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Artykuły w czasopismach na temat "DRUG LEADS TARGETING"
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Zhu, W., Y. Zhang, W. Sinko, M. E. Hensler, J. Olson, K. J. Molohon, S. Lindert i in. "Antibacterial drug leads targeting isoprenoid biosynthesis". Proceedings of the National Academy of Sciences 110, nr 1 (17.12.2012): 123–28. http://dx.doi.org/10.1073/pnas.1219899110.
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Chaitanya, MVNL, Asha Jose, P. Ramalingam, SC Mandal i PNarendra Kumar. "Multi-targeting cytotoxic drug leads from mushrooms". Asian Pacific Journal of Tropical Medicine 12, nr 12 (2019): 531. http://dx.doi.org/10.4103/1995-7645.272482.
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Kumar, Bhumika, Mukesh Pandey, Faheem H. Pottoo, Faizana Fayaz, Anjali Sharma i P. K. Sahoo. "Liposomes: Novel Drug Delivery Approach for Targeting Parkinson’s Disease". Current Pharmaceutical Design 26, nr 37 (26.10.2020): 4721–37. http://dx.doi.org/10.2174/1381612826666200128145124.
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Parkinson’s disease is one of the most severe progressive neurodegenerative disorders, having a mortifying effect on the health of millions of people around the globe. The neural cells producing dopamine in the substantia nigra of the brain die out. This leads to symptoms like hypokinesia, rigidity, bradykinesia, and rest tremor. Parkinsonism cannot be cured, but the symptoms can be reduced with the intervention of medicinal drugs, surgical treatments, and physical therapies. Delivering drugs to the brain for treating Parkinson’s disease is very challenging. The blood-brain barrier acts as a highly selective semi-permeable barrier, which refrains the drug from reaching the brain. Conventional drug delivery systems used for Parkinson’s disease do not readily cross the blood barrier and further lead to several side-effects. Recent advancements in drug delivery technologies have facilitated drug delivery to the brain without flooding the bloodstream and by directly targeting the neurons. In the era of Nanotherapeutics, liposomes are an efficient drug delivery option for brain targeting. Liposomes facilitate the passage of drugs across the blood-brain barrier, enhances the efficacy of the drugs, and minimize the side effects related to it. The review aims at providing a broad updated view of the liposomes, which can be used for targeting Parkinson’s disease.
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Suresh, Amaroju, Singireddi Srinivasarao, Yogesh Mahadu Khetmalis, Shashidhar Nizalapur, Murugesan Sankaranarayanan i Kondapalli Venkata Gowri Chandra Sekhar. "Inhibitors of pantothenate synthetase of Mycobacterium tuberculosis – a medicinal chemist perspective". RSC Advances 10, nr 61 (2020): 37098–115. http://dx.doi.org/10.1039/d0ra07398a.
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Tuberculosis, leads to numerous deaths worldwide. New drug discovery strategies are need of the hour. In the current review, we focused on the discovery of new antitubercular drugs targeting pantothenate synthetase.
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Singh, Vijai, i Pallavi Somvanshi. "Targeting the Peptide Deformylase of Mycobacterium tuberculosis Leads to Drug Discovery". Letters in Drug Design & Discovery 6, nr 7 (1.10.2009): 487–93. http://dx.doi.org/10.2174/157018009789108286.
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Pal, Rahul, Saif Hameed i Zeeshan Fatima. "Iron Deprivation Affects Drug Susceptibilities of Mycobacteria Targeting Membrane Integrity". Journal of Pathogens 2015 (2015): 1–10. http://dx.doi.org/10.1155/2015/938523.
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Multidrug resistance (MDR) acquired byMycobacterium tuberculosis(MTB) through continuous deployment of antitubercular drugs warrants immediate search for novel targets and mechanisms. The ability of MTB to sense and become accustomed to changes in the host is essential for survival and confers the basis of infection. A crucial condition that MTB must surmount is iron limitation, during the establishment of infection, since iron is required by both bacteria and humans. This study focuses on how iron deprivation affects drug susceptibilities of known anti-TB drugs inMycobacterium smegmatis, a “surrogate of MTB.” We showed that iron deprivation leads to enhanced potency of most commonly used first line anti-TB drugs that could be reverted upon iron supplementation. We explored that membrane homeostasis is disrupted upon iron deprivation as revealed by enhanced membrane permeability and hypersensitivity to membrane perturbing agent leading to increased passive diffusion of drug and TEM images showing detectable differences in cell envelope thickness. Furthermore, iron seems to be indispensable to sustain genotoxic stress suggesting its possible role in DNA repair machinery. Taken together, we for the first time established a link between cellular iron and drug susceptibility of mycobacteria suggesting iron as novel determinant to combat MDR.
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Jonchere, Barbara, Jennifer Stripay, Allison Pribnow, Frederique Zindy, Jaeki Min, Burgess Freeman, Anang Shelat, Zoran Rankovic i Martine Roussel. "PDTM-02. TARGETING THE RB PATHWAY IN MEDULLOBLASTOMA". Neuro-Oncology 21, Supplement_6 (listopad 2019): vi187. http://dx.doi.org/10.1093/neuonc/noz175.778.
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Abstract Medulloblastoma (MB), the most common malignant pediatric brain tumor, is classified into four major molecularly and histopathologically distinct subgroups, among which MYC-driven Group 3 MBs confer a poor prognosis. The Cyclin D/CDK4/CDK6/RB pathway is frequently deregulated in MB leading to uncontrolled cell proliferation, but tumors express an intact RB protein (Northcott et al., Nature, 2017). Therefore, CDK4/6 inhibitor drugs offer a possible therapeutic approach to treat MBs. Because single agent therapy ultimately leads to drug resistance, we initiated in vitro combination drug screens to identify drug classes potentiating CDK4/6 inhibitors. We used Group 3 MB patient-derived orthotopic xenografts (PDOXs), a human cell line (HDMB03), and freshly dissociated tumor cells propagated only in the mouse brain. The drug screen included 90 compounds comprising targeted and cytotoxic drugs that are FDA approved or under active clinical investigation. Using a bioluminescence-based assay that measures ATP consumption (CellTiter-Glo) to evaluate the number of viable cells, these 90 compounds were screened in combination with a fixed concentration of ribociclib, one of the three FDA approved CDK4/6 inhibitors. The primary screen, carried out in HDMB03 cells, revealed several drugs with additive or synergistic potential when combined with ribociclib, including BET inhibitors, MEK inhibitors, PI3K/mTOR inhibitors and gemcitabine. We are currently evaluating the combination of brain penetrant compounds in Group 3 MB PDOXs. The identification of potent drug combinations should provide new therapeutic options for the treatment of Group 3 MB, one of the most difficult to treat.
