127-based micelles, a major focus went to optimise the fabrication process of the F127-TPGS NPs. The optimised fabrication method for hybrid F127-TPGS resulted in a very high reproducibility after n>3 repeats leading to a consistent size 26.42 ± 0.57 nm, zeta-potential around 0.39 ± 0.99 mV, and PDI around 0.2. The drug loading (the amount of drug loaded per unit weight of the nanoparticle) was achieved at 3.80 ± 0.18% and encapsulation efficiency (the percentage of drug that is successfully entrapped into the nanoparticles) of 63.40 ± 3.00%. Bone targeted nanoparticles exhibited a high affinity to hydroxyapatite, the mineral bone matrix indicating bone targeting potentials of these NPs. In vitro cytotoxicity studies resulted in IC50 values at low micromolar range for all nanoparticles (ranging from 5-10 µM). We further studied the in vivo antitumour and anti-metastastic activity of untargeted and bone-targeted nanoparticles fabricated with Pluronic® F127 only. The results indicated that both types of nanoparticles could improve the overall condition of tumour burdened mice and inhibit the metastases to the liver, plausibly via prevention of the tumour angiogenesis.
F127-coated PLGA-based bone-targeted nanoparticles showed size 168.00 ± 1.42 nm, zeta-potential -2.83 ± 0.22 mV, and PDI around 0.2. The loading was achieved at 0.97 ± 0.11% and encapsulation efficiency of 0.97 ± 0.11%. The results of In vitro cytotoxicity studies indicated that the alendronate conjugation in these NPs could significantly reduce the cell viability in human MDA-MB-231 TNBC cells compared to the negative control and untargeted nanoparticles (p<0.0001).
In conclusion, the hybrid Pluronic® F127-TPGS based micelles had considerably smaller size than the F127-coated PLGA based NPs. Yet, both NP sizes lie within the acceptable size range for cancer therapy. All types of NPs showed great physical stability, and biocompatibility. They could solve the poor aqueous solubility of curcumin, in addition to exerting potent antitumour effect in vitro.
The results indicated that the two types of NPs described in this research are promising carriers to be developed for the selective delivery of various poorly water-soluble drugs and have great potential for further investigation.
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Erebor, Joan Onyebuchi. "Synthesis and evaluation of targeted dendrisomes as novel gene and drug delivery systems for cancer therapy". Thesis, University of Strathclyde, 2018. http://digitool.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=30187.
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Giesen, Beatriz [Verfasser], i Ulf Dietrich [Gutachter] Kahlert. "Gold Nanoparticles as Drug Delivery Systems for Brain Cancer Therapy / Beatriz Giesen ; Gutachter: Ulf Dietrich Kahlert". Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2021. http://d-nb.info/1237883814/34.
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Traore, Mahama Aziz. "Bacteria-Enabled Autonomous Drug Delivery Systems: Design, Modeling, and Characterization of Transport and Sensing". Diss., Virginia Tech, 2014. http://hdl.handle.net/10919/64326.
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The lack of efficacy of existing chemotherapeutic treatments of solid tumors is partially attributed to the limited diffusion distance of therapeutics and the low selectivity of anti-cancer drugs with respect to cancerous tissue, which also leads to high levels of systemic toxicity in patients. Thus, chemotherapy can be enhanced through improving anti-cancer drug carrier selectivity and transport properties. Several strains of gram positive (e.g. Clostridium and Bifidobacterium) and gram-negative (e.g. Salmonella Typhimurium and Escherichia coli) bacteria have been shown to possess the innate ability to preferentially colonize tumor tissues. The overall goal of this dissertation is to characterize the transport and sensing of Bacteria-Enabled Drug Delivery Systems (BEADS) in select relevant environments and to investigate the associated underlying principles. BEADS consist of an engineered abiotic load (i.e. drug-laden micro or nano-particles) and a living component (i.e. bacteria) for sensing and actuation purposes. Findings of this dissertation work are culminated in experimental demonstration of deeper penetration of the NanoBEADS within tumor tissue when compared to passively diffusing chemotherapeutic nanoparticles. Lastly, the transport mechanisms that Salmonella Typhimurium VNP20009 utilize to preferentially colonize solid tumors are also examined with the ultimate goal of engineering intelligent and more efficacious drug delivery vehicles for cancer therapy.Ph. D.
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Dalela, Manu. "Synthesis, characterization and biological evaluation of poly(styreneco-maleic anhydride) as a drug delivery vehicle for cancer therapy". Thesis, IIT Delhi, 2016. http://localhost:8080/xmlui/handle/12345678/7037.
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BABANYINAH, GODWIN KWEKU. "Theranostic Nanoparticles Folic acid-Carbon Dots-Drug(s) for Cancer". Digital Commons @ East Tennessee State University, 2021. https://dc.etsu.edu/asrf/2021/presentations/40.
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The main aim of this study is to synthesize theranostic nanoparticles (NPs) that will drastically increase the diagnostics and therapeutic efficacy for cancer. In this research, we had prepared the NPs which constitute carbon dots (CDs), the imaging agent, Folic acid, the targeting agent, and Doxorubicin (DOX) or Gemcitabine (GEM) as the chemotherapy agents. The prepared NPs include noncovalent FA-CDs-DOX, covalent CDs-FA-DOX, and covalent FA-CDs-GEM. The spectroscopy, ultraviolet-visible spectroscopy (UV-vis), fluorescence spectroscopy, and Fourier transform-infrared spectroscopy (FT-IR), were used to confirm the successful fabrication of these complexes. Through UV-vis analysis, the drug loading capacity (DLC) and drug loading efficiency (DLE) of the complexes were determined. The noncovalent series had a higher DLE of about 83% while the covalent series showed higher DLC, 70% on average indicating high drug content. The in-vitro pH-dependent drug release shows that the noncovalent FA-CDs-DOX and the covalent FA-CDs-GEM series release more drugs into the cancer cells (pH of 5.0) than into healthy normal (pH of 7.4). The sizes of NPs were measure around 2-5 nm with Dynamic light Scattering (DLS). The toxicity of CDs, CDs-drug, and FA-CDs-drug on MDA-MB468 breast cancer cell was tested through the methylthiazolytetrazolium (MTT) assay and found that the FA bonded NPs exhibited strong therapeutic efficacy. More pharmaceutical data towards the cancer cells are investigated by our research collaborators – the pharmaceutical department at ETSU and Xavier University at Louisiana.
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Babanyinah, Godwin Kweku. "Theranostic Nanoparticles Folic Acid-Carbon Dots-Drug(s) for Cancer". Digital Commons @ East Tennessee State University, 2021. https://dc.etsu.edu/etd/3892.
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This study aims to prepare theranostic nanoparticles (NPs) that are expected to increase cancer diagnostics and therapeutic efficacy. We prepared the NPs constituting carbon dots (CDs) as an imaging agent, folic acid as a targeting agent, doxorubicin (DOX), or gemcitabine (GEM) as chemotherapy agents. The NPs include noncovalent FA-CDs-DOX, covalent CDs-FA-DOX, and covalent FA-CDs-GEM. Through ultraviolet-visible spectroscopy, fluorescence spectroscopy, and Fourier transform-infrared spectroscopy, the fabrication of these NPs was confirmed. It was discovered that the high drug loading efficiency is the noncovalent series while the high drug loading capacity is the covalent series The in-vitro pH-dependent drug release data indicate the NPs release more drugs at around pH 5.0 than at pH 7.4. The NPs sizes are between 2-5 nm. The Cell viability was investigated using the Alamar Blue assay and the three NPs complexes exhibited strong therapeutic efficacy against MDA-MB-468 breast cancer cells as compared with CDs-drug.
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Farvadi, F., A. M. Tamaddon i F. Hashemi. "PEG-grafted Hyperbranched Polyethyleneimine-Oxidized Single Walled Carbon Nanotube Complex (PEG-PEI-SWNT) for Sustained Delivery of Doxorubicin". Thesis, Sumy State University, 2012. http://essuir.sumdu.edu.ua/handle/123456789/34928.
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To take advantages of single-walled carbon nanotubes (SWNTs) for cellular delivery of chemotherapeutic
agents (e.g. doxorubicin) in order to decrease doxorubicin toxicity and increase its efficacy, we aimed to
develop a novel approach to aqueous disperse and stabilize SWNTs through consequent steps of oxidation
(oxSWNT) and PEG-PEI complexation (PEG-PEI-SWNT). Doxorubicin was loaded onto the modified
SWNTs in alkalione pH with more considerable capacity ( 900 %) than those previously reported, due to
complex formation with PEI proved by UV-visible spectroscopy. The loaded carrier was stable in physiologic
simulated medium. Drug release was prolonged and dilution independent, but exhibited pH-dependent
burst release that makes SWNTs as suitable in vivo drug carriers in acidic tumor milieu.
