cRGDfK-Grafted Small-Size Quercetin Micelles For Enhancing Therapy Efficacy Of Active Ingredient From The Chinese Medicinal Herb

Pengcheng Xu,1 Haisheng Wang,2 Hongxiang Hu,3 Yong Ye,4 Yu Dong,1 Suxin Li,3 Dong Mei,3 Zhaoming Guo,3 Dan Wang,3 Yanxue Sun,1 Tengfei Yu,1 Junchan Qiao,1 Qiang Zhang3 1Department of Pharmaceutical Engineering, College of Pharmacy, Inner Mongolia Medical University, Hohhot 010110, People’s Republic of China; 2Department of Biochemistry, College of Basic Medical Sciences, Inner Mongolia Medical University, Hohhot 010110, People’s Republic of China; 3Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, People’s Republic of China; 4Department of Pharmaceutics, College of Pharmacy, Guangxi Medical University, Nanning 530021, People’s Republic of ChinaCorrespondence: Qiang Zhang Tel +86-010-82802791Email zqdodo@bjmu.edu.cnBackground: As an active ingredient of Chinese herbal medicine, quercetin (QU) can significantly induce apoptosis of tumor cells and give play to other effect such as decreasing both fibroblast population and collagen in cancer cell nest. However, the antitumor efficacy of quercetin was mostly evaluated at cellular level and rarely developed in vivo by intravenous injection, which may be ascribed to its inferior physicochemical properties including water insolubility, short plasma half-time, and insufficient enrichment in the tumor tissues.Methods: The DSPE-PEG was used to construct quercetin-loaded micelles, and the integrin ligand cRGDfK was grafted to modify the nanocarrier for enhancing its cancer-specific homing. The MALDI-TOF-MS, DLS, TEM, and UV were orderly operated to characterize guidance molecules and micelles by morphology, size distribution, Zeta potential, and drug encapsulation efficiency. In addition, the surface plasmon resonance study and real-time confocal analysis were employed to demonstrate αvβ3 integrin-overexpressing B16 cells-specific binding and uptake. After further pharmacodynamics studies in vitro and in vivo, we also evaluate systemic toxicity about cRGDfK-PM-QU.Results: The cRGDfK was successfully stitched with DSPE-PEG and modified on the surface of micelles. The ligand modification enhanced the negative charges of the micelles, but it did not induce significant changes in particle size. The quercetin micelles were about 15 nm in size and negatively charged, and had spherical morphology and high drug encapsulation efficiency. In vitro, the cRGDfK-modified micelles (cRGDfK-PM) showed αvβ3 integrin-overexpressing B16 cells-specific binding and uptake, and cRGDfK-PM-QU (QU loaded in cRGDfK-PM) induced more significant cell apoptosis and cytotoxic effects against B16 tumor cells than counterpart micelles (PM-QU). In vivo, the cRDGfK modification enhanced enrichment in B16 tumor tissue, improved the therapeutic efficacy of the quercetin-loaded micelles against B16 tumor, and exhibited lower systemic and pulmonary toxicity compared with counterpart micelles in the mouse mode.Conclusion: Quercetin as a natural product has triggered increasing interest in the antitumor field. In this study, cRGDfK-modified DSPE-PEG micelles significantly optimized quercetin therapeutic efficacy and pulmonary toxicity as well as lowered systemic toxicity.Keywords: quercetin, micelles, cRGDfK, integrin