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Ojima, Iwao. "Tumor-targeting drug delivery of chemotherapeutic agents". Pure and Applied Chemistry 83, nr 9 (24.06.2011): 1685–98. http://dx.doi.org/10.1351/pac-con-11-02-10.
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Despite the significant progress in the development of cancer detection, prevention, surgery, and therapy, there is still no common cure for this disease. In addition, the long-standing problem of chemotherapy is the lack of tumor-specific treatments. Traditional chemotherapy relies on the premise that rapidly proliferating cancer cells are more likely to be killed by a cytotoxic agent. In reality, however, cytotoxic agents have very little or no specificity, which leads to systemic toxicity, causing undesirable severe side effects. Therefore, various “molecularly targeted cancer therapies” have been developed for use in specific cancers, including tumor-targeting drug delivery systems (TTDDS). In general, a TTDDS consists of a tumor recognition moiety and a cytotoxic “warhead” connected through a “smart” linker to form a conjugate. When a multi-functionalized nanomaterial is used as the vehicle, a “Trojan horse” approach becomes possible for mass delivery of cytotoxic warheads to maximize the efficacy. This account presents the progress in the molecular approaches to the design and development of novel drug delivery systems for tumor-targeting chemotherapy in our laboratory.
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Srikanth A, Shivakmar T, Shankar Sheshu R i Selva kumar S. "Molecular modelling and evaluation of antihyperthyroid drug compound". International Journal of Review in Life Sciences 9, nr 4 (27.12.2019): 30–32. http://dx.doi.org/10.26452/ijrls.v9i4.1350.
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Drug targeting will play an essential function in drug discovery in the coming years, as the amount of structural records on protein targets keeps to rise. However, the conventional technique of drug discovery, primarily based upon random screening and systematic amendment of leads through medicinal chemistry strategies, will probably no longer to be deserted absolutely because it has doubtlessly vital advantages over shape-based strategies-specifically leads diagnosed in this way are unlikely to show a near resemblance to the herbal Ligand or substrate. They might also have gained in terms of patent novelty and selectivity. Such leads could then function the basis of structure-based totally, rational amendment programs, wherein their interactions with target receptors are described and improved molecules are designed. In the present study, an attempt is made to find suitable and better analogues of drugs used in the treatment of hyperthyroidism.
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Kaminska, Kamila K., Helene C. Bertrand, Hisashi Tajima, William C. Stafford, Qing Cheng, Wan Chen, Geoffrey Wells, Elias S. J. Arner i Eng-Hui Chew. "Indolin-2-one compounds targeting thioredoxin reductase as potential anticancer drug leads". Oncotarget 7, nr 26 (24.05.2016): 40233–51. http://dx.doi.org/10.18632/oncotarget.9579.
Pełny tekst źródłaRozprawy doktorskie na temat "DRUG LEADS TARGETING"
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Sandhaus, Shayna. "Drug Candidate Discovery: Targeting Bacterial Topoisomerase I Enzymes for Novel Antibiotic Leads". FIU Digital Commons, 2017. https://digitalcommons.fiu.edu/etd/3561.
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Multi-drug resistance in bacterial pathogens has become a global health crisis. Each year, millions of people worldwide are infected with bacterial strains that are resistant to currently available antibiotics. Diseases such as tuberculosis, pneumonia, and gonorrhea have become increasingly more difficult to treat. It is essential that novel drugs and cellular targets be identified in order to treat this resistance. Bacterial topoisomerase IA is a novel drug target that is essential for cellular growth. As it has never been targeted by existing antibiotics, it is an attractive target. Topoisomerase IA is responsible for relieving torsional strain on DNA by relaxing supercoiled DNA following processes such as replication and transcription. The aim of this study is to find novel compounds that can be developed as leads for antibiotics targeting bacterial type IA topoisomerase. Various approaches were used in order to screen thousands of compounds against bacterial type IA topoisomerases, including mixture-based screening and virtual screening. In the mixture-based screen, scaffold mixtures were tested against the M. tuberculosis topoisomerase I enzyme and subsequently optimized for maximum potency and selectivity. The optimized compounds were effective at inhibiting the enzyme at low micromolar concentrations, as well as killing the tuberculosis bacteria. In a virtual screen, libraries with hundreds of thousands of compounds were screened against the E. coli and M. tuberculosis topoisomerase I crystal structures in order to find new classes of drugs. The top hits were effective at inhibiting the enzymes, as well as preventing the growth of M. smegmatis cells in the presence of efflux pump inhibitors. Organometallic complexes containing Cu(II) or Co(III) were tested as well against various topoisomerases in order to determine their selectivity. We discovered a poison for human type II topoisomerase that has utility as an anticancer agent, as it killed even very resistant cell lines of breast and colon cancer. The Co(III) complexes were found to inhibit the bacterial topoisomerase I very selectively over other topoisomerases. The various methods of drug discovery utilized here have been successful at identifying new classes of compounds that may be further developed into antibiotic drugs that specifically target bacterial type IA topoisomerases.
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Mateo, Campins Patricia. "Recerca i caracterització de nous "leads" per al tractament del càncer". Doctoral thesis, Universitat de Barcelona, 2018. http://hdl.handle.net/10803/663545.
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La present tesi doctoral està enfocada al desenvolupament de noves petites molècules dirigides a diferents dianes del càncer. Els descobriments recents sobre la seqüenciació genòmica del càncer han revelat que molts dels gens involucrats en la regulació de la cromatina que modifiquen histones es troben sovint mutats en múltiples tipus de càncer. Entre aquests modificadors d'histones, els complexes multiproteics anomenats Polycomb Repressive Complex (PRC) estan implicats en el silenciament epigenètic, alterant principalment l'estructura de la cromatina, la pluripotència de cèl·lules mare i l'expressió de gens específics involucrats en la diferenciació i el desenvolupament cel·lulars. En particular, el component catalític del PRC2 anomenat Enhancer of Zeste Homolog 2 (EZH2) destaca per la seva sobreexpressió en diversos tipus de càncer i els seus reguladors semblen ser crítics per a la proliferació cel·lular, la formació tumoral i el manteniment de la funció de cèl·lules mare. A més a més, es pretén desenvolupar compostos multidiana que, inhibint enzims essencials per a la progressió i el desenvolupament del càncer, mostrin selectivitat per les cèl·lules cancerígenes amb l'objectiu de reduir els efectes adversos.
