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enzyme prodrug therapy

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https://www.readbyqxmd.com/read/28412325/designing-metal-contained-enzyme-mimics-for-prodrug-activation
#1
REVIEW
Baoji Du, Dan Li, Jin Wang, Erkang Wang
Enzyme-activated prodrug therapy (EAPT) is a widely-used and effective treatment method for cancer by converting the prodrugs into the drugs at the demanded time and space, whose key step is prodrug activation. Traditional prodrug activations are mostly dependent on the natural enzymes, which are unstable, expensive and hard to be functionalized. The emerging enzyme mimics, especially the metal-contained enzyme mimics (MEMs), provide a potential chance for improving the traditional EAPT because of their high stability, low cost and easiness of preparation and functionalization...
April 12, 2017: Advanced Drug Delivery Reviews
https://www.readbyqxmd.com/read/28395199/design-synthesis-and-biological-evaluation-of-nad-p-h-quinone-oxidoreductase-nqo1-targeted-oridonin-prodrugs-possessing-indolequinone-moiety-for-hypoxia-selective-activation
#2
Shengtao Xu, Hong Yao, Lingling Pei, Mei Hu, Dahong Li, Yangyi Qiu, Guangyu Wang, Liang Wu, Hequan Yao, Zheying Zhu, Jinyi Xu
The enzyme NQO1 is a potential target for selective cancer therapy due to its overexpression in certain hypoxic tumors. A series of prodrugs possessing a variety of cytotoxic diterpenoids (oridonin and its analogues) as the leaving groups activated by NQO1 were synthesized by functionalization of 3-(hydroxymethyl)indolequinone, which is a good substrate of NQO1. The target compounds (29a-m) exhibited relatively higher antiproliferative activities against NQO1-rich human colon carcinoma cells (HT-29) and human lung carcinoma (A549) cells (IC50 = 0...
March 25, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28262557/engineering-a-multifunctional-nitroreductase-for-improved-activation-of-prodrugs-and-pet-probes-for-cancer-gene-therapy
#3
Janine N Copp, Alexandra M Mowday, Elsie M Williams, Christopher P Guise, Amir Ashoorzadeh, Abigail V Sharrock, Jack U Flanagan, Jeff B Smaill, Adam V Patterson, David F Ackerley
Gene-directed enzyme-prodrug therapy (GDEPT) is a promising anti-cancer strategy. However, inadequate prodrugs, inefficient prodrug activation, and a lack of non-invasive imaging capabilities have hindered clinical progression. To address these issues, we used a high-throughput Escherichia coli platform to evolve the multifunctional nitroreductase E. coli NfsA for improved activation of a promising next-generation prodrug, PR-104A, as well as clinically relevant nitro-masked positron emission tomography-imaging probes EF5 and HX4, thereby addressing a critical and unmet need for non-invasive bioimaging in nitroreductase GDEPT...
March 16, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28259838/enzyme-responsive-peptide-dendrimer-gemcitabine-conjugate-as-a-controlled-release-drug-delivery-vehicle-with-enhanced-antitumor-efficacy
#4
Chengyuan Zhang, Dayi Pan, Jin Li, Jiani Hu, Ashika Bains, Nicholas Guys, Hongyan Zhu, Xiaohui Li, Kui Luo, Qiyong Gong, Zhongwei Guc
Stimuli-responsive peptide dendrimer-drug conjugates have presented significant potential for cancer therapy. To develop an effective nanoscale chemotherapeutic prodrug, we developed a novel enzyme-responsive PEGylated lysine peptide dendrimer-gemcitabine conjugate (Dendrimer-GEM) based nanoparticle via the highly efficient click reaction. Owing to the glycylphenylalanylleucylglycine tetra-peptide (GFLG) as an enzyme-cleavable linker to conjugate gemcitabine (GEM), the prepared nanoparticles were able to release drug significantly faster in the tumor cellular environments, which specifically contains secreted Cathepsin B, quantifiably more than 80% GEM was released with Cathepsin B compared to the condition without Cathepsin B at 24h...
March 1, 2017: Acta Biomaterialia
https://www.readbyqxmd.com/read/28257943/photodynamic-therapy-enhances-the-efficacy-of-gene-directed-enzyme-prodrug-therapy
#5
Catherine Christie, Aftin Pomeroy, Rohit Nair, Kristian Berg, Henry Hirschberg
INTRODUCTION: Gene-directed enzyme prodrug therapy (GDEPT) employing the cytosine deaminase (CD) gene, which encodes an enzyme that converts the nontoxic agent 5-fluorocytosine (5-FC) into the chemotherapeutic drug 5-fluorouracil (5-FU), has shown promise both in experimental animals and in clinical trials. Nevertheless, with the transfection systems available presently the percentage of tumor cells incorporating the desired gene is usually too low for successful therapy. We have examined the ability of photodynamic therapy (PDT) to enhance the efficacy of the metabolites, converted from 5-FC by CD gene transfected rat glioma cells...
