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enzyme prodrug therapy

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https://www.readbyqxmd.com/read/28741467/status-quo-in-antibody-drug-conjugates-can-glyco-enzymes-solve-the-current-challenges
#1
Florentina Kubizek, Britta Eggenreich, Oliver Spadiut
Over the last years, a novel class of anti-cancer drugs named antibody-drug conjugates (ADCs) has been developed. Due to their limited off-target toxicity but highly potent cytotoxicity at tumor sites, ADCs have proven to be a good alternative to ordinary cancer treatment, such as chemotherapy or combination therapy. Numerous enhancements in antibody-drug engineering led to highly potent tumor targeting drugs with a wide therapeutic window. Two ADCs (Brentuximab vedotin and Trastuzumab emtansine) are already on the market and many others in clinical trials...
July 24, 2017: Protein and Peptide Letters
https://www.readbyqxmd.com/read/28727740/genetically-engineered-suicide-gene-in-mesenchymal-stem-cells-using-a-tet-on-system-for-anaplastic-thyroid-cancer
#2
Senthilkumar Kalimuthu, Ji Min Oh, Prakash Gangadaran, Liya Zhu, Ho Won Lee, Yong Hyun Jeon, Shin Young Jeong, Sang-Woo Lee, Jaetae Lee, Byeong-Cheol Ahn
Anaplastic thyroid cancer (ATC) is the most aggressive malignancy of the thyroid, during which undifferentiated tumors arise from the thyroid follicular epithelium. ATC has a very poor prognosis due to its aggressive behavior and poor response to conventional therapies. Gene-directed enzyme/prodrug therapy using genetically engineered mesenchymal stromal cells (MSC) is a promising therapeutic strategy. The doxycycline (DOX)-controlled Tet inducible system is the most widely utilized regulatory system and could be a useful tool for therapeutic gene-based therapies...
2017: PloS One
https://www.readbyqxmd.com/read/28714209/biotransporting-self-assembled-nanofactories-using-polymer-vesicles-with-molecular-permeability-for-enzyme-prodrug-cancer-therapy
#3
Tomoki Nishimura, Yoshihiro Sasaki, Kazunari Akiyoshi
As "biotransporting nanofactories", in vivo therapeutic biocatalyst nanoreactors would enable encapsulated enzymes to transform inert prodrugs or neutralize toxic compounds at target disease sites. This would offer outstanding potential for next-generation therapeutic platforms, such as enzyme prodrug therapy. Designing such advanced materials has, however, proven challenging. Here, it is shown that self-assembled nanofactories formulate with polymeric vesicles with an intrinsically permeable membrane. The vesicles, CAPsomes, are composed of carbohydrate-b-poly(propylene glycol) and show molecular-weight-depended permeability...
July 17, 2017: Advanced Materials
https://www.readbyqxmd.com/read/28703313/mesenchymal-stem-cells-a-new-platform-for-targeting-suicide-genes-in-cancer
#4
REVIEW
Rana Moradian Tehrani, Javad Verdi, Mahdi Noureddini, Rasoul Salehi, Reza Salarinia, Meysam Mosalaei, Miganosh Simonian, Behrang Alani, Moosa Rahimi Ghiasi, Mahmoud Reza Jaafari, Hamid Reza Mirzaei, Hamed Mirzaie
One of the important strategies for the treatment of cancer is gene therapy which has the potential to exclusively eradicate malignant cells, without any damage to the normal tissues. Gene-directed enzyme prodrug therapy (GDEPT) is a two-step gene therapy approach, where a suicide gene is directed to tumor cells. The gene encodes an enzyme that expressed intracellularly where it is able to convert a prodrug into cytotoxic metabolites. Various delivery systems have been developed to achieve the appropriate levels of tumor restricted expression of chemotherapeutic drugs...
July 13, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28699219/enzyme-prodrug-therapy-engineered-into-electrospun-fibers-with-embedded-liposomes-for-controlled-localized-synthesis-of-therapeutics
#5
Rona Chandrawati, Morten T J Olesen, Thatiane C C Marini, Gurpal Bisra, Anne Géraldine Guex, Marcelo G de Oliveira, Alexander N Zelikin, Molly M Stevens
Enzyme prodrug therapy (EPT) enables localized conversion of inert prodrugs to active drugs by enzymes. Performance of EPT necessitates that the enzyme remains active throughout the time frame of the envisioned therapeutic application. β-glucuronidase is an enzyme with historically validated performance in EPT, however it retains its activity in biomaterials for an insufficiently long period of time, typically not exceeding 7 d. Herein, the encapsulation of β-glucuronidase in liposomal subcompartments within poly(vinyl alcohol) electrospun fibers is reported, leading to the assembly of biocatalytically active materials with activity of the enzyme sustained over at least seven weeks...
