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hypoxia activated prodrug

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...
October 16, 2018: Journal of Controlled Release: Official Journal of the Controlled Release Society
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
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 towards the structure-mutagenicity or structure-genotoxicity relationships have been undertaken...
October 8, 2018: Journal of Medicinal Chemistry
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...
September 29, 2018: Biomaterials
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
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
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
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 3, 2018: ACS Nano
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
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...
August 23, 2018: European Journal of Medicinal Chemistry
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
Priyamvada Jayaprakash, Midan Ai, Arthur Liu, Pratha Budhani, Todd Bartkowiak, Jie Sheng, Casey R 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 T cell checkpoint blockade against melanoma, many "cold" tumors such as prostate cancer remain unresponsive. We find that hypoxic zones are prevalent across pre-clinical prostate cancer and resist T cell infiltration even in the context of CTLA-4 and PD-1 blockade. We show that the hypoxia-activated prodrug TH-302 reduces or eliminates hypoxia in these tumors. Combination therapy with this hypoxia-prodrug and checkpoint blockade cooperate to cure more than 80% of TRAMP-C2 prostate tumors...
September 6, 2018: Journal of Clinical Investigation
Ying Zhou, Mrinmoy Maiti, Amit Sharma, Miae Won, Le Yu, Lan Xi Miao, Jinwoo Shin, Arup Podder, Kondapa Naidu Bobba, Jiyou Han, Sankarprasad Bhuniya, Jong Seung Kim
We report herein, an azo-derivative (AzP1) of FDA approved antineoplastic drug SN-38 (irinotecan analogue) as a theranostic agent with a potential for both tumor hypoxia-specific activation and therapy. The theranostic AzP1 was found to be stable within a biologically relevant pH scale and was chemically inert towards other competitive biological analytes. However, upon treatment with rat-liver microsomes, AzP1 showed a self-calibrated fluorescence enhancement at λem  = 560 nm. The cytotoxicity profile of AzP1 was tested in various cancer lines...
October 28, 2018: Journal of Controlled Release: Official Journal of the Controlled Release Society
Stephen Mf Jamieson, Peter Tsai, Maria K Kondratyev, Pratha Budhani, Arthur Liu, Neil N Senzer, E Gabriela Chiorean, Shadia I Jalal, John J Nemunaitis, Dennis Kee, Avik Shome, Way W Wong, Dan Li, Nooriyah Poonawala-Lohani, Purvi M Kakadia, Nicholas S Knowlton, Courtney Rh Lynch, Cho R Hong, Tet Woo Lee, Reidar A Grénman, Laura Caporiccio, Trevor D McKee, Mark Zaidi, Sehrish Butt, Andrew Mj Macann, Nicholas P McIvor, John M Chaplin, Kevin O Hicks, Stefan K Bohlander, Bradly G Wouters, Charles P Hart, Cristin G Print, William R Wilson, Michael A Curran, Francis W Hunter
Evofosfamide (TH-302) is a clinical-stage hypoxia-activated prodrug of a DNA-crosslinking nitrogen mustard that has potential utility for human papillomavirus (HPV) negative head and neck squamous cell carcinoma (HNSCC), in which tumor hypoxia limits treatment outcome. We report the preclinical efficacy, target engagement, preliminary predictive biomarkers and initial clinical activity of evofosfamide for HPV-negative HNSCC. Evofosfamide was assessed in 22 genomically characterized cell lines and 7 cell line-derived xenograft (CDX), patient-derived xenograft (PDX), orthotopic, and syngeneic tumor models...
August 23, 2018: JCI Insight
Cho Rong Hong, Benjamin D Dickson, Jagdish K Jaiswal, Frederik B Pruijn, Francis W Hunter, Michael P Hay, Kevin O Hicks, William R Wilson
Evofosfamide (TH-302) is a clinical-stage hypoxia-activated prodrug with proven efficacy against hypoxic cells in preclinical tumour models. TH-302 is designed to release the DNA crosslinking agent bromo-isophosphoramide mustard (Br-IPM) when reduced in hypoxic tissue. Br-IPM is considered to diffuse locally from hypoxic regions, eliciting additional tumour cell killing, but the latter 'bystander effect' has not been demonstrated directly. Previous studies with multicellular co-cultures that included cells expressing the E...