February 28, 2017: Photodiagnosis and Photodynamic Therapy
https://www.readbyqxmd.com/read/28164519/angiotensin-converting-enzyme-inhibitors-influence-on-antiplatelet-therapy-of-clopidogrel-in-acs
#6
Shuo Yang, Chanjuan Cui, Jie Zhang, Rui Qiao
BACKGROUND: Clopidogrel is a prodrug, the minority of which is converted to an active metabolite by hepatic cytochrome P450 (CYP2C19), however, most of it is metabolized to inactive substance by hepatic carboxylesterase1 (CES1). Meanwhile angiotensin-converting enzyme inhibitors (ACEIs) are mostly metabolized by CES1. We aimed to assess the impact of ACEIs on platelet inhibition by clopidogrel. METHODS: We genotyped variants CES1, CYP2C19*2 and *3 in 502 patients with acute coronary syndrome (ACS) receiving clopidogrel therapy, and analyzed the effects of ACEIs on responsiveness to clopidogrel by the vasodilator-stimulated phosphoprotein (VASP) phosphorylation assay and ADP-stimulated impedance whole blood platelet aggregation assay...
October 1, 2016: Clinical Laboratory
https://www.readbyqxmd.com/read/28148846/tumor-homing-cytotoxic-human-induced-neural-stem-cells-for-cancer-therapy
#7
Juli R Bagó, Onyi Okolie, Raluca Dumitru, Matthew G Ewend, Joel S Parker, Ryan Vander Werff, T Michael Underhill, Ralf S Schmid, C Ryan Miller, Shawn D Hingtgen
Engineered neural stem cells (NSCs) are a promising approach to treating glioblastoma (GBM). The ideal NSC drug carrier for clinical use should be easily isolated and autologous to avoid immune rejection. We transdifferentiated (TD) human fibroblasts into tumor-homing early-stage induced NSCs (h-iNSC(TE)), engineered them to express optical reporters and different therapeutic gene products, and assessed the tumor-homing migration and therapeutic efficacy of cytotoxic h-iNSC(TE) in patient-derived GBM models of surgical and nonsurgical disease...
February 1, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28116598/enterolactone-glucuronide-and-%C3%AE-glucuronidase-in-antibody-directed-enzyme-prodrug-therapy-for-targeted-prostate-cancer-cell-treatment
#8
Yunyun Di, Shaoping Ji, Philipp Wolf, Ed S Krol, Jane Alcorn
Evidence from preclinical and animal studies demonstrated an anticancer effect of flaxseed lignans, particularly enterolactone (ENL), against prostate cancer. However, extensive first-pass metabolism following oral lignan consumption results in their systemic availability primarily as glucuronic acid conjugates (ENL-Gluc) and their modest in vivo effects. To overcome the unfavorable pharmacokinetics and improve their effectiveness in prostate cancer, antibody-directed enzyme prodrug therapy (ADEPT) might offer a novel strategy to allow for restricted activation of ENL from circulating ENL-Gluc within the tumor environment...
January 23, 2017: AAPS PharmSciTech
https://www.readbyqxmd.com/read/28112512/enzyme-sensitive-and-amphiphilic-pegylated-dendrimer-paclitaxel-prodrug-based-nanoparticles-for-enhanced-stability-and-anticancer-efficacy
#9
Ning Li, Hao Cai, Lei Jiang, Jiani Hu, Ashika Bains, Jesse Hu, Qiyong Gong, Kui Luo, Zhongwei Gu
In this study, we prepared a smart polymeric vehicle for the hydrophobic drug paclitaxel (PTX) that allowed a maximum steady-state circulation and a fast intracellular release in tumors. PTX was linked to the Janus PEGylated (PEG = poly(ethylene glycol)) peptide dendrimer via an enzyme-sensitive linker glycylphenylalanylleucylglycine tetrapeptide by efficient click reaction, resulting in Janus dendritic prodrug with 20.9% PTX content. The prodrug self-assembled into nanoscale particles with appropriate nanosizes, compact morphology, and negative surface charge...
March 1, 2017: ACS Applied Materials & Interfaces
https://www.readbyqxmd.com/read/28042530/enzyme-prodrug-systems-for-cancer-gene-therapy
#10
Obeid M Malekshah, Xuguang Chen, Alireza Nomani, Siddik Sarkar, Arash Hatefi
The use of enzyme/prodrug system has gained attention because it could help improve the efficacy and safety of conventional cancer chemotherapies. In this approach, cancer cells are first transfected with a gene that can express an enzyme with ability to convert a non-toxic prodrug into its active cytotoxic form. As a result, the activated prodrug could kill the transfected cancer cells. Despite the significant progress of different suicide gene therapy protocols in preclinical studies and early clinical trials, none has reached the clinic due to several shortcomings...