July 12, 2017: Advanced Healthcare Materials
https://www.readbyqxmd.com/read/28684168/rnai-prodrugs-targeting-plk1-induce-specific-gene-silencing-in-primary-cells-from-pediatric-t-acute-lymphoblastic-leukemia-patients
#6
Iryna Kolosenko, Elin Edsbäcker, Ann-Charlotte Björklund, Alexander S Hamil, Oksana Goroshchuk, Dan Grandér, Steven F Dowdy, Caroline Palm-Apergi
Epidemiological studies of childhood leukemia survivors reveal an alarmingly high incidence of chronic health disabilities after treatment, therefore, more specific therapies need to be developed. Polo-like kinase 1 (Plk1) is a key player in mitosis and a target for drug development as it is upregulated in multiple cancer types. Small molecules targeting Plk1 are mainly ATP-competitors and, therefore, are known to elicit side effects due to lack of specificity. RNA interference (RNAi) is known for its high catalytic activity and target selectivity; however, the biggest barrier for its introduction into clinical use is its delivery...
July 3, 2017: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/28676386/prodrugs-in-medicinal-chemistry-and-enzyme-prodrug-therapies
#7
Raoul Walther, Jarkko Rautio, Alexander N Zelikin
Prodrugs are cunning derivatives of therapeutic agents designed to improve the pharmacokinetics profile of the drug. Within a prodrug, pharmacological activity of the drug is masked and is recovered within the human body upon bioconversion of the prodrug, a process that is typically mediated by enzymes. This concept is highly successful and a significant fraction of marketed therapeutic formulations is based on prodrugs. An advanced subset of prodrugs can be engineered such as to achieve site-specific bioconversion of the prodrug - to comprise the highly advantageous "enzyme prodrug therapy", EPT...
July 1, 2017: Advanced Drug Delivery Reviews
https://www.readbyqxmd.com/read/28675414/nanotekniken-kan-revolutionera-behandlingen-av-cancer-ger-nya-m%C3%A3-jligheter-att-m%C3%A3-lstyra-l%C3%A3-kemedel-men-flera-stora-utmaningar-%C3%A3-terst%C3%A3-r-att-tackla
#8
Matthias Löhr, Wouter van der Wijngaart, Björn Fagerberg
Nanoparticles for cancer therapy Nanoparticles carry a big promise in oncology, for diagnosis/imaging, therapy, or both (theragnostics). As common in medical history, there is a huge gap between the exciting experimental possibilities and data and clinical studies making use of it. Of the cell-containing nanoparticles, only one formulation using gene-directed enzyme prodrug therapy (GDEPT) with CYP2B1 and ifosfamide was used in early clinical studies. Of the cell-free nanoparticles, some drug-releasing (doxorubicin) ones are in clinical use for trans-arterial chemo-embolization (TACE) in liver tumors and metastasis...
July 3, 2017: Läkartidningen
https://www.readbyqxmd.com/read/28627471/phospholipid-drug-conjugates-as-a-novel-oral-drug-targeting-approach-for-the-treatment-of-inflammatory-bowel-disease
#9
Arik Dahan, Milica Markovic, Svetlana Epstein, Noa Cohen, Ellen M Zimmermann, Aaron Aponick, Shimon Ben-Shabat
The enzyme phospholipase A2 (PLA2) is overexpressed in the inflamed intestine in inflammatory bowel disease (IBD) patients, and in this work we aimed to exploit PLA2 as a prodrug-activating enzyme for a novel PL-drug conjugate, thereby liberating the free drug specifically in the targeted diseased tissue(s). The proposed prodrug contains a drug moiety covalently bound through a linker to the sn-2 position of a phospholipid (PL). The NSAID diclofenac was used as model molecule, and four different linker lengths (2, 4, 6 and 8 -CH2 units) were studied...
June 13, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28602669/the-selective-cytotoxicity-of-new-triazene-compounds-to-human-melanoma-cells
#10
Ana Sousa, Fábio Santos, Maria Manuela Gaspar, Susana Calado, João D Pereira, Eduarda Mendes, Ana Paula Francisco, Maria Jesus Perry
Metastatic melanoma still remains one the most difficult cancers to overcome. The aim of our research was the design of anti-tumour triazene compounds 3 for application to a melanoma-specific therapy. The strategy exploits the unique enzyme pathway of melanin biosynthesis for conversion of non-toxic prodrugs into toxic drugs in the melanoma cell. The compounds 3 were designed by coupling two active moieties, the alkylating triazenes and different tyrosinase substrates. All compounds 3 revealed to be chemically stable in isotonic phosphate buffer (PBS) at physiologic pH (t½≥48h), and most of them showed to be slowly hydrolysed in human plasma (1...
