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enzyme prodrug therapy

Rammohan Devulapally, Taehwa Lee, Aarohi Barghava-Shah, Thillai V Sekar, Kira Foygel, Sunitha V Bachawal, Jürgen K Willmann, Ramasamy Paulmurugan
AIM: Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype. Since no targeted therapy is available, gene-directed enzyme prodrug therapy (GDEPT) could be an attractive strategy for treating TNBC. MATERIALS & METHODS:  Polyethylene glycol (PEG)ylated-poly(lactic-co-glycolic acid)/polyethyleneimine nanoparticles (PLGA/PEI NPs) were synthesized and complexed with TK-NTR fusion gene. Ultrasound (US) and microbubble (MB) mediated sonoporation was used for efficient delivery of the TK-NTR-DNA-NP complex to TNBC tumor in vivo for cancer therapy...
May 2018: Nanomedicine
Huicong Zhang, Zhisu Sun, Kuanglei Wang, Na Li, Hongxiang Chen, Xiao Tan, Lingxiao Li, Zhonggui He, Jin Sun
We report a new type of amide bond-bearing cathepsin B-sensitive gemcitabine (GEM) prodrugs, capable of in situ covalently targeting circulating albumin and then making a hitchhike to the tumor. Specially, less plasma-enzyme deactivation, long plasma half-life, independence on nucleoside transporters, outstanding tumor targeting and site-specific drug release are achieved and such these multifunctional advantages contribute to the dramatically increased in vivo antitumor efficacy.
May 18, 2018: Bioconjugate Chemistry
Wakako Yano, Tatsushi Yokogawa, Takeshi Wakasa, Keisuke Yamamura, Akio Fujioka, Kunihiro Yoshisue, Eiji Matsushima, Seiji Miyahara, Hitoshi Miyakoshi, Junko Taguchi, Khoon Tee Chong, Yayoi Takao, Masayoshi Fukuoka, Kenichi Matsuo
5-Fluorouracil (5-FU) is an antimetabolite and exerts antitumor activity via intracellularly and physiologically complicated metabolic pathways. In this study, we designed a novel small molecule inhibitor, TAS-114, which targets the intercellular metabolism of 5-FU to enhance antitumor activity and modulates catabolic pathway to improve the systemic availability of 5-FU. TAS-114 strongly and competitively inhibited deoxyuridine 5'-triphosphate nucleotidohydrolase (dUTPase), a gatekeeper protein preventing aberrant base incorporation into DNA, and enhanced the cytotoxicity of fluoropyrimidines in cancer cells; however, it had little intrinsic activity...
May 10, 2018: Molecular Cancer Therapeutics
Prativa Sahoo, Paul Frankel, Julie Ressler, Margarita Gutova, Alexander J Annala, Behnam Badie, Jana Portnow, Karen S Aboody, Massimo D'Apuzzo, Russell C Rockne
Background: The aim of this study was to correlate T1-weighted dynamic contrast-enhanced MRI- (DCE-MRI-) derived perfusion parameters with overall survival of recurrent high-grade glioma patients who received neural stem cell- (NSC-) mediated enzyme/prodrug gene therapy. Methods: A total of 12 patients were included in this retrospective study. All patients were enrolled in a first-in-human study (NCT01172964) of NSC-mediated therapy for recurrent high-grade glioma...
2018: Stem Cells International
Rajesh K Singh, Sahil Kumar, D N Prasad, T R Bhardwaj
Cancer is considered as one of the most serious health problems today. The discovery of nitrogen mustard as an alkylating agent in 1942, opened a new era in the cancer chemotherapy. This valuable class of alkylating agent exerts its biological activity by binding to DNA, cross linking two strands, preventing DNA replication and ultimate cell death. At the molecular level, nitrogen lone pairs of nitrogen mustard generate a strained intermediate "aziridinium ion" which is very reactive towards DNA of tumor cell as well as normal cell resulting in various adverse side effects alogwith therapeutic implications...
April 3, 2018: European Journal of Medicinal Chemistry
Chuan Hu, Xingli Cun, Shaobo Ruan, Rui Liu, Wei Xiao, Xiaotong Yang, Yuanyuan Yang, Chuanyao Yang, Huile Gao
Chemotherapy remains restricted by poor drug delivery efficacy due to the heterogenous nature of tumor. Herein, we presented a novel nanoparticle that could not only response to the tumor microenvironment but also modulate it for deep tumor penetration and combination therapy. The intelligent nanoparticle (IDDHN) was engineered by hyaluronidase (HAase)-triggered size shrinkable hyaluronic acid shells, which were modified with NIR laser sensitive nitric oxide donor (HN), small-sized dendrimeric prodrug (IDD) of doxorubicin (DOX) as chemotherapy agent and indocyanine green (ICG) as photothermal agent into a single nanoparticle...
