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hypoxia activated prodrug

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...
July 19, 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
Sandipan Biswas, Y Rajesh, Shrabani Barman, Manoranjan Bera, Amrita Paul, Mahitosh Mandal, N D Pradeep Singh
A new strategy for the detection of hypoxia and NO succeeded by photocontrolled delivery of an anticancer agent has been demonstrated. The developed system is able to produce distinct responses (dual channel) upon interaction with hypoxia and NO. This probe can also release anticancer drugs upon photoirradiation acting potentially as both a dual-analyte imaging agent and a prodrug.
July 12, 2018: Chemical Communications: Chem Comm
Milan Grkovski, Louise Fanchon, Naga Vara Kishore Pillarsetty, James Russell, John L Humm
BACKGROUND: Quantitative imaging can facilitate patient stratification in clinical trials. The hypoxia-activated prodrug evofosfamide recently failed a phase III trial in pancreatic cancer. However, the study did not attempt to select for patients with hypoxic tumors. We tested the ability of 18 F-fluoromisonidazole to predict evofosfamide uptake in an orthotopic xenograft model (BxPC3). METHODS: Two forms of evofosfamide were used: (1) labeled on the active moiety (3 H) and (2) on the hypoxia targeting nitroimidazole group (14 C)...
June 18, 2018: EJNMMI Research
Elisabetta Gabano, Mauro Ravera, Francesca Trivero, Stefano Tinello, Andrea Gallina, Ilaria Zanellato, Marzia B Gariboldi, Elena Monti, Domenico Osella
Multi-action cisplatin-based mono- (1) and di-clofibric acid (2) Pt(iv) "combo" derivatives were synthesized via both traditional and microwave assisted procedures. The two complexes offered very good performances (IC50 values in a nanomolar range) on a panel of human tumor cell lines, including the highly chemoresistant malignant pleural mesothelioma ones. Moreover, both 1 and 2 bypass the cisplatin resistance. Indeed, cisplatin and clofibric acid, the metabolites of the Pt(iv) → Pt(ii) intracellular reduction, proved to act synergistically...
June 25, 2018: Dalton Transactions: An International Journal of Inorganic Chemistry
Sushil Kumar, Jessica D Sun, Libo Zhang, Reza Bayat Mokhtari, Bing Wu, Fanying Meng, Qian Liu, Deepthi Bhupathi, Yan Wang, Herman Yeger, Charles Hart, Sylvain Baruchel
Antiangiogenic therapy has shown promising results in preclinical and clinical trials. However, tumor cells acquire resistance to this therapy by gaining ability to survive and proliferate under hypoxia induced by antiangiogenic therapy. Combining antiangiogenic therapy with hypoxia-activated prodrugs can overcome this limitation. Here, we have tested the combination of antiangiogenic drug sunitinib in combination with hypoxia-activated prodrug evofosfamide in neuroblastoma. In vitro, neuroblastoma cell line SK-N-BE(2) was 40-folds sensitive to evofosfamide under hypoxia compared to normoxia...
August 2018: Translational Oncology
Shuting Xu, Xinyuan Zhu, Chuan Zhang, Wei Huang, Yongfeng Zhou, Deyue Yan
Cancer cells in hypoxic tumors are remarkably resistant to photodynamic therapy. Here, we hypothesize that an oxygen and Pt(II) self-generating multifunctional nanocomposite could reverse the hypoxia-triggered PDT resistance. The nanocomposite contains Pt(IV) and chlorin e6, in which upconversion nanoparticles are loaded to convert 980 nm near-infrared light into 365 nm and 660 nm emissions. Upon accumulation at the tumor site, a 980 nm laser is used to trigger the nanocomposite to generate O2 for consumption in the PDT process and to produce cytotoxic reactive oxygen species...
May 24, 2018: Nature Communications
Shingo Matsumoto, Shun Kishimoto, Keita Saito, Yoichi Takakusagi, Jeeva P Munasinghe, Nallathamby Devasahayam, Charles P Hart, Robert J Gillies, James B Mitchell, Murali C Krishna
Pancreatic ductal adenocarcinoma (PDAC) is characterized by hypoxic niches that lead to treatment resistance. Therefore, studies of tumor oxygenation and metabolic profiling should contribute to improved treatment strategies. Here, we define two imaging biomarkers that predict differences in tumor response to therapy: (i) partial oxygen pressure (pO2 ), measured by EPR imaging; and (ii) [1-13 C] pyruvate metabolism rate, measured by hyperpolarized 13 C MRI. Three human PDAC xenografts with varying treatment sensitivity (Hs766t, MiaPaCa2, and Su...