S'han posat a punt tres rutes sintètiques diferents: la preparació de derivats d'1,4-benzodioxà, la preparació d'intermedis de diarilamina i la preparació de diarilèters. Tots els compostos han estat sintetitzats mitjançant reaccions orgàniques clàssiques, han estat purificats utilitzant tècniques de separació comunes (cromatografia) i la seva elucidació estructural ha estat possible gràcies a les tècniques de Ressonància Magnètica Nuclear (RMN), Espectroscòpia de masses (EM) i Espectroscòpia d'Infraroig (IR).
Per tal d'avaluar les activitats biològiques dels compostos preparats, els laboratoris Eli Lilly han dut a terme un cribratge d'alt rendiment sobre diferents desordres (càncer, autoimmunitat, neurodegeneració i dolor, malalties endocrines i cardiovasculars, etc.). Addicionalment, s'han realitzat assajos MTT sobre línies cel·lulars d'osteosarcoma, atesa la relació significativa entre l'expressió d'EZH2 i l'augment de l'agressivitat i el mal pronòstic de l'osteosarcoma descrita en diversos estudis. Per tant, una teràpia epigenètica dirigida específicament a l'EZH2 podria constituir una nova aproximació per al tractament de l'osteosarcoma.This doctoral thesis focuses on the development of new small molecules against different cancer targets. Recent findings arisen from human cancer genome sequencing have revealed that many genes involved in the regulation of chromatin that modify histones are often mutated in a wide variety of cancers. Among these histone modifiers, multiproteic complexes named Polycomb Repressive Complex (PRC) are implicated in epigenetic silencing mainly affecting the structure of chromatin, stem cell pluripotency and expression of specific genes involved in cell differentiation and development. In particular, the catalytic component of PRC2 called Enhancer of Zeste Homolog 2 (EZH2) has drawn special attention since its overexpression has been found in several cancer types and its regulators seem to be critical for cellular proliferation, tumour formation and stem cell function maintenance. Moreover, we are looking for multitarget compounds that inhibit essential enzymes for cancer progression and development that show selectiveness against cancerous cells in order to reduce side effects. Three different synthetic routes have been set: preparation of 1,4-benzodioxan derivatives, preparation of diarylamine intermediates and preparation of diarylethers. All compounds have been prepared using classic organic reactions, purified using common separation techniques (chromatography) and their structure elucidation has been carried out through Nuclear Magnetic Resonance (NMR), Mass Spectroscopy (MS) and Infrared Spectroscopy (IS). In order to assess their biological activities, a high throughput screening has been performed at Eli Lilly laboratories over different disorders (cancer, autoimmunity, neurodegeneration and pain, endocrine and vascular diseases, etc.). In addition, MTT assays have been performed in osteosarcoma cell lines since diverse studies suggest that EZH2 expression is significantly associated with more aggressive osteosarcoma tumour behaviour and poorer patient outcome. Thus, an epigenetic therapy that pharmacologically targets EZH2 via specific inhibitors may constitute a novel approach to the treatment of osteosarcoma.
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Hu, Yanmei, Jiantao Zhang, Rami Musharrafieh, Raymond Hau, Chunlong Ma i Jun Wang. "Chemical Genomics Approach Leads to the Identification of Hesperadin, an Aurora B Kinase Inhibitor, as a Broad-Spectrum Influenza Antiviral". MDPI AG, 2017. http://hdl.handle.net/10150/626106.
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Influenza viruses are respiratory pathogens that are responsible for annual influenza epidemics and sporadic influenza pandemics. Oseltamivir (Tamiflu((R))) is currently the only FDA-approved oral drug that is available for the prevention and treatment of influenza virus infection. However, its narrow therapeutic window, coupled with the increasing incidence of drug resistance, calls for the next generation of influenza antivirals. In this study, we discovered hesperadin, an aurora B kinase inhibitor, as a broad-spectrum influenza antiviral through forward chemical genomics screening. Hesperadin inhibits multiple human clinical isolates of influenza A and B viruses with single to submicromolar efficacy, including oseltamivir-resistant strains. Mechanistic studies revealed that hesperadin inhibits the early stage of viral replication by delaying the nuclear entry of viral ribonucleoprotein complex, thereby inhibiting viral RNA transcription and translation as well as viral protein synthesis. Moreover, a combination of hesperadin with oseltamivir shows synergistic antiviral activity, therefore hesperadin can be used either alone to treat infections by oseltamivir-resistant influenza viruses or used in combination with oseltamivir to delay resistance evolution among oseltamivir-sensitive strains. In summary, the discovery of hesperadin as a broad-spectrum influenza antiviral offers an alternative to combat future influenza epidemics and pandemics.
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McGinley, Susan. "New Leads for Cancer Drugs: Targeting a Specific Biochemical Pathway in Tumors". College of Agriculture and Life Sciences, University of Arizona (Tucson, AZ), 2007. http://hdl.handle.net/10150/622135.
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Ibba, Roberta. "Antiviral drug discovery: from synthesis of virus-targeting molecules to fragment-based lead discovery for a novel host target". Doctoral thesis, Università degli Studi di Cagliari, 2020. http://hdl.handle.net/11584/284395.
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Antiviral Drug Discovery is still a great challenge due to the virus's ability to mutate in order to survive and the continuous discovery of new pathogen viruses. Viral infection is caused by the presence of a virus in the body. Antivirals are compounds, either chemically synthesised or produced by a living organism, that inhibit viral infection and replication. Antivirals interfere with one or more of the virus replication cycle stage. Based on their inhibitory mechanism, antivirals can be divided into two groups: inhibitors that target the viruses (VTAs) or inhibitors that target host cell factors (HTAs). In this thesis newly synthesised VTAs are presented, a host cell target has been studied and assessed as potential antiviral target and the results of Fragment-Based Lead Discovery project is presented, and in the last part of the thesis, synthesis of small antiviral molecules and investigation of the target are described.
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GUPTA, ANKITA. "COMPUTATIONAL CHARACTERIZATION OF NON-ACTIVE SITE MUTATION V77I IN HIV-1 PROTEASE: POSSIBLE CONTRIBUTION TO NELFINAVIR RESISTANCE AND DEVELOPMENT OF NEW DRUG LEADS TARGETING HIV-1 PROTEASE". Thesis, 2016. http://dspace.dtu.ac.in:8080/jspui/handle/repository/16058.
