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hypoxia activated prodrug

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https://www.readbyqxmd.com/read/30482722/organotypic-microfluidic-breast-cancer-model-reveals-starvation-induced-spatial-temporal-metabolic-adaptations
#1
Jose M Ayuso, Amani Gillette, Karina Lugo-Cintrón, Suehelay Acevedo-Acevedo, Ismael Gomez, Molly Morgan, Tiffany Heaster, Kari B Wisinski, Sean P Palecek, Melissa C Skala, David J Beebe
BACKGROUND: Ductal carcinoma in situ (DCIS) is the earliest stage of breast cancer. During DCIS, tumor cells remain inside the mammary duct, growing under a microenvironment characterized by hypoxia, nutrient starvation, and waste product accumulation; this harsh microenvironment promotes genomic instability and eventually cell invasion. However, there is a lack of biomarkers to predict what patients will transition to a more invasive tumor or how DCIS cells manage to survive in this harsh microenvironment...
October 25, 2018: EBioMedicine
https://www.readbyqxmd.com/read/30468124/investigational-hypoxia-activated-prodrugs-making-sense-of-future-development
#2
Min-Xia Su, Le-Le Zhang, Zhang-Jian Huang, Jia-Jie Shi, Jin-Jian Lu
Hypoxia, which occurs in most cancer cases, disrupts the efficacy of anticarcinogens. Fortunately, hypoxia can become a potential target for cancer treatment. Hypoxia-activated prodrugs (HAPs) can be selectively activated by reductase under hypoxia. Some promising HAPs have been already achieved, and many clinical trials of HAPs in different cancers are ongoing. However, none of them has been approved for clinical applications to date. Studies on HAPs have been conducted for many years, presenting some achievements and challenges...
November 23, 2018: Current Drug Targets
https://www.readbyqxmd.com/read/30464209/biological-activity-of-pt-iv-prodrugs-triggered-by-riboflavin-mediated-bioorthogonal-photocatalysis
#3
Silvia Alonso-de Castro, Alessio Terenzi, Sonja Hager, Bernhard Englinger, Adriana Faraone, Javier Calvo Martínez, Markus Galanski, Bernhard K Keppler, Walter Berger, Luca Salassa
We have recently demonstrated that riboflavin (Rf) functions as unconventional bioorthogonal photocatalyst for the activation of PtIV prodrugs. In this study, we show how the combination of light and Rf with two PtIV prodrugs is a feasible strategy for light-mediated pancreatic cancer cell death induction. In Capan-1 cells, which have high tolerance against photodynamic therapy, Rf-mediated activation of the cisplatin and carboplatin prodrugs cis,cis,trans-[Pt(NH3 )2 (Cl)2 (O2 CCH2 CH2 CO2 H)2 ] (1) and cis,cis,trans-[Pt(NH3 )2 (CBDCA)(O2 CCH2 CH2 CO2 H)2 ] (2, where CBDCA = cyclobutane dicarboxylate) resulted in pronounced reduction of the cell viability, including under hypoxia conditions...
November 21, 2018: Scientific Reports
https://www.readbyqxmd.com/read/30451487/hypoxia-activated-small-molecule-induced-gene-expression
#4
Sarah L Collins, Jaideep Saha, Laure C Bouchez, Ester M Hammond, Stuart J Conway
Hypoxia, conditions of reduced oxygen, occur in a wide variety of biological contexts, including solid tumours and bacterial biofilms, which are relevant to human health. Consequently, the development of chemical tools to study hypoxia is vital. Here we report a hypoxia-activated small molecule-mediated gene expression system using a bioreductive prodrug of the inducer isopropyl 1-thio-β-D-galactopyranoside (IPTG). As a proof-of-concept we have placed the production of a green fluorescent protein under the control of hypoxia...
