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Yin T.,China Pharmaceutical University | Wang J.,China Pharmaceutical University | Yin L.,China Pharmaceutical University | Shen L.,National Engineering and Research Center for Target Drugs | And 2 more authors.
Polymer Chemistry

The design of targeted nanosized micelles self-assembled from polymer-drug conjugates which exhibit conspicuous physical drug-loading based on excellent hydrophobic compatibility as well as sufficient release of encapsulated drugs in targeted areas remains a benchmark for drug delivery systems. Herein, our 41.8% drug loaded redox-sensitive micelles exhibit not only significantly improved drug-loading capacities, but also sufficient drug release. Based on a hyaluronic acid-disulfide-paclitaxel (HA-ss-PTX) conjugate, these core-shell structural redox-sensitive micelles mediate the reduction-triggered release of PTX (chemically conjugated ones plus physically encapsulated ones) into the tumor intracellular matrix. The redox-sensitivity is verified by morphological changes of micelles alongside in vitro release profiles within simulated reducing environments. Flow cytometry, confocal microscopy analysis and cytotoxicity assays indicate that HA-ss-PTX micelles exhibit selective tumor uptake via HA-receptor mediated endocytosis. Through the disassembly of the redox-sensitive micelles, PTX is rapidly released into the cytoplasm, inducing enhanced cytotoxicity and apoptosis against MDA-MB-231 cells. In vivo investigations on tumor-bearing mice further confirm that PTX-loaded HA-ss-PTX micelles possess much higher tumor-targeting capacity over non-sensitive controls and exhibit enhanced anti-tumor efficacy with minimal collateral damage. All the results indicate that a redox-sensitive HA-ss-PTX micelle is a promising PTX intracellular delivery carrier for efficient tumor therapy. © The Royal Society of Chemistry. Source

Bian J.,China Pharmaceutical University | Qian X.,China Pharmaceutical University | Wang N.,China Pharmaceutical University | Mu T.,China Pharmaceutical University | And 5 more authors.
Organic Letters

An efficient one-pot synthesis of 2H-pyranonaphthoquinone was achieved via a palladium-catalyzed C-H bond activation/C-C bond formation/intramolecular Tsuji-Trost reaction cascade. The unprecedented procedure exhibits excellent functional group tolerance, giving the target naphthoquinones in moderate to good isolated yields (40-88%) under mild reaction conditions. Scalable production of the product can make this reaction a method of choice for the synthesis of 2H-pyranonaphthoquinones. © 2015 American Chemical Society. Source

Xu C.,China Pharmaceutical University | He W.,China Pharmaceutical University | Lv Y.,China Pharmaceutical University | Qin C.,China Pharmaceutical University | And 2 more authors.
International Journal of Pharmaceutics

A prodrug-based nanosystem obtained by formulating prodrug and nanotechnology into a system is one of the most promising strategies to enhance drug delivery for disease treatment. Herein, we report a new nanosystem based on HA-PTX conjugates (HA-PTX Ns), which penetrated across cell membranes into cytosol, thus enhancing paclitaxel (PTX) delivery. HA-PTX Ns were successfully obtained based on HA-PTX, and their average particle size was approximately 200 nm. Importantly, unlike other prodrug-based nanosystems, HA-PTX Ns obtained cellular entry without entrapment within the lysosomal-endosomal system by using pathways including clathrin-mediated endocytosis, microtubule-associated internalization, macropinocytosis and cholesterol-dependence. Due to significant accumulation in tumors, HA-PTX Ns had more than a 4-fold decrease in tumor volume on day 14 in contrast with PTX alone. In conclusion, HA-PTX Ns could enter cells, bypass the lysosomal-endosomal system and improve PTX delivery. © 2015 Published by Elsevier B.V. Source

Lei Y.,China Pharmaceutical University | Hu T.,China Pharmaceutical University | Wu X.,China Pharmaceutical University | Wu Y.,China Pharmaceutical University | And 6 more authors.
ACS Medicinal Chemistry Letters

Prolyl hydroxylase domain 2 (PHD2) enzyme, a FeII and 2-oxoglutarate (2-OG) dependent oxygenase, mediates key physiological responses to hypoxia by modulating the levels of hypoxia inducible factor 1-α (HIF1α). PHD2 has been shown to have the therapeutic potentials for conditions including anemia and ischemic disease. Currently, many activity-based assays have been developed for identifying PHD2 inhibitors. Here we report an affinity-based fluorescence polarization method using FITC-labeled HIF1α (556-574) peptide as a probe for quantitative and site-specific screening of small molecule PHD2 inhibitors. © 2015 American Chemical Society. Source

Lei Y.,China Pharmaceutical University | Hu T.,China Pharmaceutical University | Hu M.,China Pharmaceutical University | Yang L.,China Pharmaceutical University | And 6 more authors.
Tetrahedron Letters

Abstract An improved and scalable synthetic method of N-(5-(4-cyanophenyl)-3-hydroxypicolinoyl)glycine, a promising inhibitor of PHD2, is described. The optimized route staring from commercially available 5-bromo-3-nitropicolinonitrile takes only five chemical steps and has a dramatically increased total yield of 37.6% without chromatographic purifications. © 2015 Elsevier Ltd. Source

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