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BACKGROUND
The Human immunodeficiency virus (HIV-1) protease is an attractive target for antiviral treatment and a number of therapeutically useful inhibitors have been designed against it. The emergence of drug resistant mutants of HIV-1 pose a serious problem for the conventional therapies been used so far. Here we have tried to study the effect of V77I mutation along with the co-occurring mutations L33F and K20T through multinanosecond molecular dynamics simulations. V77I is known to cause Nelfinavir (NFV) resistance in subtype B population of HIV-1 protease. We have reported the effect of this clinically relevant mutation on the binding of NFV and the conformational flexibility of the protease, and tried to generate derivates of potent drug Nelfinavir which can efficiently inhibit the wild and mutant proteases.
RESULT The study proposes that V77I-L33F mutant (DBM) showed greater flexibility and the flap separation was more with respect to the wild protease. The cavity size of stabilized DBM was also found to be increased which is responsible for the decreased interaction of Nelfinavir with all the cavity residues and hence decreased its binding affinity (Glide XP score: wild= -9.3, DBM= -7.8). On the other hand the binding affinity of V77I-L33F-K20T mutant (TPM) was found to be increased for Nelfinavir (Glide XP score= -10.3). The flap separation of TPM was less and the cavity size had also reduced with respect to wild protease.
CONCLUSION The resistant mutations had made DBM more stable in environment whereas the addition of third mutation K20T had made the protease TPM more susceptible to Nelfinavir. This lowered resistance can be the reason behind the less clinical relevance of TPM.
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Paterna, Angela. "Indole alkaloids as leads for developing effective anticancer drugs targeting multidrug resistant cancer cells". Doctoral thesis, 2017. http://hdl.handle.net/10451/28894.
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Tese de doutoramento, Química Farmacêutica e Terapêutica, Universidade de Lisboa, Faculdade de Farmácia, 2017Multidrug resistance (MDR) is the major obstacle for cancer chemotherapy. MDR is a multifactorial phenomenon that can result from several mechanisms, including an increased drug efflux, due to overexpression of ABC drug transporter proteins (P-gp, MRP1 and ABCG2), which transport anticancer drugs out of the cells, or a failure to undergo apoptosis. The development of ABC transporter inhibitors is a promising approach for overcoming MDR. The discovery of collateral sensitivity agents (CS) and the development of effective apoptosis inducers have also been considered realistic strategies. Thus, the main goal of this work was to find out new effective anticancer indole alkaloids from African plants (Apocynaceae and Rubiaceae families), targeting MDR cancer cells. The phytochemical study of the alkaloid fraction of the methanol extract of Tabernaemontana elegans yielded three novel (4-6) and five known (7-11) bisindole alkaloids of the vobasinyl-iboga type and three monoterpene indole alkaloids of the corinanthe type (1-3). Moreover, aiming at generating a small library of monoterpene indole alkaloids, the chemical derivatization of the two epimeric monoterpene indole alkaloids dregamine (1) and tabernaemontanine (2),isolated in large amount from this species, allowed the preparation of 47 derivatives. In this way, the chemical transformation of the ketone group at C-3 of both compounds (1 and 2) afforded several aromatic and aliphatic imines (1.1-1.8 and 2.1-2.6) and azines (1.16-1.27 and 2.9-2.20), a thioketone (1.9), alcohols (1.10 and 2.7), and esters (1.11 and 2.8). The N-acyl/alkylated compounds 1.12 1.15 were also obtained. From the alkaloid fraction of the methanol extract of Voacanga thouarsii, one new monoterpene indole alkaloid (16) of the iboga type and four known (12-15), along with one indole alkaloid of the sarpagine type (17) were isolated. Moreover, a new phenol, 3,4,5-trimethoxyphenol-1-O-β-D-glucopyranosyl-4′,6′-O-(E)-dicoumaroyl ester (19), and several known phenolic compounds (18, 20-22), one steroid (23) and one triterpene (24) were also obtained. The phytochemical study of Psychotria capensis yielded two norisoprenoids (28-29) and three phenolic compounds (25-27). The structures of the compounds were established from their physical and spectroscopic data (IR, MS, 1D and 2D NMR -COSY, HMBC, HMQC and NOESY-experiments). The indole alkaloids 4-8, 9, 1.1-1.5 and 2.1-2.5 were evaluated for their ability as apoptosis inducers in HCT116, and SW620 colon and HepG2 liver cancer cells. The cytotoxicity of the compounds was evaluated in the three cell lines by the MTS and lactate dehydrogenase assays. The apoptosis induction studies included Guava ViaCount flow cytometry assays, nuclear morphology evaluation by Hoechst staining, and caspase-3/7 activity assays. To explore the association of compounds-induced growth inhibition with regulation of cell cycle progression, the cellular DNA content was determined by flow cytometry, analysing the percentage of cells in different phases of the cell cycle. Moreover, in order to determine the molecular pathways by which compounds exerted their pro-apoptotic effect, key apoptosis proteins were evaluated by immunoblot analysis, using total protein extracts from HCT116, SW620 or HepG2 cells exposed to compounds. The most significant results were obtained for some hydrazones (1.4, 2.2 and 2.4) and several bisindole alkaloids (4-7 and 9). Structure-activity relationships for compounds 1, 2 and their derivatives (1.1-1.5 e 2.1-2.5) showed that the replacement of the carbonyl group of the parent compounds 1 and 2 by a hydrazone moiety, bearing a bromo-pyridine (1.4 and 2.4) or a phenyl group (2.2) seems to be responsible for their activity, which might also depend on the stereochemistry of the tetrahedral stereocenter at C-20. The induced inhibition of proliferation of HCT116 cells by bisindole alkaloids 4 and 5 was associated with G1 phase arrest, while bisindole alkaloids 6 and 9 induced G2/M cell cycle arrest. In addition, immunoblot analysis showed that exposure to compound 7 reduced the expression of anti-apoptotic proteins in the tree cell lines. The monoterpene indole alkaloids 1, 2 and their derivatives 1.1-1.15, 2.1-2.8 were also evaluated for their effects on the reversion of MDR in cancer cells mediated by P-glycoprotein using a human ABCB1-transfected mouse T-lymphoma cell model. SAR analysis showed that different substituents at C-3 and at the indole nitrogen led to different ABCB1 modulatory effects. A remarkable enhancement in MDR reversal activity was found for the imine derivatives 1.4, 1.7, 2.3 and 2.4, sharing a new aromatic moiety. Some of these indole alkaloids (1.2-1.4, 1.7-1.9, 1.12, 1.13 e 2.2-2.4) were assayed for their antiproliferative effects in combination with doxorubicin; the results showed that the tested compounds synergistically enhanced the effect of the antitumor drug. The anti-MDR reversal activity of azine derivatives (1.16-1.27 and 2.9-2.20) was evaluated using as models transfected cancer cells NHI-3T3 overexpressing P-gp, and a transfected HEK293 cell line overexpressing either MRP1 or ABCG2. In both cancer cell lines overexpressing P-gp or MRP1, a considerable MDR reversing activity was observed for compounds with an aromatic azine moiety. The strongest activity as P-gp inhibitors was found for the epimeric azines 1.16 and 2.9, which were found to be selective for this transporter. Instead, compounds 1.22 and 2.15 inhibited selectively MRP1 drug-efflux. No compound was able to inhibit ABCG2. Azine derivatives (1.16-1.27 and 2.9-2.20) were also evaluated as collateral sensitivity agents. Compounds 2.12, with an aromatic azine moiety at C-3, and compounds 1.24, 1.25, 2.17 and 2.18, sharing a new aliphatic -C=N-N=C-R at this carbon, were considered CS agents killing selectively BHK-21-MRP1 overexpressing cells. Among the compounds with selective cytotoxic activity against cancer cells overexpressing MRP1, compounds 1.23-1.25 were able to increase the depletion of glutathione by MRP1, thus triggering cell death through apoptosis. In conclusion, several indole alkaloids of both natural origin or obtained by derivatization are promising potential lead structures as MDR reversers.