When you are citing the document, use the following link http://essuir.sumdu.edu.ua/handle/123456789/34928
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Martínez, Edo Gabriel. "Radial-capped mesoporous silica nanoparticles for multiple drug delivery". Doctoral thesis, Universitat Ramon Llull, 2020. http://hdl.handle.net/10803/669168.
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En la present tesi doctoral, s'ha desenvolupat un sistema d'alliberament de fàrmacs sensible a pH basat en nanopartícules mesoporoses de sílice (MSN). Els porus de la nanopartícula estan radialment obstruïts mitjançant la funcionalització de cadenes de PEG, substituïdes amb un fàrmac en un dels seus extrems. L'objectiu d'aquesta nova metodologia és la de preservar la càrrega interna d'aquestes MSN.
En primer lloc, s'ha estudiat el concepte d'obstrucció radial per avaluar la utilitat pràctica d'aquest mètode. Per aquesta raó, diferents tipus de cadenes de PEG amb càrrega, a saber, amines quaternàries i PEG neutrals, s'han funcionalitzat sobre la MSN per estudiar la seva capacitat d'obstrucció. Com a prova de concepte, s'ha estudiat l'alliberament de safranina en medi fisiològic (pH 7.4). Els resultats obtinguts han demostrat que les cadenes de PEG que contenen una càrrega positiva obstrueixen millor els porus que les cadenes de PEG neutres de la mateixa longitud.
Utilitzant aquesta aproximació, s'ha dissenyat un sistema d'alliberament de fàrmacs per a la vehiculització de camptotecina (CPT) i topotecan (TPT). En primer lloc, un dels anteriors fàrmacs s’ha adsorbit dins dels porus de la MSN. Posteriorment, els porus s’han segellat mitjançant una cadena de PEG que conté doxorrubicina (DOX) en un dels seus extrems (DOX-PEG). L'estabilitat d'aquest sistema en condicions fisiològiques prova l'eficàcia de l'obstrucció radial. D'altra banda, en condicions àcides, es produeix un alliberament descontrolat dels fàrmacs. Així mateix, els experiments de citotoxicitat in vitro han demostrat que el sistema pot alliberar CPT i DOX en les cèl·lules cancerígenes HeLa, aconseguint un major efecte sinèrgic que la combinació de TPT i DOX.
També s'ha sintetitzat un profàrmac de la CPT amb l'objectiu d'augmentar la seva càrrega en una MSN i millorar així el seu efecte sinèrgic amb la DOX. Per dur-ho a terme, s’ha unit una cadena de PEG escindible a la CPT. Emprant aquesta estratègia s'ha aconseguit carregar un 30% més de CPT a l'interior de les MSN. El sistema mostra una gran estabilitat en condicions fisiològiques, ja que s’observa un alliberament negligible dels fàrmacs. A més, s'ha avaluat la citotoxicitat de sistema en dues línies cel·lulars diferents: HeLa i HepG2. Els resultats obtinguts demostren que el nou profàrmac sintetitzat amb combinació amb la DOX té un major efecte sinèrgic en les cèl·lules HepG2.
D'altra banda, la selectivitat de les MSN cap a les cèl·lules HepG2 s'ha millorat mitjançant la funcionalització sobre el grup DOX-PEG amb el lligant àcid glicirretinic (GA). Per fer-ho, s'ha emprat la mateixa aproximació radial establerta pels altres sistemes. Els estudis d'internalització cel·lular han demostrat que aquest nou sistema és capaç de discriminar entre cèl·lules HeLa i HepG2, acumulant-se preferentment en aquestes últimes.
Finalment, s'ha avaluat un sistema d'administració triple de medicaments amb l'objectiu de superar l'efecte de resistència dels tumors a múltiples fàrmacs. Aquesta acció es pot emprendre mitjançant la combinació d’agents quimioterapèutics, DOX i CPT, amb un agent fototerapèutic (ftalocianina). Referent a això, s'ha sintetitzat un nou conjugat de la CPT amb una ftalocianina. Aquest conjugat s'ha carregat dins dels porus de la MSN i posteriorment s'han segellat amb el grup DOX-PEG. Els experiments d'internalització cel·lular han demostrat l'endocitosi d'aquest sistema en les cèl·lules HeLa i el posterior alliberament dels fàrmacs. Així mateix, s'ha avaluat in vitro l'efecte sinèrgic entre la DOX i la CPT.En la presente tesis doctoral, se ha desarrollado un sistema de liberación de fármacos sensible a pH basado en nanopartículas mesoporosas de sílice (MSN). Los poros de la nanopartícula están radialmente obstruidos mediante la funcionalización de cadenas de PEG, sustituidas con un fármaco en uno de sus extremos. El objetivo de esta nueva metodología es la de preservar la carga interna de estas MSN. En primer lugar, se ha estudiado el concepto de obstrucción radial para evaluar la utilidad práctica de este método. Por esta razón, diferentes tipos de cadenas de PEG con carga, a saber, aminas cuaternarias y PEG neutrales, se han funcionalizado sobre la MSN para estudiar su capacidad de obstrucción. Como prueba de concepto, se ha estudiado la liberación de safranina en medio fisiológico (pH 7.4). Los resultados obtenidos han demostrado que las cadenas de PEG que contienen una carga positiva obstruyen mejor los poros que las cadenas de PEG neutrales de la misma longitud. Utilizando esta aproximación, se ha diseñado un sistema de liberación de fármacos para la vehiculización de camptotecina (CPT) y topotecán (TPT). En primer lugar, uno de los anteriores fármacos se ha adsorbido dentro de los poros de la MSN. Posteriormente, los poros se han sellado mediante una cadena de PEG que contiene doxorrubicina (DOX) en uno de sus extremos (DOX-PEG). La estabilidad de dicho sistema en condiciones fisiológicas prueba la eficacia de la obstrucción radial. Por otro lado, en condiciones ácidas, se produce una liberación descontrolada de los fármacos. Asimismo, los experimentos de citotoxicidad in vitro han demostrado que el sistema puede liberar CPT y DOX en las células cancerígenas HeLa, logrando un mayor efecto sinérgico que la combinación de TPT y DOX. También se ha sintetizado un profármaco de la CPT con el objetivo de aumentar su carga en una MSN y mejorar así su efecto sinérgico con la DOX. Para llevarlo a cabo, se ha unido una cadena escindible de PEG a la CPT. Empleando esta estrategia se ha conseguido cargar un 30% más de CPT en el interior de las MSN. El sistema muestra una gran estabilidad en condiciones fisiológicas, ya que se observa una liberación negligible de los fármacos. Además, se ha evaluado la citotoxicidad del sistema en dos líneas celulares diferentes: HeLa y HepG2. Los resultados obtenidos demuestran que el nuevo profármaco sintetizado en combinación con DOX, resulta en un mayor efecto sinérgico en las células HepG2. Por otro lado, la selectividad de las MSN hacia las células HepG2 se ha mejorado mediante la introducción del ligando ácido glicirretínico (GA) sobre el grupo DOX-PEG. Para llevarlo a cabo, se ha empleado la misma aproximación radial establecida para los otros sistemas. Los estudios de internalización celular han demostrado que este nuevo sistema es capaz de discriminar entre las células HeLa y HepG2, acumulándose preferentemente en estas últimas. Finalmente, se ha evaluado un sistema de administración triple de medicamentos con el objetivo de superar el efecto de resistencia de los tumores a múltiples fármacos. Esta acción se puede emprender mediante la combinación de medicamentos quimioterapéuticos, DOX y CPT, con un agente fototerapéutico (ftalocianina). Por esta razón, se ha sintetizado un nuevo conjugado de la CPT con una ftalocianina. Dicho conjugado se ha cargado dentro de los poros de la MSN y posteriormente se han sellado con el grupo DOX-PEG. Los experimentos de internalización celular han demostrado la endocitosis de este sistema en las células HeLa y la posterior liberación de los fármacos. Asimismo, se ha evaluado in vitro el efecto sinérgico entre la DOX y la CPT.