May 31, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28589082/genetically-engineered-vaccinia-viruses-as-agents-for-cancer-treatment-imaging-and-transgene-delivery
#11
REVIEW
Dana Haddad
Despite advances in technology, the formidable challenge of treating cancer, especially if advanced, still remains with no significant improvement in survival rates, even with the most common forms of cancer. Oncolytic viral therapies have shown great promise for the treatment of various cancers, with the possible advantages of stronger treatment efficacy compared to conventional therapy due to higher tumor selectivity, and less toxicity. They are able to preferentially and selectively propagate in cancer cells, consequently destroying tumor tissue mainly via cell lysis, while leaving non-cancerous tissues unharmed...
2017: Frontiers in Oncology
https://www.readbyqxmd.com/read/28582716/combination-of-active-targeting-enzyme-triggered-release-and-fluorescent-dye-into-gold-nanoclusters-for-endomicroscopy-guided-photothermal-photodynamic-therapy-to-pancreatic-ductal-adenocarcinoma
#12
Hui Li, Ping Wang, Yunxiang Deng, Meiying Zeng, Yan Tang, Wei-Hong Zhu, Yingsheng Cheng
Pancreatic ductal adenocarcinoma (PDAC) is one of the most devastating malignancies in patients, and there is an urgent need for an effective treatment method. Herein, we report a novel gold nanocluster-based platform for confocal laser endomicroscopy-guided photothermal therapy (PTT)/photodynamic therapy (PDT) for PDAC, which consists of four components: the PTT-carrier gold nanocluster, an active targeting ligand U11 peptide, a Cathepsin E (CTSE)-sensitive PDT therapy prodrug, and a CTSE-sensitive imaging agent (cyanine dye Cy5...
September 2017: Biomaterials
https://www.readbyqxmd.com/read/28580145/lysosome-oriented-dual-stage-ph-responsive-polymeric-micelles-for-%C3%AE-lapachone-delivery
#13
Yinjian Zhou, Ying Dong, Gang Huang, Yiguang Wang, Xiaonan Huang, Fayun Zhang, David A Boothman, Jinming Gao, Wei Liang
β-Lapachone (β-lap), a novel anticancer agent, is bioactivated by NADP(H):quinone oxidoreductase 1 (NQO1), an enzyme over-expressed in numerous tumors, including lung, pancreas, breast, and prostate cancers. Fast renal clearance and methemaglobinemia / hemolytic side-effects from the clinical formulation (β-lap-hydroxyl propyl-β-cyclodextrin complex) hindered its clinical translation. Here, we investigated a dual model pH responsive polymers for β-lap delivery. Three pH-sensitive linkages, including acylhydrazone, ketal and imine bonds for β-lap prodrug syntheses result in an aryl imine linkage the most optimal linkage...
December 14, 2016: Journal of Materials Chemistry. B, Materials for Biology and Medicine
https://www.readbyqxmd.com/read/28566438/in-vivo-antitumoral-efficacy-of-phac-algp-doxorubicin-an-enzyme-activated-doxorubicin-prodrug-in-patient-derived-soft-tissue-sarcoma-xenograft-models
#14
Jasmien Cornillie, Agnieszka Wozniak, Peter Pokreisz, Andrea Casazza, Lise Vreys, Jasmien Wellens, Ulla Vanleeuw, Yemarshet K Gebreyohannes, Maria Debiec-Rychter, Raf Sciot, Daphne Hompes, Patrick Schöffski
Given the very limited efficacy of doxorubicin (doxo) in soft tissue sarcoma, there is a clear need for more active and less toxic treatments for this family of diseases. However, due to the rarity of these malignancies and lack of reliable preclinical models, development of new therapies has lagged behind. <p>We evaluated the efficacy of PhAc-ALGP-doxorubicin (ALGP-doxo), a prodrug metabolized to doxo by peptidases present in tumor cells and/or tumor microenvironment, in a synovial sarcoma (SynSa) and two dedifferentiated liposarcoma (DDLPS) patient-derived xenograft models...
May 31, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28550753/catalase-loaded-cisplatin-prodrug-constructed-liposomes-to-overcome-tumor-hypoxia-for-enhanced-chemo-radiotherapy-of-cancer
#15
Rui Zhang, Xuejiao Song, Chao Liang, Xuan Yi, Guosheng Song, Yu Chao, Yu Yang, Kai Yang, Liangzhu Feng, Zhuang Liu
Aiming at improved therapeutic efficacies, the combination of chemotherapy and radiotherapy (chemo-radiotherapy) has been widely studied and applied in clinic. However, the hostile characteristics of tumor microenvironment such as hypoxia often limit the efficacies in both types of cancer therapies. Herein, catalase (CAT), an antioxidant enzyme, is encapsulated inside liposomes constituted by cisplatin (IV)-prodrug-conjugated phospholipid, forming CAT@Pt (IV)-liposome for enhanced chemo-radiotherapy of cancer...