Fundação para a Ciência e a Tecnologia (FCT), projeto, PTDC/QEQ-MED/0905/2012
Książki na temat "DRUG LEADS TARGETING"
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Divan, Aysha, i Janice A. Royds. 7. Molecular biology in the clinic. Oxford University Press, 2016. http://dx.doi.org/10.1093/actrade/9780198723882.003.0007.
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Environmental agents can cause genetic and epigenetic changes to DNA, the consequences of which lead to deregulation of cellular processes and pathways that cause disease. Genetic variation can either be inherited if acquired through the germline or non-heritable when the DNA changes occur in somatic (body) cells. ‘Molecular biology in the clinic’ discusses two key contemporary areas of clinical research that have benefited from an improved knowledge of their molecular basis: ageing and cancer. It shows that we are now better able to predict disease risk and design drugs that have higher clinical efficacy by targeting specific molecular pathways.
Części książek na temat "DRUG LEADS TARGETING"
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Prakash, Om, i Feroz Khan. "CoSSDb: A Database of Co-crystallized Ligand Sub-structures for Anticancer Lead Designing & Optimization". W Proceedings of the Conference BioSangam 2022: Emerging Trends in Biotechnology (BIOSANGAM 2022), 133–41. Dordrecht: Atlantis Press International BV, 2022. http://dx.doi.org/10.2991/978-94-6463-020-6_14.
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AbstractThe Discovery of the novel optimized structures of small molecules for selective targeting is one of the challenging tasks in drug designing. Bioisosteres are the key components of the lead compound, which provide hidden power to the compound scaffold for selective targeting. We are presenting a database, named CoSSDb which stands for Co-crystallized Sub-Structure Database. The CoSSDb contains ligand sub-structures as possible bioisosteres. extracted from PDB files, available in Protein Data Bank. Sub-structures were extracted through an algorithm, which utilizes the location of atoms in the 3D domain of the complex ligand & protein. It processes the relative positioning of atoms for demarcation of the influential part of the ligand, which interacts with macromolecule and provides potency to that ligand for binding with a specific binding pocket of the protein. The algorithm was used to extract sub-structures from the ligands co-crystallized with proteins involved in cancer. About 7721 x-ray crystallography PDB files were processed, and 654 non-redundant substructures were identified. These sub-structures will be useful during designing & optimization of novel ligands for selective targets. The database is freely accessible at ‘https://opticket49.wixsite.com/substructdb’.
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Kumari, Archana, i Rajesh K. Singh. "Morpholine: Pharmacophore Modulating Pharmacokinetic Properties of Anticancer Leads". W Key Heterocyclic Cores for Smart Anticancer Drug–Design Part II, 137–73. BENTHAM SCIENCE PUBLISHERS, 2022. http://dx.doi.org/10.2174/9789815040043122020008.
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The morpholine ring is considered the most preferred and versatile heterocylic ring in medicinal chemistry due to its distinctive mechanistic activities that give it various biological activities. The eminence of the morpholine ring to modulate the pharmacokinetic properties of the compound, further makes it a fundamental pharmacophore in developing lead molecules. Multi-drug resistance in cancer leads to discovering selective and potent chemotherapeutic agents. Researchers are designing and synthesizing morpholine derivatives as potential anticancer drugs those act by targeting various signaling pathways driven by various protein kinases in the cell, i.e. Ras-Raf-MEK-ERK (ERK) and PI3K/Akt/mTOR, thereby inhibiting cell proliferation and growth. The potency of natural and synthetic derivatives of morpholine makes it a drug of choice for cancer treatment. Many of the morpholine containing anticancer drugs are under clinical trials. Hence, morpholine ring synthesis also becomes a central target for various scientists using green synthesis by straightforward one-step methods. A substantial literature is available on synthetic techniques of morpholine and substituted morpholine. The present chapter updates diverse new synthetic strategies of the morpholine ring and morpholine derivatives with potent anticancer activity. The chapter will also highlight the clinical data of morpholine derivatives with anticancer activity and mechanism of action. The latest information on novel anticancer morpholine derivatives with structural activity relationship (SAR) is also included. This chapter provides information about the necessary structural modifications required in drugs' chemical structure and contribute to the anticancer drug discovery program.
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Sailaja, Inampudi, Manoj Kumar Baghel i Ivvala Anand Shaker. "Nanotechnology Based Drug Delivery for HIV-AIDS Treatment". W AIDS Updates - Recent Advances and New Perspectives [Working Title]. IntechOpen, 2021. http://dx.doi.org/10.5772/intechopen.97736.
