Mcl-1 is an anti-apoptotic protein of the Bcl-2 family and is overexpressed in a variety of human cancer types including breast, CNS, colon, lung, ovarian, prostate, leukemia and melanoma. MS1, an anticancer peptide which selectively binds to Mcl-1 has been reported to prevent its dysregulation. Peptide therapy has limited success in cancer therapeutics due to its low bioavailability, potential immunogenicity and poor metabolic stability. A biodegradable polymeric nanocarrier based strategy has been proposed to improve peptide stability and bioavailability. In the present work, PLA-PEG-PPG-PEG based tetra block copolymeric nanoparticles were designed and developed to efficiently encapsulate and deliver MS1 peptide. The hydrophilic peptide loaded nanoparticles were synthesized by double emulsion solvent evaporation method and showed an encapsulation efficiency of 86%. The MS1 loaded biodegradable nanoparticles had an average diameter of 166 nm with a zeta potential of -13mV. Further characterization of MS1 loaded NPs by FE-SEM and TEM, showed spherical morphology with uniform size distribution. MS1 NPs showed an initial burst release of 14% in 24 h followed by a sustained release upto 30 days. Studies on cellular uptake by CLSM and cytotoxicity assays of the blank polymeric nanoparticles, demonstrated that the nanoparticles were effectively taken up by the cells and showed good biocompatibility. The MS1 loaded NPs showed efficient cell proliferation inhibition, with an IC<sub>50</sub> of 48nM in MCF-7 breast cancer cells and an IC<sub>50</sub> of 840nM in THP-1 AML cells. The MS1 peptide was further co-encapsulated with chemotherapeutic drug paclitaxel in the polymeric nanoparticles to explore the potential for synergistic effect. On co-encapsulation, MS1 and paclitaxel showed an encapsulation efficiency of 90% and 95% respectively. The dual loaded nanoparticles showed an average diameter of 197nm with a zeta potential of -18.9mV. The dual loaded NPs showed an IC50 value of 0.06nM in MCF-7 cells, significantly lower than that of single loaded MS1 or paclitaxel NPs. The PLA based tetra block copolymer nanoparticles reported in the present study show high loading efficiency, sustained release, good biocompatibility and therefore have high potential for delivery of anticancer peptides alone or in combination with conventional chemotherapeutic drugs for cancer therapy.

Biodegradable tetra-block copolymeric nanoparticles for MS1 anti-cancer peptide delivery

256th National Meeting (2018)

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