November 19, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/30433782/4-hydroxy-3-nitro-5-ureido-benzenesulfonamides-selectively-target-the-tumor-associated-carbonic-anhydrase-isoforms-ix-and-xii-showing-hypoxia-enhanced-antiproliferative-profiles
#5
Alessio Nocentini, Elena Trallori, Srishti Singh, Carrie L Lomelino, Gianluca Bartolucci, Lorenzo Di Cesare Mannelli, Carla Ghelardini, Robert McKenna, Paola Gratteri, Claudiu T Supuran
Human carbonic anhydrases (CA, EC, 4.2.1.1) IX and XII are overexpressed in cancer cells as adaptive response to hypoxia and acidic conditions characteristic of many tumors. In addition, hypoxia facilitates the activity of specific oxido-reductases that may be exploited to selectively activate bioreductive prodrugs. Here, new selective CA IX/XII inhibitors, as analogues of the antitumor phase II drug SLC-0111 are described, namely ureido-substituted benzenesulfonamides appended with a nitro-aromatic moiety to yield an antiproliferative action increased by hypoxia...
November 28, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/30425475/hypoxia-activated-prodrugs-and-redox-responsive-nanocarriers
#6
REVIEW
Yun Zeng, Jingwen Ma, Yonghua Zhan, Xinyi Xu, Qi Zeng, Jimin Liang, Xueli Chen
Hypoxia is one of the marked features of malignant tumors, which is associated with several adaptation changes in the microenvironment of tumor cells. Therefore, targeting tumor hypoxia is a research hotspot for cancer therapy. In this review, we summarize the developing chemotherapeutic drugs for targeting hypoxia, including quinones, nitroaromatic/nitroimidazole, N-oxides, and transition metal complexes. In addition, redox-responsive bonds, such as nitroimidazole groups, azogroups, and disulfide bonds, are frequently used in drug delivery systems for targeting the redox environment of tumors...
2018: International Journal of Nanomedicine
https://www.readbyqxmd.com/read/30370690/tumor-starvation-induced-spatiotemporal-control-over-chemotherapy-for-synergistic-therapy
#7
Ming-Kang Zhang, Chu-Xin Li, Shi-Bo Wang, Tao Liu, Xian-Lin Song, Xiao-Quan Yang, Jun Feng, Xian-Zheng Zhang
By integrating the characteristics of each therapy modality and material chemistry, a multitherapy modality is put forward: tumor starvation triggered synergism with sensitized chemotherapy. Following starvation-induced amplification of pathological abnormalities in tumors, chemotherapy is arranged to be locally activated and accurately reinforced to perfect multitherapy synergism from spatial and temporal perspectives. To this end, glucose oxidase (GOD) and a hypoxic prodrug of tirapazamine (TPZ) are loaded in acidity-decomposable calcium carbonate (CaCO3 ) nanoparticles concurrently tethered by hyaluronic acid...
October 29, 2018: Small
https://www.readbyqxmd.com/read/30356233/an-agent-based-model-for-drug-radiation-interactions-in-the-tumour-microenvironment-hypoxia-activated-prodrug-sn30000-in-multicellular-tumour-spheroids
#8
Xinjian Mao, Sarah McManaway, Jagdish K Jaiswal, Priyanka B Patel, William R Wilson, Kevin O Hicks, Gib Bogle
Multicellular tumour spheroids capture many characteristics of human tumour microenvironments, including hypoxia, and represent an experimentally tractable in vitro model for studying interactions between radiotherapy and anticancer drugs. However, interpreting spheroid data is challenging because of limited ability to observe cell fate within spheroids dynamically. To overcome this limitation, we have developed a hybrid continuum/agent-based model (ABM) for HCT116 tumour spheroids, parameterised using experimental models (monolayers and multilayers) in which reaction and diffusion can be measured directly...