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One of the biggest challenges of the world in this 21st century is to cure HIV-AIDS. In Present scenario different antiviral drugs are available in the market to reduce the worse condition and manage improved survival rate. These drugs are manageable but their bioavailability, lower permeability and poor half life of the drugs have limitations. If the drug is preferred in higher dosage in AIDS patients, the drug leads to toxicity and adverse effects to patients and increase resistant against HIV & if the drug is preferred in lower dose along with nano carriers it will reach the target area for beneficial effect, therefore drugs Lacking of Knowledge in Potent Drug delivery systems is due to instability, chemical degradation and tissue barrier difficulties are reasons to reach drug target successfully. In this scenario Nanotechnology based antiretroviral drugs delivery holds drug and will provide to cure AIDS. Nanotechnology based deliver system Nanocarriers like Liposomes, dendrimers, Nanoparticles, Polymeric Micelles, Nanovesicles, Nanoemulsion provide the way to deliver drug to targeting tissue. Nanobased carriers revolutionized the field of Pharmaceutics and Pharmaco Kinetic’s in target drug delivery. The present study depicts nano based ARV drug provides increase efficiency with less adverse effects to control HIV. Like same way we can provide and increase nanobased drug delivery capacity to other available HIV drugs.
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Kesharwani, Payal, Kajal Kumari, Smita Jain i Swapnil Sharma. "Barriers to Targeted Drug Delivery Strategies in Brain". W Brain Tumor Targeting Drug Delivery Systems: Advanced Nanoscience for Theranostics Applications, 34–59. BENTHAM SCIENCE PUBLISHERS, 2023. http://dx.doi.org/10.2174/9789815079722123010004.
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Brain tumor is considered to be the most detrimental disease found in humans. Amongst the various brain tumors, glioblastoma has emerged as a highly invasive malignant disease that has contributed to significant mortality worldwide. Despite surgical and drug innovations, most of the patients suffering from brain tumours have shown poor prognosis, with a median life span. The presence of the blood-brain barrier (BBB) acts as a protective layer outside the brain for most of the conventional, diagnostic and therapeutic agents, which in turn leads to poor diagnosis and less efficacy in most clinical subjects. In recent years, multifunctional nanotechnology systems have been employed to deliver theranostic agents to the brain, showing promising outcomes in the treatment of various forms of cancer. The present chapter provides comprehensive information on the most recent developments in BBB crossing nanotechnology, with a slight focus on the thoughtful design of multifunctional nanoplatforms for effective BBB penetration, accurate tumor imaging, and substantial brain tumor inhibition. Besides, various physiological barriers and transportation mechanisms, different drug delivery systems for brain tumors are also highlighted. Furthermore, major advancements in brain tumor theranostics pertaining to employing different nanosystems such as liposomes, polymeric nanoparticles, bio-nano particles, and inorganic-nanoparticles for effective nano-drug delivery for theranostics in brain tumors have also been discussed.
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Chandrawanshi, Nagendra Kumar, i Shekhar Verma. "Recent Research and Development in Stem Cell Therapy for Cancer Treatment". W Handbook of Research on Advancements in Cancer Therapeutics, 514–33. IGI Global, 2021. http://dx.doi.org/10.4018/978-1-7998-6530-8.ch018.
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Cancer is the most prevalent and dangerous disease, and it leads to millions of deaths worldwide. Generally, metastatic cancer cells are not eradication by conventional surgical operative or chemotherapy-based treatment. New pathways have been established in various arenas such as unique biology, modulators regulatory mechanism, directional migration, self-renewal, etc. The individual pathways can be employed as therapeutic carriers, specific drug targeting, generation of acquiring nature immune cells, and regenerative medicine. The present scenario, stem cell therapy, focused on a promising tool for targeted cancer treatment. Stem cells also utilized as viruses and nanoparticles carry to enhance the primary therapeutic application in various dimensions such as cancer target therapy, regenerative medicine, immune-modulating therapy, and anticancer drugs screening. Furthermore, the rapid development in next-generation sequencing techniques and cancer genomics and proteomics analysis approaches are making therapeutics targeting organ-specific cancer more precise and efficient.
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Cesarini, Sara, Angelo Ranise i Andrea Spallarossa. "A Successful Application Of Parallel Synthesis To Computer-assisted Structural Optimization Of New Leads Targeting Human Immunodeficiency Virus-1 Reverse Transcriptase The Case Of Acylthiocarbamates And Thiocarbamates". W High-Throughput Lead Optimization in Drug Discovery, 117–49. CRC Press, 2008. http://dx.doi.org/10.1201/9781420006964.ch4.
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"A Successful Application of Parallel Synthesis to Computer-Assisted Structural Optimization of New Leads Targeting Human Immunodeciency Virus-1 Reverse Transcriptase: The Case of Acylthiocarbamates and Thiocarbamates". W High-Throughput Lead Optimization in Drug Discovery, 127–60. CRC Press, 2008. http://dx.doi.org/10.1201/9781420006964-7.
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Setia, Aseem, Ram Kumar Sahu, Ayodeji Folorunsho Ajayi i Emmanuel Tayo Adebayo. "Theranostics Dendrimer for Brain Tumor Diagnosis and Treatment". W Brain Tumor Targeting Drug Delivery Systems: Advanced Nanoscience for Theranostics Applications, 121–39. BENTHAM SCIENCE PUBLISHERS, 2023. http://dx.doi.org/10.2174/9789815079722123010007.
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Brain tumors have become one of the deadliest types of cancer. Tragically, the blood-brain barrier (BBB), an astringent regulatory, well-coordinated, and effectual obstacle, prevents most substances from passing through it. As a result, breaking through this hurdle is amongst the most difficult challenges in devising effective CNS therapies. In the USA, approximately seven lakh people have a principal brain malignancy, with an ample eighty-five thousand predicted to be afflicted by 2021. Capillaries are essential for delivering oxygen and nutrients to all body tissue and vital organs. The capillaries that vascularize the CNS have a special feature known as the blood-brain barrier, which enables such vessels to firmly enforce the transfer of ions, substances, and cells in-between the blood-brain barrier. This accurate estimation of CNS homeostasis leads to proper neuronal function while also protecting neural tissue from toxic substances and microorganisms, and changes in such mechanical strength are a major aspect of the pathology and transformation of various neurological diseases. Theranostic strategies were also postulated and deemed enticing in recent times. Due to the smaller size, better topical functionalization, and capability to integrate various processing elements in one system, nanotechnology is beneficial for this system. For cancer therapy, the structure of nanotherapeutic systems focusing on diagnostic and therapeutic applications is increasing tremendously. This dual system is extremely useful for personalized medicine-based clinical applications because it seeks to analyze the position of malignancy, the biodistribution of nanosized systems, along with an advanced and efficacious therapy. Proteins, molecular markers, and genes are some of the theranostic strategies that could be used to amplify the surface of the nanotheranostics particle and make benefit of the features of the micro-environment utilising stimulus-based triggers. The current chapter focused on the theranostic approach of dendrimer for brain tumor treatment. It also enlightened about various diagnostic techniques for brain tumors with a special emphasis on nanotherapeutics.