August 19, 2018: Biochemical Pharmacology
Xin Luan, Ying-Yun Guan, Hai-Jun Liu, Qin Lu, Mei Zhao, Duxin Sun, Jonathan F Lovell, Peng Sun, Hong-Zhuan Chen, Chao Fang
Vascular-targeted photodynamic therapy (VTP) is a recently approved strategy for treating solid tumors. However, the exacerbated hypoxic stress makes tumor eradication challenging with such a single modality approach. Here, a new graphene oxide (GO)-based nanosystem for rationally designed, interlocking trimodal cancer therapy that enables VTP using photosensitizer verteporfin (VP) (1) with codelivery of banoxantrone dihydrochloride (AQ4N) (2), a hypoxia-activated prodrug (HAP), and HIF-1α siRNA (siHIF-1α) (3) is reported...
August 2018: Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
Dinghua Liang, Xing Wu, Brian B Hasinoff, David E Herbert, Geoffrey K Tranmer
As part of our initial efforts into developing a tumor-targeting therapy, C-10 substituted derivatives of a camptothecin analog (SN-38) have been synthesized (2-, 3- and 4-nitrobenzyl) for use as potential hypoxia-activated prodrugs and evaluated for their cytotoxicity, topoisomerase I inhibition and electrochemical (reductive) properties. All three derivatives were found to possess reduced toxicity towards human leukemia K562 cells compared to SN-38, validating a condition for prodrug action. Using an MTS assay, IC50 's were found to be 3...
August 15, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Lian-Hua Fu, Chao Qi, Jing Lin, Peng Huang
Glucose oxidase (GOx) is an endogenous oxido-reductase that is widely distributed in living organisms. Over recent years, GOx has attracted increasing interest in the biomedical field due to its inherent biocompatibility, non-toxicity, and unique catalysis against β-d-glucose. GOx efficiently catalyzes the oxidization of glucose into gluconic acid and hydrogen peroxide (H2O2), which can be employed by various biosensors for the detection of cancer biomarkers. Various cancer therapeutic strategies have also been developed based on the catalytic chemistry of GOx: (1) the consumption of glucose provides an alternative strategy for cancer-starvation therapy; (2) the consumption of oxygen increases tumor hypoxia, which can be harnessed for hypoxia-activated therapy; (3) the generation of gluconic acid enhances the acidity of the tumor microenvironment, which can trigger pH-responsive drug release; (4) the generation of H2O2 increases the levels of tumor oxidative stress, and the H2O2 can be converted into toxic hydroxyl radicals that can kill cancer cells upon exposure to light irradiation or via the Fenton reaction...
August 28, 2018: Chemical Society Reviews
Shiying Li, Xueyan Jiang, Rongrong Zheng, Shengjia Zuo, Linping Zhao, Guiling Fan, Jinghao Fan, Yonghua Liao, Xiyong Yu, Hong Cheng
An azobenzene-based heteromeric prodrug (hNDP) was prepared for targeted chemotherapy against hypoxic tumor. hNDP could divert the parent drug from nucleus to cytoplasm with lower toxicity, while the azoreduction of hNDP in hypoxia would activate the drug with a robust anti-tumor effect by initiating the apoptosis-related biochemical cascades.
July 12, 2018: Chemical Communications: Chem Comm
Ming Liu, Lei Wang, Xiaohua Zheng, Shi Liu, Zhigang Xie
The oxygen-dependent feature of most photosensitizers (PSs) and the aggravated hypoxia tumor microenvironment seriously impede the photodynamic therapy (PDT) effectiveness. However, this undesirable impediment can be utilized to further trigger the activation of hypoxia-sensitive prodrugs. Moreover, a combined therapy can be used by associating PDT with hypoxia-activated chemotherapy. Herein, a multifunctional Hf-porphyrin nanoscale metal-organic framework (NMOF) platform [Hf/tetra(4-carboxyphenyl)porphine (TCPP)] has been synthesized, with a high porphyrin loading capacity and a well-ordered coordination array preventing porphyrin self-quenching, thus greatly improving the generation efficiency of reactive oxygen species (ROS), which is helpful for PDT...
July 25, 2018: ACS Applied Materials & Interfaces
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