July 15, 2018: Cancer Research
Michael A Evans, Po-Ju Huang, Yuji Iwamoto, Kelly N Ibsen, Emory M Chan, Yutaka Hitomi, Peter C Ford, Samir Mitragotri
Nitric oxide (NO) holds great promise as a treatment for cancer hypoxia, if its concentration and localization can be precisely controlled. Here, we report a "Trojan Horse" strategy to provide the necessary spatial, temporal, and dosage control of such drug-delivery therapies at targeted tissues. Described is a unique package consisting of (1) a manganese-nitrosyl complex, which is a photoactivated NO-releasing moiety (photoNORM), plus Nd3+ -doped upconverting nanoparticles (Nd-UCNPs) incorporated into (2) biodegradable polymer microparticles that are taken up by (3) bone-marrow derived murine macrophages...
April 21, 2018: Chemical Science
Yan Huang, Ying Tian, Yuanyuan Zhao, Cong Xue, Jianhua Zhan, Lin Liu, Xiaobo He, Li Zhang
BACKGROUND: Tumor hypoxia is considered an important factor in metastasis and disease relapse. Evofosfamide is a hypoxia-activated prodrug that selectively targets the hypoxic regions of solid tumors. As hypoxia-inducible factor-1α (HIF-1α) is overexpressed in nasopharyngeal carcinoma (NPC) tissues, we performed the present study to evaluate the efficacy profile of evofosfamide in NPC. METHODS: We evaluated the efficacy of evofosfamide as a single agent or combined with cisplatin (DDP) in the NPC cell lines CNE-2, HONE-1 and HNE-1, and in nude mouse xenograft tumor models...
May 3, 2018: Cancer communications
Francesca Vena, Ruochen Jia, Arman Esfandiari, Juan J Garcia-Gomez, Manuel Rodriguez-Justo, Jianguo Ma, Sakeena Syed, Lindsey Crowley, Brian Elenbaas, Samantha Goodstal, John A Hartley, Daniel Hochhauser
Targeting the DNA damage response (DDR) in tumors with defective DNA repair is a clinically successful strategy. The RAS/RAF/MEK/ERK signalling pathway is frequently deregulated in human cancers. In this study, we explored the effects of MEK inhibition on the homologous recombination pathway and explored the potential for combination therapy of MEK inhibitors with DDR inhibitors and a hypoxia-activated prodrug. We studied effects of combining pimasertib, a selective allosteric inhibitor of MEK1/2, with olaparib, a small molecule inhibitor of poly (adenosine diphosphate [ADP]-ribose) polymerases (PARP), and with the hypoxia-activated prodrug evofosfamide in ovarian and pancreatic cancer cell lines...
February 20, 2018: Oncotarget
Jennifer Haynes, Trevor D McKee, Andrew Haller, Yadong Wang, Cherry Leung, Deena M A Gendoo, Evelyne Lima-Fernandes, Antonija Kreso, Robin Wolman, Eva Szentgyorgyi, Douglass C Vines, Benjamin Haibe-Kains, Bradly G Wouters, Ur Metser, David A Jaffray, Myles Smith, Catherine A O'Brien
Purpose: Cancer-initiating cells (C-IC) have been described in multiple cancer types, including colorectal cancer. C-ICs are defined by their capacity to self-renew, thereby driving tumor growth. C-ICs were initially thought to be static entities; however, recent studies have determined these cells to be dynamic and influenced by microenvironmental cues such as hypoxia. If hypoxia drives the formation of C-ICs, then therapeutic targeting of hypoxia could represent a novel means to target C-ICs. Experimental Design: Patient-derived colorectal cancer xenografts were treated with evofosfamide, a hypoxia-activated prodrug (HAP), in combination with 5-fluorouracil (5-FU) or chemoradiotherapy (5-FU and radiation; CRT)...
May 1, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Xiulong Shen, Charles H Laber, Ujjal Sarkar, Fabio Galazzi, Kevin M Johnson, Nathaniel G Mahieu, Roman Hillebrand, Tarra Fuchs-Knotts, Charles L Barnes, Gary A Baker, Kent S Gates
Hypoxia-selective cytotoxins (HSCs) seek to exploit the oxygen-poor nature of tumor tissue for therapeutic gain. Typically, HSCs require activation by one-electron bioreductive enzymes such as NADPH:cytochrome P450 reductase (CYPOR). Thus, successful clinical deployment of HSCs may be facilitated by the development and implementation of diagnostic probes that detect the presence of relevant bioreductive enzymes in tumor tissue. The work described here develops analogues of the well-studied HSC tirapazamine (3-amino-1,2,4-benzotriazine 1,4-di- N-oxide, TPZ) as profluorescent substrates of the one-electron reductases involved in bioactivation of HSCs...
