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Mousumi Pal, Utpal Nandi, Debaraj Mukherjee
Ruthenium (Ru) complexes are known for their promising anticancer activity presumably due to octahedral coordination geometry, slow ligand exchange rate, the range of different oxidation states and target specificity. This review article summarizes the physicochemical processes which are responsible for the selectivity of Ru complexes toward cancer cells over the normal cells. Emphasis has been given on the activation mechanism of Ru(III) complex administered as a prodrug and then the release of active species in an acidic environment of cancer cell through normal or photo induced hydrolysis or ligand oxidation...
March 7, 2018: European Journal of Medicinal Chemistry
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
Muyang Yang, Lixia Yu, Ruiwei Guo, Anjie Dong, Cunguo Lin, Jianhua Zhang
Synergistic combination therapy by integrating chemotherapeutics and chemosensitizers into nanoparticles has demonstrated great potential to reduce side effects, overcome multidrug resistance (MDR), and thus improve therapeutic efficacy. However, with regard to the nanocarriers for multidrug codelivery, it remains a strong challenge to maintain design simplicity, while incorporating the desirable multifunctionalities, such as coloaded high payloads, targeted delivery, hemodynamic stability, and also to ensure low drug leakage before reaching the tumor site, but simultaneously the corelease of drugs in the same cancer cell...
March 15, 2018: Nanomaterials
Michał Romański, Anna Zacharzewska, Artur Teżyk, Franciszek K Główka
BACKGROUND AND OBJECTIVES: Treosulfan is a prodrug applied in the treatment of ovarian cancer and conditioning prior to stem cell transplantation. So far, the bioanalysis of treosulfan in either whole blood or red blood cells (RBC) has not been carried out. In this work, the RBC/plasma partition coefficient (Ke/p ) of treosulfan and its active monoepoxide was determined for the first time. METHODS: Male and female 10-week-old Wistar rats (n = 6/6) received an intraperitoneal injection of treosulfan at the dose of 500 mg/kg body weight...
March 14, 2018: European Journal of Drug Metabolism and Pharmacokinetics
Xizhen Lian, Yanyan Huang, Yuanyuan Zhu, Yu Fang, Rui Zhao, Elizabeth Joseph, Jialuo Li, Jean-Phillipe Pellois, Hongcai 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 bloodstream has limited its success. Here, we demonstrate 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 enzymatic conversion of paracetamol is toxic to drug-resistant cancer cells...
March 13, 2018: Angewandte Chemie
Tom Ottoboni, Mary Rose Keller, Matt Cravets, Neil Clendeninn, Barry Quart
Introduction: Fosaprepitant, an intravenous (IV) aprepitant prodrug for chemotherapy-induced nausea and vomiting prophylaxis, is associated with systemic and infusion-site reactions attributed in part to its surfactant, polysorbate 80. HTX-019 is an IV aprepitant formulation free of polysorbate 80 and other synthetic surfactants. Materials and methods: This open-label, single-dose, randomized, two-way crossover bioequivalence study compared pharmacokinetics and safety of HTX-019 and fosaprepitant...
2018: Drug Design, Development and Therapy
Boshi Huang, Xinhao Liu, Ye Tian, Dongwei Kang, Zhongxia Zhou, Dirk Daelemans, Erik De Clercq, Christophe Pannecouque, Peng Zhan, Xinyong Liu
In the present work, we described the synthesis, antiviral profiles and metabolic stability in human plasma of compound 6, a potential carbonate prodrug of HIV-1 NNRTI drug candidate RDEA427. Compound 6 was found to inhibit the wild-type (WT) and K103N/Y181C double mutant HIV-1 strains at nano- and submicromolar concentrations, respectively. Moreover, it displayed potent HIV-1 reverse transcriptase inhibitory activity (IC50  = 0.264 μM). Further stability test in human plasma showed that 6 could release its active form RDEA427 in a linearly time-independent manner, possibly acting as a potential prodrug...
March 5, 2018: Bioorganic & Medicinal Chemistry Letters
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
Atul Bhatnagar, Matthew J McKay, Megan Crumbaker, Ketan Ahire, Peter Karuso, Howard Gurney, Mark P Molloy
Abiraterone acetate is administered as a prodrug to patients with metastatic, castration-resistant prostate cancer (mCRPC) and is readily metabolized into the potent 17a-hydroxylase/17,20-lyase (CYP17) enzyme inhibitor and androgen receptor inhibitor abiraterone and Δ(4)-abiraterone (D4A), respectively. To investigate pharmacokinetic variability in abiraterone acetate metabolism we developed highly sensitive liquid chromatography/mass spectrometry (LC/MS) assays for the simultaneous quantitation of abiraterone and D4A in human plasma using high-resolution mass spectrometry (HRMS) on an Orbitrap mass spectrometer...
