Cyclic RGD modified dextran-quercetin polymer micelles for targeted therapy of breast cancer

Quercetin is a natural flavonoid found in many plants which has various pharmacological activities including antitumor effect. However, the poor water solubility and bioavailability limit the potential benefits of quercetin for patients. Thus, modifying quercetin structure and developing actively targeted drug delivery systems are extremely important for tumor precision therapy. Herein, polymer-drug conjugates dextran-quercetin (D-Q) and cRGD-dextran (R-D) were synthesized by grafting quercetin and polypeptide cRGDfk (Arg-Gly-Asp-(D-Phe)-Lys) to dextran. Then cRGD-modified dextran-quercetin polymer micelles (R-D-Q) were constructed by self-assembling of D-Q and R-D. R-D-Q micelles possessed appropriate particle size (133.4 nm), nearly neutral potential (8.14 mV) and excellent drug-loading efficiency (13.1 %) and achieved higher cytotoxicity, apoptosis induction and penetration to human breast cancer MCF-7 cells than the micelles unmodified with cRGD, which were ascribed to cRGD-integrin mediated transcytosis. R-D-Q micelles effectively suppressed tumor growth in tumor-bearing mice by delivering more quercetin throughout the tumor tissue. And R-D-Q micelles could promote the apoptosis of tumor cells by activating p38 and JNK signal pathways and suppressing ERK signal pathway. In addition, R-D-Q micelles had no damage to normal tissues of mice at therapeutic dose. These results indicate promising prospects for R-D-Q micelles as an effective drug delivery system against tumor.