In this PhD dissertation, a pH-responsive multiple drug delivery system (DDS) based on mesoporous silica nanoparticles (MSN) with a radial-capping of its pores has been developed. This is a new concept that relies on the functionalization of the particle surface with PEG chains substituted with a drug at its end to preserve the inner cargo of the MSN. First, the concept of radial-capping has been studied to assess the practical usefulness of such capping method. Thus, different types of charged PEGs, namely quaternary amines and neutral PEGs, have been introduced upon an MSN in order to study its capping ability. As a proof of concept, the dye safranin was loaded into the nanoparticles pores, which were subsequently capped with PEGs chains. Then, the release of safranin was assessed under physiological conditions (pH 7.4). The results obtained demonstrated that PEG chains possessing positive charge provides a more efficient capping than the neutral PEGs of the same length. Using this approach, a drug delivery system (DDS) based on the radial capping for the delivery of camptothecin (CPT) and topotecan (TPT) has been studied. CPT or TPT has been loaded within the pores of an MSN, and subsequently sealed with a PEG chain decorated with doxorubicin (DOX) at its end (DOX-PEG moiety). The system is stable under physiological conditions (pH 7.4) which confirms the effectiveness of the radial capping. On the other hand, under acidic pH, a burst release of drugs takes place. Furthermore, the in vitro cytotoxicity test has demonstrated that this DDS can effectively deliver CPT and DOX to HeLa cells achieving a better synergistic effect than the combination of TPT and DOX. With the aim to improve the loading of CPT to enhance the synergistic effect with the latter system (DOX-PEG moiety), a prodrug of CPT has been synthesised. To do so, a cleavable reductive short PEG chain has been bonded to CPT. An increase of loading of 30% has been achieved in comparison with the unmodified drug. The stability of the radial-capping methodology has been tested as mentioned above. Under physiological conditions, the release of drugs is negligible. The cytotoxicity activity of the system has been tested in two different cell lines: HeLa and HepG2 cells. The results showed a better synergistic effect of this new synthesised system towards HepG2 cells. In order to further improve the selectivity of the system towards HepG2 cells, the MSN were decorated with glycyrrhetinic acid (GA) ligand over the DOX-PEG moiety. Uptake studies have shown that this new system preferably accumulates in HepG2 cells in comparison to HeLa cells. Finally, a tri-deliver system of drugs has been developed with the aim to try to overcome the multiple drug-resistant (MDR) effect by the combination of chemotherapeutic drugs (DOX and CPT) with a phototherapeutic agent (phthalocyanine). In this regard, a new CPT conjugate with a phthalocyanine has been synthesised and loaded within the pores of an MSN. Then, the system has been sealed with the DOX-PEG moiety. The uptake studies have demonstrated the proper endocytosis of the system inside HeLa cells and the subsequent delivery of the three drugs in the cytoplasm and nucleus. Furthermore, the synergistic effect of DOX and CPT has been assessed in vitro.
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Guerrant, William. "Targeted histone deacetylase inhibition". Diss., Georgia Institute of Technology, 2012. http://hdl.handle.net/1853/44907.
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Histone deacetylase (HDAC) inhibitors (HDACi) have demonstrated a wealth of biological effects, including anti-proliferative, anti-inflammatory, anti-parasitic, and cognition-enhancing activities. The recent FDA approvals of the inhibitors SAHA and FK-228 have validated HDACi clinical use in cutaneous T cell lymphoma, while numerous clinical trials are currently ongoing using HDACi against a variety of disease states. While the future of the HDAC field looks increasingly promising, there are lingering issues hindering broader use. Recent data point to dysregulation of specific HDAC isoforms in many disease states. However, most current HDACi are pan-inhibitors, lacking the specificity to target individual isoforms. Adding to this, there are currently 18 identified HDAC isoforms, and most lack a defined crystal structure, further complicating the task of designing isoform-specific inhibitors. Most importantly, HDACi have demonstrated a lack of efficacy against solid tumors in the clinic, a major obstacle to broader use in cancer therapy. Several of these issues could more fully be addressed through specific targeting of HDACi, and could bring HDACi into wider and more efficacious pharmaceutical use. Targeting the specific tissue or organelle where HDAC dysregulation occurs could confer greater efficacy in vivo. To this end, we have created four classes of compounds: (1) aryltriazolyl HDACi that potently inhibit HDAC activity and prostate cancer cell growth, (2) dual-targeted inhibitors of Topoisomerase II and HDAC and (3) dual-targeted inhibitors of Topoisomerase I and HDAC, both of which have potent inhibition against both target enzymes as well as cancer cell lines, and finally (4) macrocyclic HDACi that potently inhibit the growth of lung cancer cell lines and preferentially target lung tissue in vivo.
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Nadal, Bufi Ferran. "Peptide-based drugs to inhibit LDH5, a potential target for cancer therapy". Thesis, Queensland University of Technology, 2022. https://eprints.qut.edu.au/232526/1/Ferran_Nadal%20Bufi_Thesis.pdf.
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This thesis investigates novel strategies to target lactate dehydrogenase 5 (LDH5), a protein involved in cancer. After decades of research without success, this thesis reports the development of the first molecules able to inhibit the activity of LDH5 with an alternative mechanism of action: disrupting its structure. To do that, an emerging class of drugs called peptides are explored. The lead peptide of this work successfully kills breast cancer cells via LDH5 inhibition. The validation of this strategy is relevant because it can be applied to many other cancer targets that have been traditionally considered “undruggable”.
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Schilb, Andrew L. "OPTIMIZATION OF NON-VIRAL GENE DELIVERY SYSTEM FOR IMAGE-GUIDED THERAPY FOR TRIPLE NEGATIVE BREAST CANCER". Case Western Reserve University School of Graduate Studies / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=case1627484657204883.
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Foy, Susan Patricia. "Multifunctional Magnetic Nanoparticles for Cancer Imaging and Therapy". Case Western Reserve University School of Graduate Studies / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=case1319836040.
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Peralta, Donna V. "Synthesis and Applications of Mutimodal Hybrid Albumin Nanoparticles for Chemotherapeutic Drug Delivery and Phototherml Therapy Platforms". ScholarWorks@UNO, 2014. http://scholarworks.uno.edu/td/1886.
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Progress has been made in using human serum albumin nanoparticles (HSAPs) as carrier systems for targeted treatment of cancer. Human serum albumin (HSA), the most abundant human blood protein, can form HSAPs via a desolvation and crosslinking method, with the size of the HSAPs having crucial importance for drug loading and in vivo performance. Gold nanoparticles have also gained medicinal attention due to their ability to absorb near-infrared (NIR) light. These relatively non-toxic particles offer combinational therapy via imaging and photothermal therapy (PPTT) capabilities.
A desolvation and crosslinking approach was employed to encapsulate gold nanoparticles (AuNPs), hollow gold nanoshells (AuNSs), and gold nanorods (AuNRs), into efficiently sized HSAPs for future tumor heat ablation via PPTT. The AuNR-HSAPs, AuNP-HSAPs and AuNS-HSAPs had average particle diameters of 222 ± 5, 195 ± 9 and 156 ± 15, respectively.
We simultaneously encapsulated AuNRs and the anticancer drug paclitaxel (PAC), forming PAC-AuNR-HSAPs with overall average particle size of 299 ± 6 nm. Loading of paclitaxel into PAC-AuNR-HSAPs reached 3μg PAC/mg HSA. PAC-AuNR-HSAPs experienced photothermal heating of 46 ˚C after 15 minutes of NIR laser exposure; the temperature necessary to cause severe cellular hyperthermia. There was a burst release of paclitaxel up to 188 ng caused by the irradiation session, followed by a temporal drug release.
AuNR-HSAPs were tested for ablation of renal cell carcinoma using NIR irradiation in vitro. Particles created with the same amount of AuNRs, but varying HSA (1, 5 or 20 mg) showed overall particle size diameters 409 ± 224, 294 ± 83 and 167 ± 4 nm, respectively. Increasing HSAPs causes more toxicity under non-irradiated treatment conditions: AuNR-HSAPs with 20 mg versus 5 mg HSA caused cell viability of 64.5% versus 87%, respectively. All AuNR-HSAPs batches experienced photothermal heating above 42 ˚C. Coumarin-6, was used to visualize the cellular uptake of AuNR-HSAPs via fluorescence microscopy.
Finally, camptothecin (CPT) an antineoplastic agent and BACPT (7-butyl-10-aminocamptothecin) were loaded into HSAPs to combat their aqueous insolubility. BACPT-HSAPs loaded up to 5.25 micrograms BACPT/ mg of HSA. CPT encapsulation could not be determined. BACPT-HSAPs and CPT-HSAPs showed cytotoxicity to human sarcoma cells in vitro.
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Lahori, Deeksha. "Combination of nitric oxide and polymer based drug delivery system to improve the effectiveness of a peptide inhibitor in cancer therapy outcomes". Thesis, University of Sydney, 2020. https://hdl.handle.net/2123/24311.