October 2018: PLoS Computational Biology
https://www.readbyqxmd.com/read/30339904/liposomal-formulation-of-hypoxia-activated-prodrug-for-the-treatment-of-ovarian-cancer
#9
Vidhi M Shah, Duc X Nguyen, Adel Al Fatease, Pragnesh Patel, Brianna Cote, Yeonhee Woo, Rohi Gheewala, Yvonne Pham, Man Gia Huynh, Christen Gannett, Deepa A Rao, Adam W G Alani
In this work, a new sphingomyelin-cholesterol liposomal formulation (CPD100Li) for the delivery of a hypoxia activated prodrug of vinblastine, mon-N-oxide (CPD100), is developed. The optimized liposomal formulation uses an ionophore (A23187) mediated pH-gradient method. Optimized CPD100Li is characterized for size, drug loading, and stability. The in vitro toxicity of CPD100Li is assessed on different aspects of cell proliferation and apoptosis of ES2 ovarian cancer under normoxic and hypoxic conditions. The pharmacokinetics of CPD100Li in mice as well as the influence of A23187 on the retention of CPD100 are assessed...
December 10, 2018: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/30323592/overcoming-tumor-hypoxia-as-a-barrier-to-radiotherapy-chemotherapy-and-immunotherapy-in-cancer-treatment
#10
REVIEW
Kaitlin Graham, Evan Unger
Hypoxia exists to some degree in most solid tumors due to inadequate oxygen delivery of the abnormal vasculature which cannot meet the demands of the rapidly proliferating cancer cells. The levels of oxygenation within the same tumor are highly variable from one area to another and can change over time. Tumor hypoxia is an important impediment to effective cancer therapy. In radiotherapy, the primary mechanism is the creation of reactive oxygen species; hypoxic tumors are therefore radiation resistant. A number of chemotherapeutic drugs have been shown to be less effective when exposed to a hypoxic environment which can lead to further disease progression...
2018: International Journal of Nanomedicine
https://www.readbyqxmd.com/read/30295477/nitro-group-containing-drugs
#11
Kunal Nepali, Hsueh-Yun Lee, Jing-Ping Liou
The nitro group is considered to be a versatile and unique functional group in medicinal chemistry. Despite a long history of use in therapeutics, the nitro group has toxicity issues and is often categorized as a structural alert or a toxicophore, and evidence related to drugs containing nitro groups is rather contradictory. In general, drugs containing nitro groups have been extensively associated with mutagenicity and genotoxicity. In this context, efforts toward the structure-mutagenicity or structure-genotoxicity relationships have been undertaken...
November 1, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/30292942/nitric-oxide-as-an-all-rounder-for-enhanced-photodynamic-therapy-hypoxia-relief-glutathione-depletion-and-reactive-nitrogen-species-generation
#12
Yongyan Deng, Fan Jia, Shengyu Chen, Zhida Shen, Qiao Jin, Guosheng Fu, Jian Ji
A glutathione (GSH)-sensitive supramolecular nitric oxide (NO) nanogenerator is developed as an all-rounder for enhanced photodynamic therapy (PDT). By integrating GSH-sensitive NO prodrug into the system via LEGO-like host-guest interaction, the nanocarrier could not only deplete intracellular GSH, but also relieve hypoxia at tumor sites through NO mediated blood vessel relaxation. Furthermore, reactive nitrogen species (RNS) with enhanced biocidal activity could be produced by the reaction between NO and reactive oxygen species (ROS), generated from α-cyclodextrin (α-CD) conjugated S-nitrosothiol and light-activated chlorin e6 (Ce6) respectively...
December 2018: Biomaterials
https://www.readbyqxmd.com/read/30279659/bystander-effects-of-hypoxia-activated-prodrugs-agent-based-modeling-using-three-dimensional-cell-cultures
#13
Cho R Hong, Gib Bogle, Jingli Wang, Kashyap Patel, Frederik B Pruijn, William R Wilson, Kevin O Hicks
Intra-tumor heterogeneity represents a major barrier to anti-cancer therapies. One strategy to minimize this limitation relies on bystander effects via diffusion of cytotoxins from targeted cells. Hypoxia-activated prodrugs (HAPs) have the potential to exploit hypoxia in this way, but robust methods for measuring bystander effects are lacking. The objective of this study is to develop experimental models (monolayer, multilayer, and multicellular spheroid co-cultures) comprising 'activator' cells with high expression of prodrug-activating reductases and reductase-deficient 'target' cells, and to couple these with agent-based models (ABMs) that describe diffusion and reaction of prodrugs and their active metabolites, and killing probability for each cell...