March 27, 2018: Biomaterials
Needa A Virani, Elangovan Thavathiru, Patrick McKernan, Kathleen Moore, Doris M Benbrook, Roger G Harrison
Approximately 75% of ovarian cancer is diagnosed once metastasis to the peritoneal cavity has occurred. A large proportion of patients eventually develop platinum-resistive tumors, which are considered terminal. In order to provide an alternative a novel fusion protein, mCTH-ANXA5, has been developed for the treatment of recurrent, metastatic ovarian cancer. The fusion protein combines annexin V (ANXA5), an ovarian tumor and tumor vasculature targeting protein, with mutated cystathionine gamma-lyase (mCTH), an enzyme that converts selenomethionine (SeMet) into toxic methylselenol, which generates reactive oxygen species and eventual tumor cell death...
March 21, 2018: Cancer Letters
Jean Felix Mukerabigwi, Zhishen Ge, Kazunori Kataoka
Therapeutic nanoreactors have been proposed as nanoplatforms to treat diseases through in situ production of therapeutic agents. When this treatment strategy is applied in cancer therapy, it can efficiently in situ produce the highly toxic anticancer drugs from low-toxic prodrugs or some biomolecules in tumor tissues, which can maximize the therapeutic efficacy with a significantly low systemic toxicity. An ideal therapeutic nanoreactor can provide the reaction space, protect the loaded fragile catalysts, target to the desired pathological site, and be selectively activated...
March 23, 2018: Chemistry: a European Journal
Anna K Winther, Betina Fejerskov, Marja Ter Meer, Najah B S Jensen, Ross Dillion, Jeremy E Schaffer, Rona Chandrawati, Molly M Stevens, Leo J Schultze Kool, Ulf Simonsen, Alexander N Zelikin
Nitric oxide (NO) is a highly potent but short-lived endogenous radical with a wide spectrum of physiological activities. In this work, we developed an enzymatic approach to the site-specific synthesis of NO mediated by biocatalytic surface coatings. Multilayered polyelectrolyte films were optimized as host compartments for the immobilized β-galactosidase (β-Gal) enzyme through a screen of eight polycations and eight polyanions. The lead composition was used to achieve localized production of NO through the addition of β-Gal-NONOate, a prodrug that releases NO following enzymatic bioconversion...
March 23, 2018: ACS Applied Materials & Interfaces
Xizhen Lian, Yanyan Huang, Yuanyuan Zhu, Yu Fang, Rui Zhao, Elizabeth Joseph, Jialuo Li, Jean-Philippe Pellois, Hong-Cai Zhou
Prodrug activation, by exogenously administered enzymes, for cancer therapy is an approach to achieve better selectivity and less systemic toxicity than conventional chemotherapy. However, the short half-lives of the activating enzymes in the bloodstream has limited its success. Demonstrated here is that a tyrosinase-MOF nanoreactor activates the prodrug paracetamol in cancer cells in a long-lasting manner. By generating reactive oxygen species (ROS) and depleting glutathione (GSH), the product of the enzymatic conversion of paracetamol is toxic to drug-resistant cancer cells...
May 14, 2018: Angewandte Chemie
Raquel T Yokoda, Bolni M Nagalo, Mitesh J Borad
Gastrointestinal malignancies are challenging cancers with considerable economic and societal impacts on health care systems worldwide. While advances in surgical approaches have provided benefits to a proportion of patients, only modest improvements have been attained in the treatment of patients with advanced disease, resulting in limited improvement in survival rates in these patients. Oncolytic adenoviruses are being developed to address gastrointestinal malignancies. Each platform has evolved to maximize tumor-cell killing potency while minimizing toxicities...
March 11, 2018: Biomedicines
Daniel Elbaum, Maria G Beconi, Edith Monteagudo, Annalise Di Marco, Maria S Quinton, Kathryn A Lyons, Andrew Vaino, Steven Harper
In cells, phosphorylation of pantothenic acid to generate phosphopantothenic acid by the pantothenate kinase enzymes is the first step in coenzyme A synthesis. Pantothenate kinase 2, the isoform localized in neuronal cell mitochondria, is dysfunctional in patients with pantothenate kinase-associated neurodegeneration. Fosmetpantotenate is a phosphopantothenic acid prodrug in clinical development for treatment of pantothenate kinase-associated neurodegeneration, which aims to replenish phosphopantothenic acid in patients...
2018: PloS One
Gregor Fuhrmann, Rona Chandrawati, Paresh A Parmar, Timothy J Keane, Stephanie A Maynard, Sergio Bertazzo, Molly M Stevens
Extracellular vesicles (EVs) have recently gained significant attention as important mediators of intercellular communication, potential drug carriers, and disease biomarkers. These natural cell-derived nanoparticles are postulated to be biocompatible, stable under physiological conditions, and to show reduced immunogenicity as compared to other synthetic nanoparticles. Although initial clinical trials are ongoing, the use of EVs for therapeutic applications may be limited due to undesired off-target activity and potential "dilution effects" upon systemic administration which may affect their ability to reach their target tissues...