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The recent development in the field of nanotechnology offers the opportunity to alter the pharmacokinetic profiles of drugs, reducing off-target toxicity and improving therapeutic index, and ultimately patient outcome. This study aims to use a biodegradable and biocompatible material which is a modified form of the glucose polymer ‘dextran’. Aldehyde-functionalised dextran is the oxidised form of dextran to introduce aldehyde functionality for stably chemical loading therapeutic agents for its potential application in cancer treatment. Cancer is a heterogeneous disease caused by the progressive accumulation of genetic mutations in many biological processes such as apoptosis, cell cycle, cell growth and metabolic activities. Developing new therapies for cancer treatment to reduce the mortality rate is of utmost importance. Recently, cyclo-((2-Nal)-Leu-Ser-(2-Nal)-Arg) acetate pentapeptide (c2) which inhibits the enzyme involved in prostaglandin pathway has been implicated in glioblastoma, breast and prostate cancer therapy. It has passed clinical trials however poses bioavailability issues. This project addressed the solubility issue of c2 which was improved greatly using dextran-based platform as a nanocarrier system. In addition, to improve cytotoxic response of c2 in vitro, for the first time c2 was doped with small molecule nitric oxide donor (c2-NO). This project also explored the synergistic effects of c2 loaded dextran nanoparticles and nitric oxide donor molecules (c2-NO-DEX-CHO) in the treatment of glioblastoma, prostate and breast cancer cells using 2D monolayer and 3D tumor spheroids. The cytotoxicity was also assessed on the normal fetal lung fibroblast cells. In monolayers, cell viability was assessed using Alamar blue assay. Results showed a significant decrease in cell viability at higher concentrations for prostate, breast and brain cancer cell lines treated with c2 encapsulated dextran nanocarriers compared to c2 only. Moreover, there was a great reduction in cell viability and IC50 values for cells treated with c2 doped nitric oxide donor molecules and the combination of c2 conjugated dextran nanocarriers with nitric oxide compared to free c2 in glioblastoma, prostate and breast cells. This suggests that our novel formulations of modified c2 and its conjugated forms with dextran and nitric oxide donor were effective in improving its cytotoxicity in cell monolayers. The formulations were further assessed in 3D tumor spheroids, as a representative model for the tumor microenvironment over a period of 9 days. In MCF-7 tumor spheroids, a decrease in diameter was observed on day 9 with these novel formulations compared to untreated spheroids. In glioblastoma U87MG cells, the spheroid diameter gradually decreased in c2-NO and c2-NO-DEX-CHO treated cells compared to untreated cells. This shows that drug after being encapsulated in a polymeric dextran nanocarrier along with nitric oxide donor modification has been able to successfully reduce the tumor (size) meshwork and enhance its antitumor activity.
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VERDERIO, PAOLO. "Synthesis and Biofunctionalization of Novel Composite Nanocarriers for Targeted Detection and Treatment of Malignant Cells". Doctoral thesis, Università degli Studi di Milano-Bicocca, 2014. http://hdl.handle.net/10281/50789.
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At present, mammary carcinoma is the second most common type of malignant tumor in adult women after lung cancer, as more than one million women are diagnosed with breast cancer every year. Despite advances in diagnosis and treatment, which have resulted in a decrease in mortality in this decade, breast cancer remains a major public health problem. Nevertheless, the heterogeneity of human breast cancer in terms of genetic features, molecular profiles and clinical behavior represents a constraint obstructing the discovery of a solution to the disease. It is currently considered that the chances of success of therapy may increase if the tumor cells are selectively removed before they can evolve to their mature stages up to metastases production.
Recently, to overcome these hurdles, monoclonal antibodies (mAb) coupled within nanomaterials have been designed to improve tissue targeting and penetration in early diagnosis of breast cancer. Among the molecular targets considered for the treatment of breast cancer cells so far, my primary goal has been focused on two examples involving overexpression and/or gene amplification of epidermal breast cancer receptors such as “Human Epidermal growth factor Receptor 2” (HER2), transferrin receptor (TfR) and urokinase plasminogen activator receptor (uPAR) proteins.
In the first study spherical silica nanoparticles (SiNPs) have been conjugated with the anti-HER2 scFv800E6 antibody, by both oriented protein ligation and unoriented protein ligation. The targeting efficiency of nanocomplexes have been evaluated and compared with free scFv and the whole monoclonal antibody Trastuzumab (Tz) in HER2 positive breast cancer cells (MCF7). In a parallel study, we adopted the same concept optimizing the conjugation through an oriented ligation of Transferrin protein onto fluorescent SiNPs, for the selective targeting of TfR in A549 a lung cancer cell model. In a second project, multifunctional iron oxide nanoparticles (MNPs), which combine magnetic properties and fluorescence emission have been functionalized with a bimodular genetic fusion protein, called HALO–U11, comprising a small peptide of 11 amino acids (U11) that has a high affinity for uPAR receptor and the HALO protein as a nanomaterial capture module. The targeting efficiency of this system have been compared in both uPAR(+) and uPAR(−) cell lines.
In parallel to cancer diagnosis accomplished with inorganic nanomaterials, my attention turned to cancer therapy. According to this purpose, it has been developed an organic nanoformulation for drug delivery of potentially new therapeutic compounds for breast cancer. Indeed, poly(lactide-co-glycolyde) nanoparticles (PLGA NPs), the most studied polymer as tool for several drugs against different kinds of malignancies, have been developed by a single-emulsion process, with the aim to encapsulate natural and artificial curcuminoids; these molecules have been shown to possess a wide range of pharmacological activities, including anti-inflammatory, antioxidant and anticancer effects. PLGA NPs have exhibited a curcumin release following a Fickian-law diffusion over 10 days in vitro; later on, it has been investigated the possibility to study the intracellular degradation of PLGA NPs associated with a specific G2/M blocking effect on MCF7 breast cancer cells caused by curcumin release in the cytoplasm, which provided direct evidence on the mechanism of action of this nanoformulation.
In conclusion, able to provide both accurate diagnosis and effective therapy of breast cancer, novel hybrid nanostructures have being developed intensely. The goal of this approach is to obtain targeted multimodal nanoparticles capable of being vectors of therapy, a source of signals for diagnosis and monitoring of endogenous response at the same time.
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Holden, Christopher A. "MODIFIED PAMAM DENDRIMERS IN TUNABLE DRUG-DELIVERY SYSTEMS: A SUSTAINED-RELEASE DENDRIMER HYDROGEL FOR ANTI-GLAUCOMA DRUGS AND SURFACE-ENGINEERED MACROPHAGES AS NANOPARTICLE CARRIERS FOR TARGETED ANTI-CANCER THERAPY". VCU Scholars Compass, 2017. http://scholarscompass.vcu.edu/etd/5038.
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Two specific drug-delivery applications were sought in this work using polyamidoamine (PAMAM) dendrimers. One drug-delivery system used a novel dendrimer hydrogel (DH) for sustained delivery of anti-glaucoma drugs. In this work, PAMAM G3.0 dendrimers were covalently bonded with poly(ethylene glycol) (PEG12000) molecules which were subsequently acrylated, resulting in photocurable DH conjugates. For pharmacological studies, DH were loaded with a solution of intraocular pressure lowering drugs, brimonidine and timolol maleate, and were characterized for in vitro release and ex vivo transport and uptake. DH formulations were shown to increase the loading of drug molecules, increase transcorneal drug delivery, and exhibit sustained-delivery of drug molecules. A second drug-delivery system, utilizing cell-surface engineering, intended to increase the targeting ability of highly toxic anti-cancer drugs to curtail systemic effects. In particular, Qdots and 5-(aminoacetamido) fluorescein-labeled polyamidoamine dendrimer G4.5, both of which were coated with amine-derivatized polyethylene glycol, were immobilized to the sodium periodate-treated surface of RAW264.7 macrophages through a transient Schiff base linkage. Further, a reducing agent sodium cyanoborohydride was applied to reduce Schiff bases to stable secondary amine linkages. The distribution of nanoparticles on the cell surface was observed by fluorescence microscopy and was found to be dependent on the stability of the linkages tethering nanoparticles to the cell surface.
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Hervault, A. M. M. "Development of a doxorubicin-loaded dual pH- and thermo-responsive magnetic nanocarrier for application in magnetic hyperthermia and drug delivery in cancer therapy". Thesis, University College London (University of London), 2017. http://discovery.ucl.ac.uk/1566981/.
