| Quercetin (3,3’,4’,5,7-pentahydroxy flavone) is a powerful anticancer drug originally isolated from Sophora japonica L. and is well-known for its wide spectrum of biological, pharmacological, and medical benefits. Several studies have provided evidence of the role of quercetin (QT) in the therapy of various human cancers, such as breast cancer, lung cancer, and cervical cancer. In spite of this broad range of pharmacological properties, the use of quercetin in clinic is limited due to its poor solubility (1μg/mL) in water, low hydrophilicity (log P of1.81), minimal bioavailability (<2%in humans), gastrointestinal instability and extensive first pass metabolism before reaching the systemic circulation.Recently, enormous attempts to address these serious problems include formulating quercetin in various carriers such as inclusion complexes, emulsions, liposome, nanocrystals, polymeric micelles and nanoparticals. In general, preparation of drug-polymer conjugates with self-assembly properties has distinctive advantages over conventional polymeric nanoscale drug delivery systems, especially using natural polymers as drug carriers. For instance, hyaluronic acid (HA) a natural anionic non-sulfated glycosaminoglycan is distributed widely in the synovial and extracellular matrix. More importantly, HA is a ligand which could recognize CD44and the receptor for HA-mediated motility that are abundantly over-expressed on the surface of many types of tumor cells, therefore combination of HA with drug is supposed to potentially increase the cellular uptake and realize drug targeted delivery by receptor-mediated endocytosis. Besides, good biocompatibility and biodegradability also prompt HA as an appealing drug carrier.Based on the rationale, we designed HA-QT conjugates which were synthesized by linking the hydroxy of quercetin via a succinate ester to adipic dihydrazide-modified hyaluronic acid. Their morphology demonstrated that the prepared prodrugs could self-assemble to form micelles possessing spherical shape, average diameter of172.1nm with a narrow size distribution and surface potential of-20.3mV. The HA-QT micelles exhibited significant sustained and pH-dependent drug release behaviors without dramatic initial burst.The cytotoxicity and internalization of HA-QT conjugate micelles into MCF-7breast cancer cells and L929mouse fibroblast cells were analyzed through MTT assay, fluorescence microscopy and flow cytometry. Compared with free quercetin, the HA-QT micelles showed higher inhibition on tumor cells. Moreover, HA-QT micelles were able to selectively deliver drugs to cancer cells (CD44-overexpressing cell lines) via CD44receptor-mediated endocytosis.The in vivo pharmacokinetics was investigated after an i.v. administration in rats. Promisingly, slow blood clearance and prolonged the half-life of quercetin were achieved for the HA-quercetin micelles compared with the parent drug. In fact, as a key therapeutic index of drug, the area under-the-curve (AUC0-∞) was also increased by4.9times.To evaluate the safety of the formulations, HA-QT conjugate micelles were investigated with the hemolysis and rabbit ear vein irritation test. The hemolysis percentage was below5%. Following intravenous administration, HA-QT conjugate micelles produced no obvious discoloration, damage and morphological changes along marginal ear vein.Taken together, HA-QT conjugate micelles can be considered as an attractive drug delivery system for targeted anti-tumor therapy, thereby enhancing the therapeutic efficacy. |
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