Positively Charged Combinatory Drug Delivery Systems against Multi-Drug-Resistant Breast Cancer: Beyond the Drug Combination

Abstract

The formation and development of cancer is usually accompanied by angiogenesis and is related to multiple pathways. The inhibition of one pathway by monotherapy might result in the occurrence of drug resistance, tumor relapse, or metastasis. Thus, a combinatory therapeutic system that targets several independent pathways simultaneously is preferred for the treatment. To this end, we prepared combinatory drug delivery systems consisting of cytotoxic drug SN38, pro-apoptotic KLAK peptide, and survivin siRNA with high drug loading capacity and reductive responsiveness for the treatment of multi-drug-resistant (MDR) cancer. With the help of positive charge and the synergistic effect of different drug, the combinatory systems inhibited the growth of doxorubicin-resistant breast cancer cells (MCF-7/ADR) efficiently. Interestingly, the systems without siRNA showed more superior in vivo anticancer efficacy than those with siRNA which exhibited enhanced in vitro cytotoxicity and pro-apoptotic ability. This phenomenon could be attributed to the preferential tumor accumulation, strong tumor penetration, and excellent tumor vasculature targeting ability of the combinatory micelles of SN38 and KLAK. As a result, a combinatory multitarget therapeutic system with positive charge induced tumor accumulation and vasculature targeting which can simultaneously inhibit the growth of both tumor cell and tumor vasculature was established. This work also enlightened us to the fact that the design of combinatory drug delivery systems is not just a matter of simple drug combination. Besides the cytotoxicity and pro-apoptotic ability, tumor accumulation, tumor penetration, or vascular targeting may also influence the eventual antitumor effect of the combinatory system.