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Magnetic nanocarriers have attracted increasing attention for multimodal cancer therapy due to the possibility to deliver heat and drugs locally. The enhancement of the anti-cancer effect of chemotherapy with application of concurrent hyperthermia has been noticed more than thirty years ago. However, combining magnetic nanoparticles with drug molecules in the same nanoformulation has only recently emerged as a promising tool for the simultaneous application of hyperthermia and chemotherapy. In this work, initial experimentation was primarily focused on the synthesis of magnetic nanoparticles of high saturation magnetisation to develop efficient mediators of heat based on an iron core and a bismuth shell. However, such nanoparticles could not be obtained due to the impossibility to grow the bismuth shell on the iron nanoparticle surface. The rest of this study reports the development of a novel magnetic nanocomposites (MNCs) made of an iron oxide core and a pH- and thermo-responsive polymer shell, that can be used as both mediators of heat and drug carriers. The conjugation of the anticancer drug doxorubicin to the thermo-responsive MNCs via acid-cleavable imine linkers provides advanced features for the targeted delivery of doxorubicin via the combination of magnetic targeting, and dual pH- and thermo-responsive behaviour, which offers spatial and temporal control over the release of the drug. The nanoparticles exhibit a superparamagnetic behaviour with a saturation magnetization around 78 emu/g and good heating properties in an alternating magnetic field. Almost a complete doxorubicin release was obtained under acidic tumour pH and hyperthermia conditions. Finally, in vitro studies on human glioma and breast cancer cell lines and on a murine prostate carcinoma cell line confirmed that thermo-chemotherapy applied via the developed smart delivery system exhibits a substantial increase in cytotoxicity as compared to standalone therapies, and almost complete cell death was observed while applying low thermal and chemotherapeutic doses.
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Mott, Landon Alexander. "TOWARDS THE RATIONAL DESIGN AND APPLICATION OF POLYMERS FOR GENE THERAPY: INTERNALIZATION AND INTRACELLULAR FATE". UKnowledge, 2019. https://uknowledge.uky.edu/cme_etds/99.
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Gene therapy is an approach for the treatment of acquired cancers, infectious disease, degenerative disease, and inherited genetic indications. Developments in the fields of immunotherapies and CRISPR/Cas9 genome editing are revitalizing the efforts to move gene therapy to the forefront of modern medicine. However, slow progress and poor clinical outcomes have plagued the field due to regulatory and safety concerns associated with the flagship delivery vector, the recombinant virus. Immunogenicity and poor transduction in certain cell types severely limits the utility of viruses as a delivery agent of nucleic acids. As a result, significant efforts are being made to develop non-viral delivery systems that perform mechanistically similarly to viral delivery but lack immunogenic factors. Though safer, existing agents lack the efficacy inherent in the natural design of viral vectors. Clinical relevance of non-viral vectors will therefore depend on the ability to engineer optimized systems for cellular delivery in physiological environments.
Progress in non-viral vector design for gene delivery requires a deep understanding of the various barriers associated with nucleic acid delivery, including cell surface interaction, internalization, endosomal escape, cytosolic transport, nuclear localization, unpackaging, etc. Further, it requires a knowledge of vector design properties (surface chemistry, charge, size, shape, etc.) and how these physical parameters affect interactions with the cellular environment. Of these interactions, charge is shown to govern how particles are internalized and subsequently processed, thereby affecting the intracellular fate and efficacy of delivery. Charge also affects the in-serum stability where negative zeta potential improves stability and circulation time. Therefore, it is important to understand the effects of polyplex charge and other parameters on the internalization and intracellular fate of polyplexes for gene therapy.
In chapter 2, studies are performed to delineate the effects of polyplex charge on the cellular internalization and intracellular processing of polymer-mediated gene delivery. Charge is shown to affect the endocytic pathway involved in internalization, and the caveolin-dependent and macropinocytosis pathways lead to higher gene delivery efficacy, likely due to avoidance of acidified compartments such as late endosomes and lysosomes. In chapters 3-4, novel nanoparticles carrying DNA, RNA, and antioxidants are assessed for therapeutic effect with an emphasis on studying the internalization mechanisms and resulting effect on efficacy. Novel RNA delivery agents are shown to benefit from EGFR-targeting aptamer and nanoceria/PEI hybrids are demonstrated to provide simultaneous antioxidant and gene therapy. Finally, chapter 5 demonstrates the use of silencing RNA and CRISPR/Cas9 genome editing to study the prevalence of gene targets in vivo.
The overall goal of this work is to contribute to the design and application of novel nanoparticles for gene delivery and offer insight into the engineering of novel polyplexes. It remains clear that route of internalization is key to successful gene delivery, and designing polyplexes to enter through non-acidified endocytic pathways is highly beneficial to transgene expression. This can be achieved through incorporation of surface chemistries that trigger internalization through targeted pathways and is the source of further work in the lab.
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Wei, Tuo. "Systèmes innovants de délivrance de médicaments basés sur des nanomicelles pour le traitement du cancer". Thesis, Aix-Marseille, 2015. http://www.theses.fr/2015AIXM4031.
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Une faible biodisponibilité et une haute toxicité des médicaments anticancéreux, ajoutées à une résistance aux médicaments, constituent des obstacles majeurs pour le traitement du cancer. L'application des nanotechnologies pour la délivrance de médicaments est largement pressentie pour aborder ces problèmes. Premièrement, nous avons utilisé un peptide CRGDK comme ligand spécifique pour les cellules cancéreuses que nous avons conjugué au DSPE-PEG2000 pour préparer les nanomicelles encapsulant le médicament anticancéreux doxorubicine. Le peptide CRGDK conjugué aux nanomicelles provoque la liaison aux récepteurs à NRP-1, conduisant à l'absorption cellulaire spécifique et à l’amélioration de l'activité anticancéreuse in vitro. Les résultats in vivo ont également confirmé que les nanomicelles décorées de CRGDK pourraient efficacement pénétrer et s’accumuler dans les tumeurs profondes.Deuxièmement, nous avons a été consacrée à la mise au point de nanomicelles originales utilisant un dendrimère amphiphile (AmDM). Ces nanomicelles sont capables d’encapsuler efficacement la doxorubicine. Les taux de remplissage de ces nanomicelles sont extrêmement élevés. Ces nanomicelles montrent une efficacité supérieure à la doxorubicine libre et ceci sur divers types de cellules cancéreuses. De plus, ce mécanisme de pénétration cellulaire permet à ces nanomicelles de contourner le relargage du médicament médié par la pompe à efflux glycoprotéine, et ainsi surmonter la résistance à la doxorubicine. L’étude sur souris montre également un excellent effet anticancéreux associé à une diminution des effets toxiques de la doxorubicinePoor tumor penetration and high toxicity of anticancer drugs, together with the developed drug resistance constitute challenging hurdles for cancer therapy. The application of nanotechnology for anticancer drug delivery is expected to address these issues and bring new hope for cancer treatment. In the first part of my PhD thesis, we used a new tumor-penetrating peptide, CRGDK, to conjugate onto the surface of doxorubicin encapsulated DSPE-PEG2000 nanomicelles. The CRGDK peptide conjugated on the nanomicelles triggered specific binding to Nrp-1 receptors, leading to enhanced cellular uptake and anticancer activity in vitro. The in vivo results further confirmed that the CRGDK-decorated nanomicelles could efficiently accumulate and penetrate into deeper tumors. In the second part of my PhD thesis, we established an original nanomicellar drug delivery system based on an amphiphilic dendrimer (AmDM), which could generate supramolecular micelles to effectively encapsulate the anticancer drug doxorubicin (DOX) with high drug loading capacity (> 40%), thanks to the unique dendritic structure creating large void space for drug accommodation. The resulting AmDM/DOX nanomicelles are able to specifically accumulate at tumor sites via EPR effect and penetrate deeper into tumor tissues thanks to their small size. Most importantly, these nanomicelles exhibit significantly improved anticancer activity and reduced systemic toxicity, and are very effective even towards drug resistant cancers by virtue of their macropinocytotic cell uptake mechanism and their ability to bypass cell drug efflux pumps
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Bon, Romero Ignacio. "Development and characterization of a new hydrogel for endoscopic resection. Efficacy as a drug-delivery platform for local therapy in colorectal cancer and experimental colitis animal models". Doctoral thesis, Universitat Autònoma de Barcelona, 2019. http://hdl.handle.net/10803/667190.
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L'endoscòpia és un procediment mínimament invasiu que permet diagnosticar condicions dins del
tracte gastrointestinal, respiratori o urinari, mitjançant un endoscopi que s'insereix a través d'un orifici
corporal. Els avenços en la medicina endoscòpica han conduït al desenvolupament d'una endoscòpia
terapèutica que permet als metges tractar nombroses condicions mitjançant tècniques endoscòpiques
com l'eliminació de pòlips i tumors primerencs.
La resecció endoscòpica de lesions grans condueix a defectes extensius de la mucosa i exposició
submucosa, amb un risc substancial de complicacions (hemorràgia, estenosi i perforació), ja que els
nostres enfocaments mecànics i tèrmics actuals són ineficaços en el tancament i resolució de les
lesions produïdes per la resecció endoscòpica. D'altra banda, hi ha una creixent demanda de
procediments endoscòpics secundaris als programes de detecció colorectal, a causa de la incidència
creixent de càncer colorectal (CCR) i malaltia inflamatòria intestinal (MII) i no hi ha solució per a
l'administració sostinguda de teràpies bioactives per al tractament local de lesions inflamatòries o
tumorals.