September 2017: Biomaterials
https://www.readbyqxmd.com/read/28522586/antitumor-synergism-and-enhanced-survival-with-a-tumor-vasculature-targeted-enzyme-prodrug-system-rapamycin-and-cyclophosphamide
#16
John J Krais, Needa Virani, Partick H McKernan, Quang Nguyen, Kar-Ming Fung, Vassilios I Sikavitsas, Carla D Kurkjian, Roger G Harrison
Mutant cystathionine gamma-lyase was targeted to phosphatidylserine exposed on tumor vasculature through fusion with annexin A1 or annexin A5.  Cystathionine gamma-lyase E58N, R118L, and E338N mutations impart non-native methionine gamma-lyase activity, resulting in tumor-localized generation of highly toxic methylselenol upon systemic administration of non-toxic selenomethionine.  The described therapeutic system circumvents systemic toxicity issues using a novel drug delivery/generation approach and avoids the administration of non-native proteins and/or DNA required with other enzyme prodrug systems...
May 18, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28459452/targeting-genomic-rearrangements-in-tumor-cells-through-cas9-mediated-insertion-of-a-suicide-gene
#17
Zhang-Hui Chen, Yan P Yu, Ze-Hua Zuo, Joel B Nelson, George K Michalopoulos, Satdatshan Monga, Silvia Liu, George Tseng, Jian-Hua Luo
Specifically targeting genomic rearrangements and mutations in tumor cells remains an elusive goal in cancer therapy. Here, we used Cas9-based genome editing to introduce the gene encoding the prodrug-converting enzyme herpes simplex virus type 1 thymidine kinase (HSV1-tk) into the genomes of cancer cells carrying unique sequences resulting from genome rearrangements. Specifically, we targeted the breakpoints of TMEM135-CCDC67 and MAN2A1-FER fusions in human prostate cancer or hepatocellular carcinoma cells in vitro and in mouse xenografts...
June 2017: Nature Biotechnology
https://www.readbyqxmd.com/read/28457884/substrate-mediated-enzyme-prodrug-therapy
#18
REVIEW
Betina Fejerskov, Morten T Jarlstad Olesen, Alexander N Zelikin
Substrate mediated enzyme prodrug therapy (SMEPT) is a biomedical platform developed to perform a localized synthesis of drugs mediated by implantable biomaterials. This approach combines the benefits and at the same time offers to overcome the drawbacks for traditional pill-based drug administration and site-specific, implant mediated drug delivery. Specifically, SMEPT offers the flexibility of delivering multiple drugs - individually as monotherapy, in sequence, or as a combination therapy, all of which is also accomplished in a site-specific manner...
April 27, 2017: Advanced Drug Delivery Reviews
https://www.readbyqxmd.com/read/28454453/targeting-assay-of-a-fusion-protein-applied-in-enzyme-prodrug-therapy
#19
Hao Wang, Jin-Jian Liu, Xiao-Liang Zhou
Tumor growth and metastasis are dependent on angiogenesis. The overexpression of integrin αvβ3 on angiogenic vessels and on numerous malignant human tumor cells suggests that these labeled ligands of integrin are potentially suitable for molecular imaging and in targeted therapy of tumors. In previous studies, we added a β-lactamase variant with reduced immunogenicity to the cyclic peptide RGD4C, resulting in the fusion protein RGD4CβL, which is suitable for use in targeted enzyme prodrug therapy (TEPT), a promising treatment for tumors...
April 2017: Oncology Letters
https://www.readbyqxmd.com/read/28446024/enhanced-vector-design-for-cancer-gene-therapy-with-hierarchical-enhancement-of-therapeutic-transgene-expression
#20
Maria B Kostina, Alexader V Sass, Elena A Stukacheva, Igor V Korobko, Eugeny D Sverdlov
A set of vectors for Cre recombinase-dependent expression of hybrid suicidal FCU1 transgene was constructed which included two-plasmid system where FCU1 and Cre transgenes reside in separate vectors, and single-plasmid variants when a single plasmid bears both transgenes. To improve safety profile and specificity in cancer gene therapy applications, as well as to assure stable propagation of plasmids in bacterial cells, Cre/LoxP system components were optimized. Bicistronic vector with Cre expression cassette placed between LoxP sites unidirectionally with FCU1 cDNA resulted in higher therapeutic efficiency compared to double-plasmid system in enzyme-prodrug suicide cancer gene therapy scheme...
April 27, 2017: Human Gene Therapy Methods
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