2018: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/30279233/a-phase-1-2-study-of-evofosfamide-a-hypoxia-activated-prodrug-with-or-without-bortezomib-in-subjects-with-relapsed-refractory-multiple-myeloma
#14
Jacob P Laubach, Chia-Jen Liu, Noopur S Raje, Andrew J Yee, Philippe Armand, Robert L Schlossman, Jacalyn Rosenblatt, Jacquelyn Hedlund, Mike G Martin, Craig H Reynolds, Kenneth Shain, Ira Zackon, Laura Stampleman, Patrick Henrick, Bradley J Rivotto, Kalvis Hornburg, Henry Dumke, Stacey Chuma, Alexandra Savell, Damian Handisides, Stewart Kroll, Kenneth C Anderson, Paul G Richardson, Irene M Ghobrial
PURPOSE: The presence of hypoxia in the diseased bone marrow presents a new therapeutic target for multiple myeloma (MM). Evofosfamide (formerly TH-302) is a 2-nitroimidazole prodrug of the DNA alkylator bromo-isophosphoramide mustard that is selectively activated under hypoxia. A phase 1/2 study investigating evofosfamide in combination with dexamethasone (EvoD) and in combination with bortezomib and dexamethasone (EvoBorD) in relapsed/refractory MM. EXPERIMENTAL DESIGN: 59 patients initiated therapy, 31 received EvoD and 28 received EvoBorD...
October 2, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/30265899/light-triggered-theranostic-liposomes-for-tumor-diagnosis-and-combined-photodynamic-and-hypoxia-activated-prodrug-therapy
#15
Kai Zhang, Yuedong Zhang, Xiangdan Meng, Huiting Lu, Huan Chang, Haifeng Dong, Xueji Zhang
Hypoxia tumor microenvironment is a major challenge for photodynamical therapy (PDT), and hypoxia-activated chemotherapy combined PDT could be promising for enhanced anticancer therapy. In this study, we report an innovative 2-nitroimidazole derivative conjugated polyethylene glycol (PEG) amphoteric polymer theranostic liposome encapsulated a photosensitizer Chlorin e6 (Ce6), hypoxia-activated prodrug Tirapazamine (TPZ) and gene probe for synergistic photodynamic-chemotherapy. Ce6-mediated PDT upon irradiation with a laser induces hypoxia, which leads to the disassembly of the liposome and activates the antitumor activity of TPZ for improved cancer cell-killing...
December 2018: Biomaterials
https://www.readbyqxmd.com/read/30265804/erythrocyte-membrane-cloaked-metal-organic-framework-nanoparticle-as-biomimetic-nanoreactor-for-starvation-activated-colon-cancer-therapy
#16
Lu Zhang, Zhenzhen Wang, Yan Zhang, Fangfang Cao, Kai Dong, Jinsong Ren, Xiaogang Qu
Shutting down glucose supply by glucose oxidase (GOx) to starve tumors has been considered to be an attractive strategy in cancerous starvation therapy. Nevertheless, the in vivo applications of GOx-based starvation therapy are severely restricted by the poor GOx delivery efficiency and the self-limiting therapeutic effect. Herein, a biomimetic nanoreactor has been fabricated for starvation-activated cancer therapy by encapsulating GOx and prodrug tirapazamine (TPZ) in an erythrocyte membrane cloaked metal-organic framework (MOF) nanoparticle (TGZ@eM)...