Per resoldre aquestes necessitats de l’endoscòpia terapèutica hem desenvolupat un nou hidrogel,
Covergel, que s'aplica directament a través de l'endoscopi sobre les lesions de la mucosa després dels
procediments endoscòpics terapèutics. Covergel ha demostrat sòlides propietats curatives en models
preclínics. Covergel és biocompatible, biodegradable i bioactiu; té una viscositat i capacitat d'adhesió
apropiades, es pot aplicar fàcilment a través de l'endoscopi i promou la reepitelització fisiològica.
Aquesta composició s'ha desenvolupat buscant les substàncies i les seves proporcions que millorarien
la viscositat, l'adherència i la resistència a la degradació bacteriana. La solució optimitzada resultant
presenta la interessant propietat de convertir-se en un gel a l'entrar en contacte amb les mucoses, el
que s'aconsegueix mitjançant un augment de la seva viscositat inherent amb la temperatura. En la
seva forma de gel, el hidrogel pot romandre adherit a la mucosa durant un llarg període de temps
(almenys 36 h), actuant així com un escut per evitar lesions tèrmiques després de EMR o ESD. Hem
obtingut resultats positius en estudis de prova de concepte de lesions induïdes per dany tèrmic derivat
de EMR en rates i porcs que mostren una eficàcia estadísticament significativa en la curació de la
mucosa del nou hidrogel.
A mes a mes, també hem testat la capacitat d'administració sostinguda de fàrmacs del nostre hidrogel,
actuant com una plataforma alliberadora de fàrmacs per administrar molècules petites i anticossos
monoclonals per tractar localment les lesions de la mucosa en CRC o IBD. Els resultats obtinguts
han sigut prometedors ja que, no nomes hem demostrat que la aplicació d’una plataforma alliberadora
de fàrmacs a traves de l’endoscopi es possible, sinó que a mes a mes es efectiva en la resolució de les
malalties en els models animals testats.
Aquest estudi suposa la creació d’una nou hidrogel per a millorar l’endoscòpia terapèutica i dotar-la
de noves eines per a incrementar els casos en el que es possible fer servir endoscòpia evitant així
altres procediments terapèutics mes invasius.Endoscopy is a minimally invasive procedure that allows diagnosing conditions inside the gastrointestinal, respiratory or urinary tract, by means of an endoscope which is inserted through a body passageway. Advances in endoscopic medicine have led to the development of therapeutic endoscopy that enables physicians to treat numerous conditions using endoscopic techniques such as the removal of polyps and early tumors. Endoscopic resection of large lesions leads to extensive mucosal defects and submucosal exposure, with a substantial risk of complications (haemorrhage, stenosis and perforation), as our current mechanical and thermal approaches are ineffective in the closure and resolution of injuries produced by endoscopic resection. On the other hand, there is a growing demand for endoscopic procedures secondary to colorectal detection programs, due to the increasing incidence of colorectal cancer (CCR) and intestinal inflammatory disease (IBD). Moreover, there is no solution for sustained administration of bioactive therapies for the local treatment of inflammatory or tumoral lesions. To solve these needs of therapeutic endoscopy we have developed a new hydrogel, Covergel, which is applied directly through the endoscope on mucous lesions after endoscopic therapeutic procedures. Covergel has demonstrated solid healing properties in preclinical models. Covergel is biocompatible, biodegradable and bioactive; it has an appropriate viscosity and adhesion capacity, it can be easily applied through the endoscope and promotes physiological re-epithelialization. This composition has been developed looking for the substances and their proportions that would improve viscosity, adherence and resistance to bacterial degradation. The resulting optimized solution presents the interesting property of becoming a gel when it comes into contact with the mucous membranes, which is achieved by increasing its viscosity with temperature. In its gel form, the hydrogel can remain attached to the mucosa for a long period of time (at least 36 hours), acting as well as a shield to avoid thermal injuries after EMR or ESD. We have obtained positive results in studies of evidence of lesions induced by thermal damage derived from EMR in rats and pigs that show a statistically significant efficacy in the cure of the mucosa of the new hydrogel. In addition, we have also tested the ability of sustained drug administration of our hydrogel, acting as a drug-delivery platform to administer small molecules and monoclonal antibodies to locally treat mucous injuries in CRC or IBD. The results obtained have been promising since, not only have we shown that the application of a drug-delivery platform through the endoscope is possible but is also effective in the resolution of diseases in animal models tested. This study involves the creation of a new hydrogel to improve therapeutic endoscopy and provide it with new tools to increase the cases in which it is possible to use endoscopy thus avoiding other more invasive therapeutic procedures.
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Croissant, Jonas. "NANOMÉDECINE THÉRANOSTIQUE ACTIVÉE À DEUX-PHOTONS POUR LE TRAITEMENT DU CANCER". Thesis, Montpellier, Ecole nationale supérieure de chimie, 2014. http://www.theses.fr/2014ENCM0004/document.
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La nanomédecine activée à deux-photon est devenue l'un des principaux candidats à l'accomplissement de la sélectivité spatiotemporelle nécessaire pour la nanomédecine. En effet, la raison d'être de l'application médicale de nanotechnologie dans le domaine du traitement du cancer est de diminuer et supprimer les effets secondaires causés par les techniques actuelles telles que la chimiothérapie et la radiothérapie, à cause de leur manque de sélectivité. Parmi diverses nanoparticules (NPs), les nanoparticules de silice mésoporeuse (MSN) ont attiré une attention croissante dans la dernière décennie pour leur faible cytotoxicité, leur internalisation cellulaire et excrétion, et leur capacité de combiner de nombreuses fonctions à la fois pour le diagnostique et la thérapie de cancers via un seul nanovéhicule : l'ainsi appelée nanomédecine théranostique.Dans cette thèse, des MSN pour l'activation à un et deux-photon d'imagerie par fluorescence, de délivrance de principe actifs et d'acides nucléiques, et de photothérapie dynamique (PTD), seront présentées. Premièrement, le relargage contrôlé de molécules encapsulées dans des MSN fonctionnalisées avec des nanovalves est considéré par effet plasmonique. La photodégradation contrôlée de la silice soumise à l'effet photothermique de NPs d'or est ensuite étudiée. Deuxièmement, l'activation biphotonique est considérée pour la délivrance contrôlée de molécules anticancéreuses in-vitro par avec des nano-rotor et des nano-valves, ainsi que la fonctionnalisation de surface des NPs par des dérivés d'ammonium- azobenzene pour la délivrance d'acides nucléiques. Troisièmement, des MSN multifonctionnelles incorporant des photosensibilisateurs à deux-photon sont systématiquement étudiées en termes de leurs propriétés optiques et photophysiques; la sélection du meilleur matériau est suivie d'applications biomédicales in-vitro.De plus, deux types de nanomatériaux émergeant sont également élaborés pour la nanomédecine activée à deux-photon, des NPs de polysilsesquioxane pontés (BS) et d'organosilice mésoporeuse périodiques (PMO). Ces matériaux furent élaborés sans précurseur de silice (tétraéthoxysilane par exemple), et seulement à partir de bis- ou multi-organoalkoxysilane, afin d'obtenir le plus haut pourcentage de matière organique pour l'application ciblée. En conséquence, des NPs de BS et de PMO hybrides à base de disulfures se révélèrent être des outils biodégradables, et les NPs à base de photosensibilisateurs furent appliquées pour la PTD à deux-photon. Des NPs de BS et de cœur-coquille d'or-BS sont synthétisées pour d'efficaces imagerie et PTD à deux-photon, tandis que des NPs de PMO servirent de nano-plateformes théranostiques. En outre, diverse NPs de PMO multipodes à surface spécifique très élevées sont présentées pour la construction de structuration complexe à l'échelle nanométrique.Enfin, des nano-conteneurs d'MSN composées de cœur d'oxyde de fer (Fe3O4@MSN) sont décrites pour de multiples applications. D'une part, l'élaboration de NPs MSN (et PMO) magnétiques sensibles à deux-photon est étudiée en tant que perspective pour la délivrance de gène combinant l'imagerie par résonance magnétique. D'autre part, les conteneurs de Fe3O4@MSN sont misent en œuvre et appliqués pour la dépollution de métaux lourds via la fonctionnalisation d'un ligand de type acide diéthylène triamine penta acétique. L'augmentation de l'efficacité de la dépollution est étudiée par la fonctionnalisation de la surface extérieure et/ou des pores des Fe3O4@MSNTwo-photon actuated nanomedicine has become one of the main proponents for the achievement of the spatiotemporal selectivity needed for nanomedicine. Indeed, the raison d'être of the medical application of nanotechnology in the field of cancer treatment is to lower and suppress the side effects caused by current techniques such as chemotherapy and radiotherapy, due to their lack of selectivity. Among various nanoparticles (NPs), mesoporous silica nanoparticles (MSN) have attracted increasing attention over the past decade for their low cytotoxicity, cellular internalization and excretion, and the ability to carry multiple features for both the diagnosis and therapy of cancers in a single nanovehicle: the so-called theranostic nanomedicine.In this dissertation, I will describe MSN for one and/or two-photon-actuated fluorescence imaging, drug-delivery, gene delivery and photodynamic therapy (PDT). First, plasmonically-triggered cargo delivery via MSN nanovalves and designed mesoporous silica