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J Kogan, Marcelo, Francisco Salazar-Cornejo, Abraham Gajardo i Ramón Rodrigo. "Improvement of Nitric Oxide Availability in Myocardial Ischemia/reperfusion: Role of Nanotechnology as a Therapeutic Approach". W Blood Oxidant Ties: The Evolving Concepts in Myocardial Injury and Cardiovascular Disease, 148–66. BENTHAM SCIENCE PUBLISHERS, 2023. http://dx.doi.org/10.2174/9789815165012123010011.
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In the search for an effective treatment against myocardial damage caused by oxidative stress, it has become necessary to generate new therapies that overcome the difficulties and failures observed in conventional therapies. Therefore, nanotechnology and nanoparticle development may open new horizons for the control and therapy of oxidative stress and associated myocardial damage. The term nanomaterials describe materials with nanoscale dimensions (< 100 nm). In this chapter, different nanoparticle drug delivery systems, along with their targeting strategies, and how they can help to improve therapeutic failure in oxidative stress using nanoparticles in the control of myocardial infarction and oxidative stress will be discussed. Achieving an inhibition of oxidative stress producers or improving the endogenous antioxidant capacity through drug delivery by nanoparticles increases the drug’s aqueous solubility, protects its degradation, allows prolonged release, and improves the bioavailability, determining a targeted delivery, and decreases the toxic side effects. It leads to new therapeutic opportunities for both monotherapies and combined therapies, benefiting from nanoparticles' particularities associated with increased solubility, bioavailability, and specificity.
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Garg, Ashish, Vijay Sagar Madamsetty, Sumel Ashique, Vinod Gauttam i Neeraj Mishra. "Targeted Nanocarriers-based Approach For Prostate Cancer Therapy". W Therapeutic Nanocarriers in Cancer Treatment: Challenges and Future Perspective, 133–62. BENTHAM SCIENCE PUBLISHERS, 2023. http://dx.doi.org/10.2174/9789815080506123010008.
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Prostate cancer is the most common malignancy in men, with elevated morbidity and mortality. The current management, along with dope, leads to chemo defiance. On molecular imaging, many researchers have assisted with staging, restaging, early diagnosis, and, particularly, prostate cancer healing. At the site of cancer, treatment of prostate cancer, including chemo, has encountered many difficulties, such as quick clearance of dope or defiance of drug and short accumulation. Nanotechnology applications and their use in biomedicine to deliver various therapeutic carriers fitted to relieve deputy chemotherapy for cancer treatment. The tumor-targeted dope delivery-related carriers are outlined for prostate cancer healing. Among them, the developing nanotechnology has introduced several innovative new testing technologies, and medications for prostate cancer nanotechnology can significantly increase the management operation of prostate cancer by using specific physical and chemical properties, targeting techniques, or anchoring with imaging / pharmacological substances to provide an innovative theranostics device. This chapter focused on the ultra-modern outgrowth in the observation of nanomaterial and the identity of prostate cancer, including the representation of modes used to point biomolecules operationalization and the various prostate cancers along with nanoparticles, multifunctional nanoplatforms, and nano-related methods of dope delivery in the administration.
Streszczenia konferencji na temat "DRUG LEADS TARGETING"
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Williams, Alicia M., i Pavlos P. Vlachos. "Dynamics of Magnetic Drug Targeting in Cardiovascular Flows". W ASME 2007 Summer Bioengineering Conference. American Society of Mechanical Engineers, 2007. http://dx.doi.org/10.1115/sbc2007-176632.
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In spite of the level of sophistication and development of medicine, the effective delivery of drugs remains an unsolved problem. The conventional method to deliver drugs is to inject them intravenously to the patient, or administer a pill capsule. The medicine diffuses through the bloodstream without regard to the location of the malady. For many types of diseases, the inefficiency of this method leads to increased dosage requirements, which can cause the patient to experience adverse side effects.
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Shi, Yihui, Chandraiah Lagisetti Lagisetti, Amanda S. Joyner, Lidia C. Sambucetti i Thomas R. Webb. "Abstract 4365: Targeting the SF3B1 spliceosome protein: Development of a reporter for HTS screen and pharmacodynamic profiling of small molecule drug leads". W Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.am2015-4365.
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Hicks, Stuart W., Katharine C. Lai, Yong Yi, Prerak Shah, Cristina L. Gavrilescu, Joe Ponte, Callum M. Sloss i Angela Romanelli. "Abstract 1073: Increased internalization and processing of the CD37-targeting antibody-drug conjugate, naratuximab emtansine (IMGN529), in the presence of rituximab leads to enhanced potency in diffuse large B-cell lymphoma models". W Proceedings: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC. American Association for Cancer Research, 2017. http://dx.doi.org/10.1158/1538-7445.am2017-1073.
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Cooper, Daniel B., i Pavlos P. Vlachos. "Parametric Investigation of Magnetic Particle Transport for Targeted Drug Delivery Applications". W ASME 2011 Summer Bioengineering Conference. American Society of Mechanical Engineers, 2011. http://dx.doi.org/10.1115/sbc2011-53889.
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In recent years, there has been significant clinical and research interest in magnetic drug targeting (MDT). MDT allows the targeted delivery of drugs only to the affected sites, alleviating the rest of the body from the potential toxic or other side effects of the drug. The underlying concept of MDT is to attach drugs to small magnetic particles which can then be manipulated by a magnetic field designed to attract the drug carrying particles to the target site [1]. This will lead to increasing localized accumulation of the drug at the target site. MDT can have great implications on pharmaceutical treatments, ranging from oncology to cardiology and beyond [2, 3].
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Geerligs, Marion, Lambert C. A. v. Breemen, Gerrit W. M. Peters, Paul A. J. Ackermans, Cees W. J. Oomens i Frank P. T. Baaijens. "Mechanical Properties of the Epidermis and Stratum Corneum Determined by Submicron Indentation In Vitro". W ASME 2009 Summer Bioengineering Conference. American Society of Mechanical Engineers, 2009. http://dx.doi.org/10.1115/sbc2009-204412.
