Co-Delivery of Doxorubicin and Conferone by Novel pH-Responsive β-Cyclodextrin Grafted Micelles Triggers Apoptosis of Metastatic Human Breast Cancer Cells

Adjuvant-aided combination chemotherapy is one of the most effective ways of cancer treatment by overcoming the multidrug resistance (MDR) and reducing the side-effects of anticancer drugs. In this study Conferone (Conf) was used as adjuvant in combination with Doxorubicin (Dox) for induction of apoptosis to MDA-MB-231 cells. Herein, the novel biodegradable amphiphilic β-cyclodextrin grafted poly maleate-co-PLGA was synthesized by thiol-ene addition and ring-opening process. Micelles obtained from novel copolymer showed exceptional properties such as small size of around 34.5 nm, CMC of 0.1 μg/mL, and cell internalization of around 100 % at 30 min. These novel engineered micelles were used for combination delivery of doxorubicin-conferone with high encapsulation efficiency of near 100 % for both drugs. Our results show that combination delivery of Dox and Conf to MDA-MB-231 cells had synergistic effects ( CI <1). According to cell cycle and Annexin-V apoptosis analysis, Dox-Conf loaded micelle significantly induce tumor cell apoptosis (more than 98 % of cells population showed apoptosis at IC 50 = 0.259 μg/mL). RT-PCR and western-blot tests show that Dox-Conf loaded βCD-g-PMA-co-PLGA micelle induced apoptosis via intrinsic pathway. Therefore, the unique design of multi-functional pH-sensitive micelles open a new perspective for the development of nanomedicines for combination chemo-adjuvant therapy against malignant cancer.