photodegradation is presented. Then, in-vitro two-photon-triggered drug delivery with azobenzene-functionalized MSN such as nanoimpellers and fluorescent nanovalves, along with preliminary studies of gene delivery via ammonium-functionalized nanoimpellers are discussed. Multifunctional MSN incorporating a two-photon photosensitizer are systematically studied in terms of the resulting optical and photophysical properties of the NPs, and then used for in-vitro biomedical applications.Furthermore, two kinds of emerging nanomaterials are also designed for two-photon actuated nanomedicine, bridged silsesquioxane (BS) and periodic mesoporous organosilica (PMO) NPs. These nanomaterials are elaborated without silica precursor (e.g. tetraethoxysilane) and solely with bis- or tetra-organoalkoxysilanes, thus providing materials with the highest organic content for the targeted applications. Consequently, disulfide-based hybrid BS and PMO NPs were elaborated as biodegradable nanomedical tools, and photosensitizer-based BS and PMO NPs were used for efficient in-vitro PDT. BS and gold-BS core-shells NPs are constructed for ultrabright two-photon imaging and efficient PDT, while two-photon functionalized PMO NPs serve as theranostic nanocarriers. Besides, versatile multipodal ethylene-benzene PMO NPs with very high surface areas are presented as a promising strategy for the design of structural complexities at the nanoscale.Finally, iron oxide core MSN shell (Fe3O4@MSN) nanocontainers are described for versatile applications. The design of two-photon-sensitive magnetic MSN and PMO core-shell nanovehicles is presented as a perspective for gene delivery and magnetic resonance imaging. Furthermore, Fe3O4@MSN containers are constructed for heavy metal removal of twelve of the most toxic metal ions through the diethylene triamine pentaacetic acid (DTPA) ligand. The enhancement of the pollutant removal efficiency is studied by selective surface and/or porous DTPA functionalizations
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Champeau, Mathilde. "Dissolving microneedles for an optimal transdermal delivery of an active principle used in photodynamic therapy : development and proof of concept". Thesis, Lille 2, 2020. http://www.theses.fr/2020LIL2S007.
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Les cancers de la peau de type non mélanome constituent un enjeu sanitaire majeur : l’OMS en dénombre 2 à 3 millions par an. Pour les traiter, il faut parfois recourir à une résection chirurgicale localisée. Pour éviter ce geste, la thérapie photodynamique (PDT) est un traitement alternatif intéressant. Actuellement utilisée en clinique, la PDT consiste à appliquer sur la peau lésée une crème contenant un précurseur photosensible qui après métabolisation et sous excitation lumineuse induit la mort cellulaire. Néanmoins, cette technique atteint ses limites thérapeutiques lorsque la crème ne pénètre pas dans les couches lésées et profondes de la peau. Pour améliorer la délivrance de la PDT, un patch de microaiguilles (MAs) soluble dont la longueur des MAs peut être comprise entre 400 à 750μm a été développé permettant ainsi d’atteindre l’interface épiderme/derme sans induire de douleur. L’acide hyaluronique, polymère connu pour sa biocompatibilité, solubilité et biodégradabilité, a été choisi comme matériau constitutif du patch et a été mélangé avec l’acide aminolévunique (précurseur photosensible, 5-ALA). Un procédé de fabrication simple et robuste dit de moulage a été mis en place dans une perspective de potentielle industrialisation. Du fait de l’absence d’un modèle réaliste de lésions cutanées, nous avons choisi d’en développer un sur des rats en leur appliquant des doses d’UV-B quotidiennes. Ce modèle a été validé par des études d’histologie et de pharmacocinétique et a permis de tester l’efficacité du patch in vivo. Lorsque le patch a été appliqué sur les lésions précancéreuses, il s’est dissous en 1 heure, a libéré le 5-ALA qui s’est ensuite métabolisé en protoporphyrin IX (PpIX). Un taux significatif de fluorescence dû à la PpIX a été recueilli et montre qu’après excitation lumineuse, un traitement PDT pourrait être efficace. Aussi, afin de réduire la douleur ressentie pendant une session PDT, l’illumination commencerait juste après l’application du patch pour éviter l’accumulation de PpIX et a fortiori une réaction photochimique douloureuse. De ce fait, un système lumineux dont nous avons contrôlé les propriétés optiques, thermiques et temporelles a été couplé au patch de MAs. Ce système portatif et simple d’utilisation pourrait proposer un traitement PDT tout-en-un qui répond aux critères de rapidité, d’efficacité de traitement et de confort du patientNon-melanoma skin cancers are on the rise with 2 to 3 million people diagnosed each year and are sometimes treated by local ablation therapy. To avoid this surgery, photodynamic therapy (PDT) appears as an advantageous treatment. Currently used in clinics, PDT consists of applying a cream containing a photosensitive precursor to the damaged skin, which, then metabolizes and under light excitation inducescell death. However, this technique is not fully effective if the skin lesion extends into the deep skin layers. To improve the therapeutic treatment of this type of skin cancer, a patch with dissolving microneedles (MNs) was develop to reach the deep layers of lesions that are difficult to treat. Hyaluronic acid, known for its biocompatibility, solubility and biodegradability, was chosen as the constituent material, and mixed with the 5-aminolevulinic acid (photosensitive precursor, 5-ALA). To ensure the best penetration without causing pain by touching the nerve endings, an optimal “pencil-tip” design was defined with MNs length going from 400 to 750μm. A simple and robust manufacturing process called solvent casting molding method, has been set up which is an asset for potential industrialization. In absence of realistic skin lesions model,we chose to establish one on rats skin by applying daily UV-B doses. Histology and pharmacokinetic studies validated the presence of precancerous skin lesions and the MN-patch in vivo efficiency was therefore tested. After one hour application on the injured rat skin, the MN-patch dissolved and released the 5-ALA that further metabolized to protoporphyrin IX (PpIX). A significant level of PpIX fluorescence was recorded suggesting that after light excitation, a PDT session could be effective. In parallel, to reduce pain felt during PDT treatment, a light device with suitable optical and thermal properties was conceived and coupled to the MN-patch. The idea would be to start the illumination directly after MN-patch application in order to avoid a painful photochemical reaction. This wearable and easy to use system purpose a all-in-one PDT processing which fulfills the criterion of patient compliance, better efficiency and speed of treatment
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Blaudszun, André-René [Verfasser], i Gerhard [Akademischer Betreuer] Wenz. "Ex vivo activated human T lymphocytes as living drug delivery vehicles for cancer therapy : in vitro studies with nanoparticulate idarubicin and complexed mTHPP as payload / André-René Blaudszun. Betreuer: Gerhard Wenz". Saarbrücken : Saarländische Universitäts- und Landesbibliothek, 2016. http://d-nb.info/1100061568/34.
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Thomas, Sean Casey. "A Developed and Characterized Orthotopic Rat Glioblastoma Multiforme Model". Thesis, Virginia Tech, 2020. http://hdl.handle.net/10919/100772.
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This thesis project serves to fill experimental gaps needed to advance the goal of performing pre-clinical trials using an orthotopic rat glioblastoma model to evaluate the efficacy of high-frequency electroporation (H-FIRE) and QUAD-CTX tumor receptor-targeted cytotoxic conjugate therapies, individually and in combination, in selectively and thoroughly treating glioblastoma multiforme. In order to achieve this, an appropriate model must be developed and characterized. I have transduced F98 rat glioma cells to express red-shifted firefly luciferase, which will facilitate longitudinal tumor monitoring in vivo through bioluminescent imaging. I have characterized their response to H-FIRE relative to DI TNC1 rat astrocytes. I have demonstrated the presence of the molecular targets of QUAD in F98 cells. The in vitro characterization of this model has enabled preclinical studies of this promising glioblastoma therapy in an immunocompetent rat model, an important step before advancing ultimately to clinical human trials.Master of Science
Treating glioblastoma multiforme (GBM), a form of cancer found in the brain, has not been very successful; patients rarely live two years following diagnosis, and there have been no major breakthrough advances in treatment to improve this outlook for decades. We have been working on two treatments which we hope to combine. The first is high-frequency electroporation (H-FIRE), which uses electrical pulses to kill GBM cells while leaving healthy cells alive and blood vessels intact. The second is QUAD-CTX, which combines a toxin with two types of protein that attach to other proteins that are more common on the surface of GBM cells than healthy cells. We have shown these to be effective at disproportionately killing human GBM cells growing in a lab setting. Before H-FIRE and QUAD-CTX may be tested on humans, we need to show them to be effective in an animal model, specifically rats. I have chosen rat glioma cells that will behave similarly to human GBM and a rat species that will not have an immune response to them. I have made these cells bioluminescent so that we may monitor the tumors as they grow and respond to our treatments. I have also shown that QUAD-CTX kills these rat glioma cells, as does H-FIRE. Because of this work, we are ready to begin testing these two treatments in rats.