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The outer skin layers are important drug and vaccine delivery targets in the treatment of diseases. These skin layers possess some important characteristics making them favorable sites for pain-free delivery with minimal damage: a rich population of immunologically sensitive cells as well as the lack of blood vessels and sensory nerve endings [1]. Until today, however, the development of effective cell targeting methods is acquainted with many challenges. A collective shortcoming is a poor understanding of the key mechanical properties of the outer skin layers, e.g. the stratum corneum and epidermis. The anisotropic, dynamic and very complex nature of skin makes it difficult to perform proper mechanical testing as well as to obtain reliable, reproducible data. The stratum corneum is an effective physical barrier of dead cells with a “brick-and-mortar” structure, while the viable epidermis mainly consists of actively migrating keratinocytes constantly undergoing massive morphological and compositional changes. As a consequence, the structure differences among the skin layers lead to significant variations in mechanical properties. Since there is no method available to determine the mechanical behavior of isolated viable epidermis in vivo or in vitro, the mechanical behavior of epidermis and stratum corneum only are investigated here. A commercially available indentation system has been adapted to enable the measurement of these thin soft tissues in an in vitro set up. Combining the outcomes of the two skin layer types leads to an assessment of the contribution of the viable epidermis to the mechanical behavior of skin. To our knowledge, no data have been published yet regarding mechanical bulk properties of (viable) epidermis, while no consistency exists with respect to those of the stratum corneum.
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Thomas, Antony, Paige Baldwin i Yaling Liu. "Ultrasound Mediated Enhancement of Nanoparticle Uptake in PC-3 Cancer Cells". W ASME 2013 2nd Global Congress on NanoEngineering for Medicine and Biology. American Society of Mechanical Engineers, 2013. http://dx.doi.org/10.1115/nemb2013-93115.
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Ultrasound in the presence of microbubbles brings in transient increase in cell membrane permeability, which allows the entry of foreign molecules into cells. This platform has been applied in in vitro and in vivo gene delivery studies in recent years[1–2]. The frequently used microbubbles are air or inert gas encapsulated in a protein, lipid or polymer which is commonly used as FDA approved contrast agents in diagnostic ultrasound. On exposure to ultrasound the microbubbles lead to formation of small pores on the cell membrane. This work concentrates on application of this platform to enhance cellular uptake of nanoparticles and thereby achieve enhanced drug delivery. Nanoparticles can be manipulated at the nano level and have been applied in the realm of cancer detection and treatment for imaging, targeting tumors, and drug delivery purposes [2].
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Mirkhani, Seyed Nima, Tinotenda Gwisai, Michael G. Christiansen i Simone Schuerle. "Scalable and Spatially Selective Actuation of Living Microrobots". W THE HAMLYN SYMPOSIUM ON MEDICAL ROBOTICS. The Hamlyn Centre, Imperial College London London, UK, 2023. http://dx.doi.org/10.31256/hsmr2023.55.
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In drug delivery, one key challenge is to minimize off- target accumulation in healthy regions, which can lead to toxicity or other associated complications. To address this challenge, drug delivery platforms can be designed either to localize the accumulation of active compounds to the target site or to selectively activate the portion that arrives in the targeted tissue. In the case of living bacterial therapeutics or bacteria-based biohybrid microrobots, bacteria can be equipped with onboard sensing, aiding their preferred accumulation in target regions such as tumors [1]. Nevertheless, robust tumor colonization by bacteria is still limited by low administrable doses and biological barriers that permit only a small portion to reach a target site after intravenous administration. Therefore, strategies that provide a means to target external energy to bacteria in a spatially selective manner can offer a much-needed element for enhanced targeting of living therapeutics [2]. Magnetotactic bacteria (MTB) are a group of bacteria noted for their intrinsic responsiveness to magnetic fields, and have been investigated as a drug carriers and potential living therapeutics. We previously demonstrated the possibility for enhancing tumor colonization using a scalable magnetic torque-based control approach employing a homogenous rotational magnetic field [3]. Here, we increase the spatial selectivity of this technique by employing a magnetostatic selection field that suppresses off target torque-based actuation.
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Shahat, Ayman EL, Mohamed Osama Abd Elmeguid, Luis Gerardo, Abdalla Saleh Saleh, Saeed Mohamed Almazrouei, Ali Sulaiman Bin Sumaida, Ahmed Abdulla Al Mutawa i in. "Successful Delivery of the First Extended Reach Well Using an Integrated Multidisciplinary Approach; A Case Study in a Mature Field, Onshore Abu Dhabi UAE". W ADIPEC. SPE, 2022. http://dx.doi.org/10.2118/211492-ms.
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Abstract Drilling extended reach drilling (ERD) wells starting from the planning phase and engaging various disciplines including drilling, cementing, drilling fluids and geoscience teams. The pre-well engagement and integration between multiple disciplines are vital to define the associated drilling/geosteering challenges and accordingly optimize the drilling program to deliver a successful ERD well. These challenges are included and not limited to geological model uncertainties, differential sticking, high torque and drag, ECD limitation, friction factors and expected mud losses. An integrated and optimized plan was constructed to meet the associated challenges. The drilling engineering team optimized the bottom hole assembly (BHA) design in all sections to ensure a smooth profile using optimum drill bits designs. The BHA included LWD technologies to mitigate the geological challenges and helping in determining the casing points and geosteering operations. A new generation of intelligent fully rotating high dogleg pushthe-bit rotary steerable system was selected with matched drilling bits to geosteer the well in the thin target layer while maintaining the planned target trajectory with minimum borehole tortuosity by means of realtime drilling optimization. Effective collaboration led to successful delivery of the first extended reach well, the geosteering objectives were achieved with 100% reservoir contact and delivered 20,000 feet targeting thin carbonate layer and overcoming the complex geology environment. The well was drilled to record depth of 32,300 feet with 29% ROP improvement in same field. ECD was always maintained below the fracture gradient along with optimal hole cleaning without cuttings buildup or tight hole while reducing the wellbore friction to ensure smooth pulling out of hole operation. Cementing operations were successfully achieved and ensured zonal isolation. Furthermore, a customized and innovative drilling fluid with free RDF Non Aqueous Fluid (NAF) and compatible lubricant were deployed along the different hole sections to reduce the expected induced losses and provide proper hole cleaning. The cementing program has been optimized for the 18 5/8", 13 3/8" and 9 5/8" casings using an innovative flexible expandable lead and tail slurries with enhanced mechanical properties to mitigate the expected losses while cementing and ensure proper isolation across all formations. The best practice of the multidisciplinary approach along with the captured lessons learned opens the door to drill more challenging wells. in addition, it proved that proper planning and execution can shift the boundaries further and gave confidence to drill even deeper.