December 2016: Current Pharmacology Reports
https://www.readbyqxmd.com/read/28017891/self-immolative-nanoparticles-for-simultaneous-delivery-of-microrna-and-targeting-of-polyamine-metabolism-in-combination-cancer-therapy
#11
Ying Xie, Tracy Murray-Stewart, Yazhe Wang, Fei Yu, Jing Li, Laurence J Marton, Robert A Casero, David Oupický
Combination of anticancer drugs with therapeutic microRNA (miRNA) has emerged as a promising anticancer strategy. However, the promise is hampered by a lack of desirable delivery systems. We report on the development of self-immolative nanoparticles capable of simultaneously delivering miR-34a mimic and targeting dysregulated polyamine metabolism in cancer. The nanoparticles were prepared from a biodegradable polycationic prodrug, named DSS-BEN, which was synthesized from a polyamine analog N(1),N(11)-bisethylnorspermine (BENSpm)...
January 28, 2017: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/28005335/tumor-specific-multiple-stimuli-activated-dendrimeric-nanoassemblies-with-metabolic-blockade-surmount-chemotherapy-resistance
#12
Yachao Li, Xianghui Xu, Xiao Zhang, Yunkun Li, Zhijun Zhang, Zhongwei Gu
Chemotherapy resistance remains a serious impediment to successful antitumor therapy around the world. However, existing chemotherapeutic approaches are difficult to cope with the notorious multidrug resistance in clinical treatment. Herein, we developed tumor-specific multiple stimuli-activated dendrimeric nanoassemblies with a metabolic blockade to completely combat both physiological barriers and cellular factors of multidrug resistance. With a sophisticated molecular and supramolecular engineering, this type of tumor-specific multiple stimuli-activated nanoassembly based on dendrimeric prodrugs can hierarchically break through the sequential physiological barriers of drug resistance, including stealthy dendritic PEGylated corona to optimize blood transportation, robust nanostructures for efficient tumor passive targeting and accumulation, enzyme-activated tumor microenvironment targeted to deepen tumor penetration and facilitate cellular uptake, cytoplasmic redox-sensitive disintegration for sufficient release of encapsulated agents, and lysosome acid-triggered nucleus delivery of antitumor drugs...
December 27, 2016: ACS Nano
https://www.readbyqxmd.com/read/27986921/development-of-a-cancer-marker-activated-enzymatic-switch-from-the-herpes-simplex-virus-thymidine-kinase
#13
Nirav Y Shelat, Sidhartha Parhi, Marc Ostermeier
Discovery of new cancer biomarkers and advances in targeted gene delivery mechanisms have made gene-directed enzyme prodrug therapy (GDEPT) an attractive method for treating cancer. Recent focus has been placed on increasing target specificity of gene delivery systems and reducing toxicity in non-cancer cells in order to make GDEPT viable. To help address this challenge, we have developed an enzymatic switch that confers higher prodrug toxicity in the presence of a cancer marker. The enzymatic switch was derived from the herpes simplex virus thymidine kinase (HSV-TK) fused to the CH1 domain of the p300 protein...
December 15, 2016: Protein Engineering, Design & Selection: PEDS
https://www.readbyqxmd.com/read/27986920/annexin-directed-%C3%AE-glucuronidase-for-the-targeted-treatment-of-solid-tumors
#14
Katrin P Guillen, Eliza A Ruben, Needa Virani, Roger G Harrison
Enzyme prodrug therapy has the potential to remedy the lack of selectivity associated with the systemic administration of chemotherapy. However, most current systems are immunogenic and constrained to a monotherapeutic approach. We developed a new class of fusion proteins centered about the human enzyme β-glucuronidase (βG), capable of converting several innocuous prodrugs into chemotherapeutics. We targeted βG to phosphatidylserine on tumor cells, tumor vasculature and metastases via annexin A1/A5. Phosphatidylserine shows promise as a universal marker for solid tumors and allows for tumor type-independent targeting...
February 2017: Protein Engineering, Design & Selection: PEDS
https://www.readbyqxmd.com/read/27986535/reduction-of-quinones-and-nitroaromatic-compounds-by-escherichia-coli-nitroreductase-a-nfsa-characterization-of-kinetics-and-substrate-specificity
#15
Benjaminas Valiauga, Elsie M Williams, David F Ackerley, Narimantas Čėnas
NfsA, a major FMN-associated nitroreductase of E. coli, reduces nitroaromatic compounds via consecutive two-electron transfers. NfsA has potential applications in the biodegradation of nitroaromatic environment pollutants, e.g. explosives, and is also of interest for the anticancer strategy gene-directed enzyme prodrug therapy. However, the catalytic mechanism of NfsA is poorly characterized. Here we examined the NADPH-dependent reduction of quinones (n = 16) and nitroaromatic compounds (n = 12) by NfsA...
