cm5012718_si_001.pdf (3.35 MB)
Dual-Responsive Polymer Micelles for Target-Cell-Specific Anticancer Drug Delivery
journal contributionposted on 2014-08-12, 00:00 authored by Xing Guo, Chunli Shi, Guang Yang, Jie Wang, Zhenghong Cai, Shaobing Zhou
Efficient delivery of therapeutic agents with nanocarriers into the nucleus to achieve high therapeutic efficiency is still a major challenge for cancer therapy due to mucosal barriers, nonspecific uptake, and intracellular drug resistance. In this study, we develop a dual-responsive polymer micelle system with sheddable polyethylenimine (PEI) shells for actively targeted drug delivery. This system exhibits an ultrasensitive negative-to-positive charge reversal in response to the extracellular pH value, resulting in greatly enhanced uptake by cancer cells via electrostatic interaction. Moreover, the active targeting ability can further promote the selective uptake of the nanocarriers in the cancer cell. Once the micelles escape from the lysosomes, the disulfide linkages can be cleaved by GSH in the cytoplasm, and in turn the hydrophilic PEI shell is deshielded, leading to the rapid release of the encapsulated agent into the nuclei. The antitumor activity in 4T1 tumor-bearing mice reveals that this novel system possesses a long blood circulation due to the originally negatively charged surface and can significantly promote the cell internalization and intracellular drug release, thus leading to a high therapeutic efficacy against resistant tumors and fewer side effects to normal tissues.
GSHmucosal barriersuptakecancer cellsintracellular drug resistanceantitumor activityPEI shellmicelleside effectsencapsulated agentextracellular pH valuenanocarriersystem exhibitscell internalizationcancer cellblood circulationsheddable polyethyleniminedisulfide linkagesintracellular drug releasedrug deliverynovel systemcancer therapy