Co-Delivery of a π-π Stacked Dual Anticancer Drug Combination with Nanocarriers for Overcoming Multi

• 作 者: Xiao Wei Yi Wang Xiang Xiong Xing Guo Lei Zhang Xiaobin Zhang Shaobing Zhou
• 机 构: Key Laboratory of Advanced Technologies of Materials, Ministry of Education, School of Materials Sci
• 出 处: 第十一届全国表面工程大会暨第八届全国青年表面工程学术会议
• 发表日期: 2016年4期
• 关键词: π-π stack nanocarrier multidrug resistance tumor metastasis co-delivery

　　Despite progress, combination therapy of various functional drugs to enhance the efficiency against multidrug resistance (MDR) still exists challenges. Here, we presented a new method to co-deliver a π–π stacked dual anticancer drug combination with an actively targeted, pH- and reduction-responsive polymer nan micelle (phenylboronic acid-polyethylene glycol-disulfide bond-poly(-ε-caprolactone) termed as PBA-PEG-ss-PCL) to overcome MDR and tumor metastasis. Different from other means, two broad-spectrum chemotherapeutics, doxorubicin (DOX) and 10-hydroxycamptothecin (HCPT) with π-conjugated aromatic structures, were integrated into one nanosystem via a π-π stacking force. In detail, DOX was chemically conjugated to the polymer backbone via a pH-responsive hydrazone bond to the harvested PBA-PEG-ss-PCL-hyd-DOX copolymer; HCPT was encapsulated in the inner core of the micelles and formed a π-stacked combination with DOX to acquire HCPT-loaded PBA-PEG-ss-PCL-hyd-DOX (DOX+HCPT-M) micelles. Consequently, the micelles accumulated at the tumor sites by the enhanced permeation and retention (EPR) effect and were subsequently selectively internalized by MDR tumor cells via PBA-mediated endocytosis. Then, they escaped from lysosomes and disassembled via the cleavage of the hydrazone bond and disulfide bond, which was triggered by the low intracellular pH and the high glutathione (GSH) environment. Most importantly, these drugs had a great capacity to elude the recognition of drug pumps for the cytoplasmic delivery of chemotherapeutics due to the slight structure change between the drug molecules. Thus, the π-stacked dual cargos effectively entered the cell nucleus to induce mitochondria-dependent apoptosis followed by the decreased expression of Bcl-2 and increased expression of Bax and caspase-9/3. In this way, this strategy simultaneously prevented the lung metastasis of MDR tumor cells. Collectively, this versatile nanocarrier provides a great clinical potency for application in mDR breast cancer therapy.