January 15, 2017: Archives of Biochemistry and Biophysics
https://www.readbyqxmd.com/read/27974807/long-term-neprilysin-inhibition-implications-for-arnis
#16
REVIEW
Duncan J Campbell
Neprilysin has a major role in both the generation and degradation of bioactive peptides. LCZ696 (valsartan/sacubitril, Entresto), the first of the new ARNI (dual-acting angiotensin-receptor-neprilysin inhibitor) drug class, contains equimolar amounts of valsartan, an angiotensin-receptor blocker, and sacubitril, a prodrug for the neprilysin inhibitor LBQ657. LCZ696 reduced blood pressure more than valsartan alone in patients with hypertension. In the PARADIGM-HF study, LCZ696 was superior to the angiotensin-converting enzyme inhibitor enalapril for the treatment of heart failure with reduced ejection fraction, and LCZ696 was approved by the FDA for this purpose in 2015...
March 2017: Nature Reviews. Cardiology
https://www.readbyqxmd.com/read/27966832/design-of-block-copolymer-micellar-aggregates-for-co-delivery-of-enzyme-and-anticancer-prodrug
#17
Hongping Li, Lulu Chen, Yuting Shi, Binbin Yuan, Yingxia Ma, Hua Wei, Guanghui Zhao
Traditional enzyme-prodrug therapy (EPT) is a two-step strategy, which has many serious deficiencies, so having a one-step EPT treatment becomes a problem of immediate interest. This study aims to achieve an effective co-delivery of horseradish peroxidase (HRP) as a kind of enzyme for prodrug activation and ethyl 3-indoleacetate (EIA) as anticancer prodrug. A ternary block copolymer PEG-PAsp(AED)-CA consisting of poly(ethylene glycol) (PEG), reduction-sensitive poly (N-(2,2'-dithiobis(ethylamine)) aspartamide) PAsp(AED), and cholic acid (CA) was synthesized and assembled into spherical micelles which encapsulated EIA in its hydrophobic core and HRP in a reduction-sensitive interlayer...
December 14, 2016: Chemistry, An Asian Journal
https://www.readbyqxmd.com/read/27754187/sp-04-2-lcz-696-a-new-paradigm-shift-for-the-treatment-of-heart-failure
#18
ByungSu Yoo
Heart failure (HF) represents a significant healthcare issue because of its ever-increasing prevalence, poor prognosis and complex pathophysiology. The cornerstone of modern drug therapy in chronic HF is the inhibition of neurohormonal activation that plays a crucial role in the pathophysiology of HF development and progression and, more specifically, of the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system. LCZ696 is a first-in-class, angiotensin receptor NEP inhibitor (ARNI) that consists of a supramolecular complex of a molecule of the ARB valsartan in combination with a molecule of the NEP inhibitor prodrug AHU377 (also known as sacubitril)...
September 2016: Journal of Hypertension
https://www.readbyqxmd.com/read/27749047/stimulus-responsive-prochelators-for-manipulating-cellular-metals
#19
Qin Wang, Katherine J Franz
Metal ions are essential for a wide range of physiological processes, but they can also be toxic if not appropriately regulated by a complex network of metal trafficking proteins. Intervention in cellular metal distribution with small-molecule or peptide chelating agents has promising therapeutic potential to harness metals to fight disease. Molecular outcomes associated with forming metal-chelate interactions in situ include altering the concentration and subcellular metal distribution, inhibiting metalloenzymes, enhancing the reactivity of a metal species to elicit a favorable biological response, or passivating the reactivity of a metal species to prevent deleterious reactivity...
November 15, 2016: Accounts of Chemical Research
https://www.readbyqxmd.com/read/27737561/translating-antibody-directed-enzyme-prodrug-therapy-adept-and-prospects-for-combination
#20
Surinder K Sharma, Kenneth D Bagshawe
The generation of cytotoxic drugs, selectively within tumours, from non-toxic prodrugs by targeted enzymes provides a powerful system for cancer therapy. In the form of Antibody directed enzyme prodrug therapy (ADEPT), this approach has shown feasibility in the clinic. Areas covered: Although numerous enzyme prodrug combinations have been reported over the last two decades, only the CPG2 ADEPT system has progressed to clinical trials. Using readily available components such as chemical antibody enzyme conjugate or recombinant multifunctional fusion protein, delivery of a specific enzyme to tumours, its elimination from non-tumour sites and prodrug activation has been achieved with therapeutic benefit in the clinic...
January 2017: Expert Opinion on Biological Therapy
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