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Babatunde, Oluwaseun Oyeniyi. "Exploring the potential of Rhodobacter sphaeroides in photodynamic therapy of tumors". Bowling Green State University / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=bgsu1624793446693196.
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Babatunde, Oluwaseun Oyeniyi. "Exploring the potential of Rhodobacter sphaeroides in photodynamic therapy of tumors". Bowling Green State University / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=bgsu1624793446693196.
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Bretin, Ludovic. "Thérapie photodynamique (PDT) dans un modèle in vitro et in vivo de cancer colorectal : utilisation d'un photosensibilisateur nanovectorisé". Thesis, Limoges, 2019. http://www.theses.fr/2019LIMO0052/document.
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Le cancer colorectal (CCR) est l’un des cancers les plus diagnostiqués dans le monde mais surtout le 2ème cancerle plus mortel. Malgré les progrès de la recherche médicale dans les traitements anticancéreux, de nombreux effetssecondaires subsistent chez les patients ainsi que l’apparition de résistances aux traitements conventionnels. Ledéveloppement de nouvelles stratégies thérapeutiques anticancéreuses est donc nécessaire afin d’améliorer la priseen charge de ces patients. La thérapie photodynamique (PDT) utilisant des photosensibilisateurs (PS) se présentecomme une stratégie thérapeutique innovante limitant fortement ces effets secondaires indésirables. La PDT a étéapprouvée pour le traitement de certains cancers grâce à la génération d’espèces réactives de l’oxygènecytotoxiques uniquement après photoactivation des PS. Cependant, une faible solubilité et un manque de sélectivitédes PS vis à vis des sites tumoraux sont les principales limites en clinique. En effet, l’administration ciblée demédicaments est un point essentiel dans la thérapie anticancéreuse. La nanomédecine par l’utilisation denanoparticules permet d’améliorer le ciblage tumoral car elles sont capables de s’accumuler spontanément dansles tumeurs solides grâce à l’effet de perméabilité et de rétention accrue. L’objectif de cette étude a été dedémontrer l’intérêt de la vectorisation de la 5-(4-hydroxyphényl)-10,15,20-triphénylporphyrine-xylane (TPPOHX)sur des nanoparticules de silice (SNPs) afin d’augmenter l’efficacité anticancéreuse par un meilleur ciblagetumoral du traitement. Il a été démontré une augmentation significative de l’efficacité anticancéreuse des TPPOHXSNPs-PDT grâce à l’amélioration de l’internalisation cellulaire par rapport à la TPPOH libre-PDT sur 3 lignéescellulaires de CCR humain. De plus, il a été caractérisé que la mort cellulaire induite par les TPPOH-X SNPs-PDTest dépendante de la voie apoptotique et que l’autophagie joue un rôle de résistance à la mort cellulaire. Par ailleurs,in vivo et en l’absence de toxicité, les TPPOH-X SNPs-PDT induisent une augmentation de l’efficacitéanticancéreuse grâce à un meilleur ciblage tumoral par rapport à la TPPOH libre-PDT. Cette étude a donc permisde démontrer l’intérêt de la combinaison de la PDT et de la nanomédecine afin d’améliorer les futurs traitementsanticancéreuxColorectal cancer (CRC) is one of the most common cancer globally but above all the second leading cause ofdeath for oncological reasons. Despite medical research advances in anti-cancer treatments, many side effectspersist in patients as well as development of resistances to conventional treatments. The development of new anticancertherapeutic strategies is necessary in order to improve care of patients. Photodynamic therapy (PDT) usingphotosensitizers (PS) comes as an innovative therapeutic strategy severely restricting these undesirable sideeffects. PDT has been approved for treatment of some cancers due to the generation of cytotoxic reactive oxygenspecies only with photoactivated PS. However, low physiological solubility and lack of selectivity towards tumorsites are the main limitations of their clinical use. Indeed, targeted drug delivery is a crucial point in cancer therapy.Nanomedicine through the use of nanoparticles improves tumor-targeting because they are able to spontaneouslyaccumulate in solid tumors through an enhanced permeability and retention effect. The purpose of this study wasto prove added value of 5-(4-hydroxyphenyl)-10,15,20-triphenylporphyrin-xylan (TPPOH-X) vectorization bysilica nanoparticles (SNPs) in order to enhance anti-cancer efficacy through better tumor-targeting. It has beendemonstrated significant anti-cancer efficacy increase of TPPOH-X SNPs-PDT thanks to cellular uptakeimprovement relative to free TPPOH-PDT in 3 human CRC cell lines. Moreover, it has been characterized thatcell death induced by TPPOH-X SNPs-PDT is conducted via apoptosis and autophagy acts as a resistance pathwayto cell death. Furthermore, in vivo and without toxicity, TPPOH-X SNPs-PDT induce an elevated anti-cancerefficacy through improvement of tumor-targeting compared to free TPPOH-PDT. This study therefore highlightedthe added value of PDT and nanomedicine combination in order to improve future cancer treatments
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Liu, Juan. "Nouveaux systèmes nanométriques et ph dépendant pour le transport de médicaments contre les phénomènes de résistances". Thesis, Aix-Marseille, 2016. http://www.theses.fr/2016AIXM4072.
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La résistance aux médicaments constitue un obstacle majeur pour le traitement du cancer. Les systèmes nanoparticulaires de délivrance de médicaments (nanoparticule drug delivery system, NDDS) sont pressentis pour apporter un nouvel espoir dans le traitement du cancer afin de surmonter la résistance aux médicaments en délivrant spécifiquement l’agent anticancéreux dans la lésion tumorale par effet EPR. Cela aura pour effet d’augmenter la concentration locale en médicaments et par conséquent d’améliorer l'efficacité thérapeutique tout en épargnant les tissus sains afin d'éviter les effets secondaires liés à la thérapie. Dans la mesure où la tumeur a souvent un microenvironnement acide, nous souhaiterions en outre doter nos nanoparticules NDDS d’une sensibilité pH-dépendante afin de permettre une délivrance spécifique dans la tumeur. Au cours de cette thèse, nous avons élaboré différents NDDSs sensibles aux variations de pH en employant des stratégies différentes. Ces NDDSs peuvent spécifiquement libérer le médicament au niveau du tissu tumoral et dans les cellules elles-mêmes à des valeurs de pH acides. En augmentant la concentration intracellulaire de médicament, l'objectif de surmonter la résistance aux médicaments pourrait ainsi être atteint. La présente étude a permis de fournir de nouvelles connaissances sur la conception de nano-transporteurs pour surmonter la résistance multidrogue par l’élaboration de NDDS sensibles au pH et constitue donc un exemple illustrant parfaitement le fait que les progrès des nanotechnologies peuvent être avantageusement mis en œuvre pour développer de nouvelles perspectives thérapeutiquesDrug resistance presents a great hurdle to cancer treatment. Nanotechnology-based drug delivery systems (NDDSs) are widely expected to bring new hope for cancer therapy to overcome drug resistance by specifically delivering anticancer drugs to tumor lesions via the EPR effect, hence increasing local drug concentrations and consequently enhancing therapeutic efficacy, and at the same time, sparing healthy tissues to avoid side effects. As tumors often have an acidic microenvironment, we would like to further endow the NDDS with a pH-responsive drug releasing property for specific tumor targeting. In this thesis, we established different pH-responsive NDDSs by employing different strategies. These NDDSs could specifically control drug release at tumor tissues and within tumor cells in response to acidic pH. By increasing the intracellular drug concentration, the goal of circumventing drug resistance in cancer was achieved. The present study provides new insights into the design of nanocarriers to overcome drug resistance through pH-responsive drug delivery, and illustrates how advances in nanotechnology can be advantageously implemented to enhance therapeutic outcomes
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Franke, Christina E. "Tobacco Mosaic Virus Nanocarrier for Restored Cisplatin Efficacy in Platinum-Resistant Ovarian Cancer". Case Western Reserve University School of Graduate Studies / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=case1493810190306879.
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