October 23, 2018: ACS Nano
https://www.readbyqxmd.com/read/30223141/cox-2-inhibition-mediated-anti-angiogenic-activatable-prodrug-potentiates-cancer-therapy-in-preclinical-models
#17
Hyeong Seok Kim, Amit Sharma, Wen Xiu Ren, Jiyou Han, Jong Seung Kim
Anti-angiogenesis, i.e., blocking the angiogenic pathway, has been considered as an important component in current cancer therapeutic modalities. However, the associated benefits have proven to be modest as tumor angiogenesis and regrowth persist, probably due to other ill-defined complex angiogenic mechanisms. Herein, we developed an indomethacin (IMC) incorporating system to mediate hypoxia responsive prodrug (TA) and diagnostic agent (DA) in cancer theranostic applications. Cyclooxygenase 2 (COX-2) elevated expression in several cancer types is closely associated with severe tumor supporting vascularization factors...
December 2018: Biomaterials
https://www.readbyqxmd.com/read/30199705/structure-activity-relationship-study-of-hypoxia-activated-prodrugs-for-proteoglycan-targeted-chemotherapy-in-chondrosarcoma
#18
Donia Ghedira, Aurélien Voissière, Caroline Peyrode, Jamil Kraiem, Yvain Gerard, Elise Maubert, Magali Vivier, Elisabeth Miot-Noirault, Jean-Michel Chezal, Farhat Farhat, Valérie Weber
Due to an abundant chondrogenic, poorly vascularized and particularly hypoxic extracellular matrix, chondrosarcoma, a malignant cartilaginous tumour, is chemo- and radio-resistant. Surgical resection with wide margins remains the mainstay of treatment. To address the lack of therapy, our strategy aims to increase anticancer drugs targeting and delivery in the tumour, by leveraging specific chondrosarcoma hallmarks: an extensive cartilaginous extracellular matrix, namely the high negative fixed charge density and severe chronic hypoxia...
October 5, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/30192132/hypoxia-activated-anticancer-prodrug-for-bioimaging-tracking-drug-release-and-anticancer-application
#19
Wei Liu, Haitong Liu, Xiaoran Peng, Guoqiang Zhou, Dandan Liu, Shenghui Li, Jinchao Zhang, Shuxiang Wang
A novel anticancer theranostic prodrug, FDU-DB-NO2 , specifically activated by hypoxia for selective two-photon imaging hypoxia status, real-time tracking drug release, and solid tumor therapy was designed. The devised prodrug consists of an anticancer drug floxuridine (FDU), a fluorescence dye precursor 4'-(diethylamino)-1,1'-biphenyl-2-carboxylate (DB), and a hypoxic trigger 4-nitrobenzyl group. In normal cells, FDU-DB-NO2 is "locked". Whereas in tumor cells, the prodrug is "unlocked" by hypoxia and results in fluorescent dye 7-(diethylamino)coumarin (CM) generation along with FDU release...
September 14, 2018: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/30188869/targeted-hypoxia-reduction-restores-t-cell-infiltration-and-sensitizes-prostate-cancer-to-immunotherapy
#20
Priyamvada Jayaprakash, Midan Ai, Arthur Liu, Pratha Budhani, Todd Bartkowiak, Jie Sheng, Casey Ager, Courtney Nicholas, Ashvin R Jaiswal, Yanqiu Sun, Krishna Shah, Sadhana Balasubramanyam, Nan Li, Guocan Wang, Jing Ning, Anna Zal, Tomasz Zal, Michael A Curran
Despite the success of immune checkpoint blockade against melanoma, many "cold" tumors like prostate cancer remain unresponsive. We found that hypoxic zones were prevalent across preclinical prostate cancer and resisted T cell infiltration even in the context of CTLA-4 and PD-1 blockade. We demonstrated that the hypoxia-activated prodrug TH-302 reduces or eliminates hypoxia in these tumors. Combination therapy with this hypoxia-prodrug and checkpoint blockade cooperated to cure more than 80% of tumors in the transgenic adenocarcinoma of the mouse prostate-derived (TRAMP-derived) TRAMP-C2 model...
November 1, 2018: Journal of Clinical Investigation
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