March 6, 2018: Journal of Pharmaceutical and Biomedical Analysis
Daria Tretiakova, Natalia Onishchenko, Ivan Boldyrev, Ilya Mikhalyov, Alexander Tuzikov, Nicolai Bovin, Evgeniy Evtushenko, Elena Vodovozova
Previously, we proposed a liposomal formulation of melphalan (Mlph)-a chemotherapeutic alkylating agent-incorporated in a fluid lipid bilayer in the form of dioleoylglyceride ester. In this work, we compared the stabilizing effect of different amphiphiles included in the Mlph-liposomes, such as phosphatidylinositol (PI), ganglioside GM1 , a conjugate of N-carboxymethyl-modified oligoglycine with dioleoylphosphatidylethanolamine (acidic lipopeptide), and polyethylene glycol (2000 Da) conjugated with dipalmitoylphosphatidylethanolamine (PEG-lipid), upon incubation in human serum...
March 1, 2018: Colloids and Surfaces. B, Biointerfaces
Zhimin Tao, Mandar Deepak Muzumdar, Alexandre Detappe, Xing Huang, Eric Xu, Yingjie Yu, Tarek H Mouhieddine, Haiqin Song, Tyler Jacks, P Peter Ghoroghchian
Human pancreatic ductal adenocarcinoma (PDAC) contains a distinctively dense stroma that limits the accessibility of anticancer drugs, contributing to its poor overall prognosis. Nanoparticles can enhance drug delivery and retention in pancreatic tumors and have been utilized clinically for their treatment. In preclinical investigations, various mouse models differentially recapitulate the microenvironmental features of human PDAC. Here, we demonstrate that through utilization of different organic co-solvents and by doping of a homopolymer of poly(ε-caprolactone), a diblock copolymer composition of poly(ethylene oxide)- block-poly(ε-caprolactone) may be utilized to generate biodegradable and nanoscale micelles with different physical properties...
March 13, 2018: Nano Letters
Xiaomeng Wan, Yuanzeng Min, Herdis Bludau, Andrew Keith, Sergei S Sheiko, Rainer Jordan, Andrew Z Wang, Marina Sokolsky-Papkov, Alexander V Kabanov
Nanoparticle-based systems for concurrent delivery of multiple drugs can improve outcomes of cancer treatments, but face challenges because of differential solubility and fairly low threshold for incorporation of many drugs. Here we demonstrate that this approach can be used to greatly improve the treatment outcomes of etoposide (ETO) and platinum drug combination ("EP/PE") therapy that is the backbone for treatment of prevalent and deadly small cell lung cancer (SCLC). A polymeric micelle system based on amphiphilic block copolymer poly(2-oxazoline)s (POx) poly(2-methyl-2-oxazoline-block-2-butyl-2-oxazoline-block-2-methyl-2-oxazoline) (P(MeOx-b-BuOx-b-MeOx) is used along with an alkylated cisplatin prodrug to enable co-formulation of EP/PE in a single high-capacity vehicle...
March 13, 2018: ACS Nano
Farzad Seidi, Ratchapol Jenjob, Daniel Crespy
Incorporating labile bonds inside polymer backbone and side chains yields interesting polymer materials that are responsive to change of environmental stimuli. Drugs can be conjugated to various polymers through different conjugation linkages and spacers. One of the key factors influencing the release profile of conjugated drugs is the hydrolytic stability of the conjugated linkage. Generally, the hydrolysis of acid-labile linkages, including acetal, imine, hydrazone, and to some extent β-thiopropionate, are relatively fast and the conjugated drug can be completely released in the range of several hours to a few days...
March 13, 2018: Chemical Reviews
Yan Liu, Dongyang Zhao, Mengchi Sun, Wei Wei, Yingli Wang, Jiahua Zhou, Ruoshi Zhang, Jian Wang, Haotian Zhang, Zhonggui He, Qiming Kan, Jin Sun
5-Fluorouracil (5-FU) is one of the important antitumor drugs and is widely used to treat various types of cancers. However, its administration is limited to intravenous route due to poor oral bioavailability. Herein, we hypothesized that the maleimide group-containing 5-FU prodrug (EMC-5-FU) could improve the intestinal mucoadhesion because the maleimide end group can covalently target thiol residues of mucin glycoprotein covering the intestinal enterocytes. In vitro bioadhesion results showed that EMC-5-FU exhibited good affinity to the cysteine-rich subdomains of mucin and NMR studies successfully verified the covalent attachment of EMC-5-FU to mucin...
