Rational Design of Polymeric Hybrid Micelles with Highly Tunable Properties to Co-Deliver MicroRNA-34a and Vismodegib for Melanoma Therapy

摘要

A polymeric hybrid micelle (PHM) system with highly tunable properties is reported to co-deliver small molecule and nucleic acid drugs for cancer therapy; this system is structurally simple and easy-to-fabricate. The PHM consists of two amphiphilic diblock copolymers, polycaprolactone-polyethylenimine (PCL-PEI) and polycaprolactone-polyethyleneglycol (PCL-PEG). PHMs are rationally designed with different physicochemical properties by simply adjusting the ratio of the two diblock copolymers and the near neutral PHM-2 containing a low ratio of PCL-PEI achieves the optimal balance between high tumor distribution and subsequent cellular uptake after intravenous injection. Encapsulating Hedgehog (Hh) pathway inhibitor vismodegib (VIS) and microRNA-34a (miR-34a) into PHM-2 generates the VIS/PHM-2/34a co-delivery system. VIS/PHM-2/34a shows synergistic anticancer efficacy in murine B16F10-CD44(+) cells, a highly metastatic tumor model of melanoma. VIS/PHM-2/34a synergistically attenuates the expression of CD44, a vital receptor indicating the metastasis of melanoma. Intriguingly, inhibiting Hh pathway by VIS is accompanied by downregulation of CD44 expression, revealing that Hh signaling might be an upstream regulator of CD44 expression in melanoma. Thus, co-delivery of miR-34a and VIS demonstrates great potential in cancer therapy, and PHM offers a structurally simple and highly tunable platform for the co-delivery of small molecule and nucleic acid drugs in tumor combination therapy.