April 2018: Advanced Materials
Kanchan Chauhan, Juan M Hernandez-Meza, Ana G Rodríguez-Hernández, Karla Juarez-Moreno, Prakhar Sengar, Rafael Vazquez-Duhalt
BACKGROUND: Tamoxifen is the standard endocrine therapy for breast cancers, which require metabolic activation by cytochrome P450 enzymes (CYP). However, the lower and variable concentrations of CYP activity at the tumor remain major bottlenecks for the efficient treatment, causing severe side-effects. Combination nanotherapy has gained much recent attention for cancer treatment as it reduces the drug-associated toxicity without affecting the therapeutic response. RESULTS: Here we show the modular design of P22 bacteriophage virus-like particles for nanoscale integration of virus-driven enzyme prodrug therapy and photodynamic therapy...
February 20, 2018: Journal of Nanobiotechnology
S V Kalinichenko, M V Shepelev, P N Vikhreva, I V Korobko
describe a novel hybrid tumor-specific promoter, ARE-hTERT, composed of the human TERT gene promoter (hTERT) and the antioxidant response element (ARE) from the human GCLM gene promoter. The hybrid promoter retains the tumor specificity of the basal hTERT promoter but is characterized by an enhanced transcriptional activity in cancer cells with abnormal activation of the Nrf2 transcription factor and upon induction of oxidative stress. In the in vitro enzyme-prodrug cancer gene therapy scheme, ARE-hTERT promoter-driven expression of CD : UPRT (yeast cytosine deaminase : uracil phosphoribosyltransferase) chimeric protein induced a more pronounced death of cancer cells either upon treatment with 5-fluorouracil (5FC) alone or when 5FC was combined with chemotherapeutic drugs as compared to the hTERT promoter...
October 2017: Acta Naturae
Fatma Haddad, Maryam Sawalha, Yahya Khawaja, Anas Najjar, Rafik Karaman
Background : Parkinson's disease is an aggressive and progressive neurodegenerative disorder that depletes dopamine (DA) in the central nervous system. Dopamine replacement therapy, mainly through actual dopamine and its original prodrug l-dopa (LD), faces many challenges such as poor blood brain barrier penetration and decreased response to therapy with time. Methods : The prodrugs described herein are ester, amide, dimeric amide, carrier-mediated, peptide transport-mediated, cyclic, chemical delivery systems and enzyme-models prodrugs designed and made by chemical means, and their bioavailability was studied in animals...
December 25, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Praveen Reddy Adiyala, Venkatesh Tekumalla, Ibrahim Bin Sayeed, V Lakshma Nayak, Apoorva Nagarajan, Mohd Adil Shareef, Burri Nagaraju, Ahmed Kamal
Cancer chemotherapy has several limitations such as often insufficient differentiation between malign tissue and benign tissue. The clinical utility of the pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are inadequate because of the lack of selectivity for tumor tissues, high reactivity of the pharmacophoric imine functionality, low water solubility, and stability. To address these limitations two new β-glucoside prodrugs of PBDs have been synthesized and evaluated for their potential use in selective therapy of solid tumors by ADEPT...
February 2018: Bioorganic Chemistry
Tugba Gungor, Gulden Yetis, Ferah Cömert Onder, Esra Tokay, Tugba Taşkın Tok, Ayhan Celik, Mehmet Ay, Feray Kockar
BACKGROUND: Directed Enzyme Prodrug Therapy (DEPT) as an alternative method against conventional cancer treatments, in which the non-toxic prodrug is converted to highly cytotoxic derivative, has attracted an ample attentions in recent years for cancer therapy studies. OBJECTIVE: The metabolite profile, cell cytotoxicity and molecular modeling interactions of a series of nitro benzamides with Ssap-NtrB were investigated in this study. METHOD: A series of nitro-substituted benzamide prodrugs (1-4) were synthesized and firstly investigated their enzymatic reduction by Ssap-NtrB (S...
November 29, 2017: Medicinal Chemistry
Amit Sharma, Eun-Joong Kim, Hu Shi, Jin Yong Lee, Bong Geun Chung, Jong Seung Kim
The high incidence of colorectal cancer worldwide is currently a major health concern. Although conventional chemotherapy and surgery are effective to some extent, there is always a risk of relapse due to associated side effects, including post-surgical complications and non-discrimination between cancer and normal cells. In this study, we developed a small molecule-based theranostic system, Gal-Dox, which is preferentially taken up by colon cancer cells through receptor-mediated endocytosis. After cancer-specific activation, the active drug Dox (doxorubicin) is released with a fluorescence turn-on response, allowing both drug localization and site of action to be monitored...
February 2018: Biomaterials
Michelle H Rich, Abigail V Sharrock, Kelsi R Hall, David F Ackerley, Joanna K MacKichan
OBJECTIVES: To characterize the activities of two candidate nitroreductases, Neisseria meningitidis NfsA (NfsA_Nm) and Bartonella henselae (PnbA_Bh), with the nitro-prodrugs, CB1954 and metronidazole, and the environmental pollutants 2,4- and 2,6-dinitrotoluene. RESULTS: NfsA_Nm and PnbA_Bh were evaluated in Escherichia coli over-expression assays and as His6 -tagged proteins in vitro. With the anti-cancer prodrug CB1954, both enzymes were more effective than the canonical O2 -insensitive nitroreductase E...
February 2018: Biotechnology Letters
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