Design, Fabrication and Evaluation of Stabilized Polymeric mixed micelles for Effective Management in Cancer Therapy.

Abstract

Cancer is one of the most common and fatal disease, chemotherapy is the major treatment against many cancer types. The anti-apoptotic BCL-2 protein's expression was increased in many cancer types and Venetoclax (VLX; BCL-2 inhibitor) is a small molecule, which selectively inhibits this specified protein. In order to increase the clinical performance of this promising inhibitor as a repurposed drug, polymeric mixed micelles formulations approach was explored. The Venetoclax loaded polymeric mixed micelles (VPMM) were prepared by using Pluronic® F-127 and alpha tocopherol polyethylene glycol 1000 succinate (TPGS) as excipients by thin film hydration method and characteristics. The percentage drug loading capacity, entrapment efficiency and in-vitro drug release studies were performed using HPLC method. The cytotoxicity assay, cell uptake and anticancer activities were evaluated in two different cancer cells i.e. MCF-7 (breast cancer) and A-549 (lung cancer). Particle size, polydispersity index and zeta potential of the VPMM was found to be 72.88 ± 0.09nm, 0.078 ± 0.009 and -4.29 ± 0.24mV, respectively. The entrapment efficiency and %drug loading were found to be 80.12 ± 0.23% and 2.13% ± 0.14%, respectively. The IC50 of VLX was found to be 4.78, 1.30, 0.94µg/ml at 24, 48 and 72h, respectively in MCF-7 cells and 1.24, 0.68, and 0.314µg/ml at 24, 48, and 72h, respectively in A549 cells. Whereas, IC50 of VPMM was found to be 0.42, 0.29, 0.09µg/ml at 24, 48 and 72h, respectively in MCF-7 cells and 0.85, 0.13, 0.008µg/ml at 24, 48 and 72h in A549 cells, respectively, indicating VPMM showing better anti-cancer activity compared to VLX. The VPMM showed better cytotoxicity which was further proven by other assays and explained the anti-cancer activity is shown through the generation of ROS, nuclear damage,apoptotic cell death and expression of caspase-3,7, and 9 activities in apoptotic cells. The current investigation revealed that the Venetoclax loaded polymeric mixed micelles (VPMM) revealed the enhanced therapeutic efficacy against breast and lung cancer in vitro models.