Investigation of drug/microRNA co-delivery system for simultaneously inhibiting both common cancer cells and cancer stem cells

摘要

In the past decades, polymeric nano-drug delivery system has made great progress in the treatment of malignant tumor. However, the tumor faces recurrence and metastasis when stopping target drug or gene therapy, resulting in more serious complications. Recent study revealed that this phenomenon lies in the existence of a small group of specific cells in the cancer cells, called "cancer stem cells", which are highly tolerant of normal chemotherapy and genetherapy.Although specific microRNA can effectively inhibit the growth of cancer stem cells and metastasis. The solo treatment of cancer stem cells can't effective inhibit the proliferation of tumor, because there were a large number of common cancer cells existing in tumor tissues, and mature common cancer cells possibly mutated into cancer stem cells. This project plans to design a kind of reduction sensitivite cationic polymeric micelles. In the hydrophilic cationic outer shell, the micelles complex microRNAs via electrostatic interaction which can inhibit the growth and metastasis of cancer stem cells and promote cancer stem cells differentiation into common cancer cells; Meanwhile, in the hydrophobicity inner core, the micelles load adriamycin with efficient anti-proliferation effect to common tumor cells, in order to achieve the purpose of inhibiting both common cancer cells and cancer stem cells simultaneously, and enhancing anti-tumor therapeutic effect, preventing recurrence and metastasis of tumor. The results indicated the cationic polymeric micelles could stablily encapsulate the DOX, and complex microRNAs on the surfaces of micelles via electrostatic interaction. The nano-size of the both empty micelles and DOX-encapsulated micelles was range from 50 nm to 200 nm while narrow size distribution. The cytotoxicity experiments demonstrated that the PAA-g-PEG/PArg micelles have good biocompatibility as same as control sample, compared with Dox-incorporated PAA-g-PEG/PArg micelle group, the co-delivery of drug and gene PAA-g-PEG/PArg micelles groups were more efficiently internalized into MCF-7 cells, and enhance the ability of inhibitting cell proliferation by CLSM and flow cytometry test. In the MCF-7-bearing nude mouse models, the PAA-g-PEG/PArg micelles groups could efficiently accumulate in the tumor site by the fluorescence optical imaging technique, meanwhile, it demonstrated excellent solid tumor growth inhibition effect and the capacity for preventing recurrence and metastasis of tumor by investigating the tumor volume and body weight changes, as well as survive study of the tumor-bearing Balb/c mice. The PAA-g-PEG/PArg cationic polymeric micelles as a safe and high efficiency drug delivery system was expected to be a promising co-delivery carrier system that enables simultaneously targeting delivery hydrophobic chemotherapy drugs and negative charge of therapeutic siRNA molecules to tumor tissue and significantly enhanced antitumor effects. National Natural Science Foundation of China (Grant No. 21174090,51403138; and Young Teachers Science Foundation of Sichuan University (Grant No. 20HSCU11016)..