March 12, 2018: Drug Delivery and Translational Research
Alexis Viel, Jérôme Henri, Salim Bouchène, Julian Laroche, Jean-Guy Rolland, Jacqueline Manceau, Michel Laurentie, William Couet, Nicolas Grégoire
PURPOSE: The objective was the development of a whole-body physiologically-based pharmacokinetic (WB-PBPK) model for colistin, and its prodrug colistimethate sodium (CMS), in pigs to explore their tissue distribution, especially in kidneys. METHODS: Plasma and tissue concentrations of CMS and colistin were measured after systemic administrations of different dosing regimens of CMS in pigs. The WB-PBPK model was developed based on these data according to a non-linear mixed effect approach and using NONMEM software...
March 12, 2018: Pharmaceutical Research
Rebecca P Chen, Daniel Blackstock, Qing Sun, Wilfred Chen
Inspired by the remarkable ability of natural protein switches to sense and respond to a wide range of environmental queues, here we report a strategy to engineer synthetic protein switches by using DNA strand displacement to dynamically organize proteins with highly diverse and complex logic gate architectures. We show that DNA strand displacement can be used to dynamically control the spatial proximity and the corresponding fluorescence resonance energy transfer between two fluorescent proteins. Performing Boolean logic operations enabled the explicit control of protein proximity using multi-input, reversible and amplification architectures...
March 12, 2018: Nature Chemistry
Jun He, Xinchi Feng, Kai Wang, Changxiao Liu, Feng Qiu
BACKGROUND: Quality control of Chinese medicine (CM) is an effective measure to ensure the safety and efficacy of CM in clinical practice, which is also a key factor to restrict the modernization process of CM. Various chemical components exist in CM and the determination of several chemical components is the main approach for quality control of vast majority of CM in the present. However, many components determined lack not only specificity, but also biological activities. This is bound to greatly reduce the actual value of quality standard of CM...
February 28, 2018: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
Zhihao Zha, Karl Ploessl, Brian P Lieberman, Limin Wang, Hank F Kung
INTRODUCTION: Glutamine is an essential source of energy, metabolic substrates, and building block for supporting tumor proliferation. Previously, [18 F](2S,4R)4-fluoroglutamine (4F-Gln) was reported as a glutamine-related metabolic imaging agent. To improve the in vivo kinetics of this radiotracer, two new dipeptides, [18 F]Gly-(2S,4R)4-fluoroglutamine (Gly-4F-Gln) and [18 F]Ala-(2S,4R)4-fluoroglutamine (Ala-4F-Gln) were investigated. METHODS: Radiolabeling was performed via 2-steps18 F-fluorination...
February 13, 2018: Nuclear Medicine and Biology
Sauraj, S Uday Kumar, Vinay Kumar, Ruchir Priyadarshi, P Gopinath, Yuvraj Singh Negi
In the present study, novel pH-responsive prodrug nanoparticles based on xylan-curcumin (xyl-cur) conjugate were developed to enhance the therapeutic efficacy of curcumin in cancer therapy. The synthesis of xyl-cur conjugate (prodrug) was confirmed by FT-IR,1 H NMR, UV-vis and fluorescence spectroscopy. The xyl-cur prodrug was subsequently self-assembled in to nanoparticles (xyl-cur prodrug NPs) in an aqueous medium with the average particle size 253 nm and the zeta potential of -18.76 mV. The xyl-cur prodrug NPs were highly pH-sensitive in nature and most of the drug was released at lower pH...
May 15, 2018: Carbohydrate Polymers
Antonio Di Martino, Marina E Trusova, Pavel S Postnikov, Vladimir Sedlarik
An innovative microcarrier based on a carboxy-enriched and branched polylactic acid derivative was developed to enhance the in vitro phototoxicity of the photosensitizer and prodrug 5-aminolevulinic. Microparticles, prepared by double emulsion technique and loaded with the prodrug were carefully characterized and the effect of the polymer structure on the chemical, physical and biological properties of the final product was evaluated. Results showed that microparticles have a spherical shape and ability to allocate up to 30 μg of the photosensitizer per mg of carrier despite their difference in solubility...
March 3, 2018: Journal of Photochemistry and Photobiology. B, Biology
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