March 16, 2018: Journal of Organic Chemistry
Richard W Chapman, Zhili Li, Michel R Corboz, Helena Gauani, Adam J Plaunt, Donna M Konicek, Franziska G Leifer, Charles E Laurent, Han Yin, Dany Salvail, Chad Dziak, Walter R Perkins, Vladimir Malinin
INS1009 is a long acting pulmonary vasodilator prodrug of treprostinil (TRE) that is formulated in a lipid nanoparticle for inhaled delivery by nebulization. This study examined the ability of INS1009 to inhibit vasoconstriction in the pulmonary vasculature of rats and dogs and the extent to which local activity within the lung contributes to its activity. Rats received a single dose of INS1009 by nose-only inhalation or were given a continuous intravenous (i.v.) infusion of TRE, followed by an i.v. challenge of the thromboxane mimetic pulmonary vasoconstrictor U46619 and the increase in pulmonary arterial pressure (PAP) was measured...
April 2018: Pulmonary Pharmacology & Therapeutics
Andrew Brenner, Richard Zuniga, Jessica D Sun, John Floyd, Charles P Hart, Stew Kroll, Lisa Fichtel, David Cavazos, Laura Caflisch, Aleksandra Gruslova, Alessia Lodi, Stephano Tiziani
Background: Antiangiogenic therapy is known to induce a greater degree of hypoxia, including in glioblastoma (GBM). Evofosfamide (Evo) is a hypoxia-activated prodrug which is reduced leading to the release of alkylating agent bromo-isophosphoramide mustard. We assessed the safety, tolerability, preliminary efficacy, and biomarkers of Evo plus bevacizumab (Bev) in Bev refractory glioblastoma. Methods: Twenty-eight patients with Bev refractory GBM were enrolled in a dose escalation study receiving from 240mg/m2 (cohort 1) to 670mg/m2 (cohort 4) of Evo every 2 weeks in combination with Bev...
February 5, 2018: Neuro-oncology
Shujing Liu, Michael T Tetzlaff, Tao Wang, Xiang Chen, Ruifeng Yang, Suresh M Kumar, Adina Vultur, Pengxiang Li, James S Martin, Meenhard Herlyn, Ravi Amaravadi, Bin Li, Xiaowei Xu
Angiogenesis is a critical step during tumor progression. Anti-angiogenic therapy has only provided modest benefits in delaying tumor progression despite its early promise in cancer treatment. It has been postulated that anti-angiogenic therapy may promote the emergence of a more aggressive cancer cell phenotype by generating increased tumor hypoxia-a well-recognized promoter of tumor progression. TH-302 is a 2-nitroimidazole triggered hypoxia-activated prodrug (HAP) which has been shown to selectively target the hypoxic tumor compartment and reduce tumor volume...
December 29, 2017: Oncotarget
Peichen Zhao, Shuangshuang Ren, Yumei Liu, Wei Huang, Chao Zhang, Jian He
The combination of W18 O49 and tirapazamine (TPZ) core has been first introduced into the preparation of poly(ε-caprolactone)-poly(ethylene glycol) (PL) surrounded nanoparticles (NPs). The aim of using W18 O49 is employing its capability of reacting with the absorbed O2 to generate reactive oxygen species (ROS) when exposed to a long-wavelength laser at 808 nm to increase skin penetration and body tolerance. In this work, we have demonstrated that W18 O49 unit gives rise to more hypoxic tumor microenvironment and activates the prodrug TPZ to achieve hypoxia-activated chemotherapy, which could be monitored by the intracellular ROS/hypoxia detection and in vivo positron emission tomography imaging...
January 31, 2018: ACS Applied Materials & Interfaces
Aurélien Voissiere, Valérie Weber, Yvain Gerard, Françoise Rédini, Florian Raes, Jean-Michel Chezal, Françoise Degoul, Caroline Peyrode, Elisabeth Miot-Noirault
Due to its abundant chondrogenic matrix and hypoxic tissue, chondrosarcoma is chemo- and radio-resistant. Our group has developed a proteoglycan targeting strategy by using a quaternary ammonium (QA) function as a carrier of DNA alkylating agents to chondrosarcoma environment. Here, we assessed the relevance of this strategy applied to hypoxia-activated prodrugs, by conjugating a QA to 2-nitroimidazole phosphoramidate. This derivative, named as 8-QA , was evaluated respectively to its non-QA equivalent and to a QA-conjugated but non-hypoxia activated...
November 10, 2017: Oncotarget
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