Bifunctional Oxaliplatin (IV) Prodrug Based pH-Sensitive PEGylated Liposomes for Synergistic Anticancer Action Against Triple Negative Breast cancer

Abstract

Triple negative breast cancer (TNBC) exhibits higher susceptibility towards oxaliplatin (OXA) due to a faulty DNA damage repair system. However, the unfavorable physicochemical properties and risk of toxicities limit the clinical utility of OXA. Therefore, to impart kinetic inertness, site-specific delivery, and multidrug action, an octahedral Pt(IV) prodrug was developed by using chlorambucil (CBL) as a choice of ligand. The combination of OXA and CBL exhibited synergistic anti-cancer action in TNBC cell lines. Further, to maximize tumor-specific delivery, intracellular accumulation, and in-vivo performance, the developed prodrug (OXA-CBL) was encapsulated in pH-sensitive PEGylated liposomes into (OXA-CBL/PEG-Liposomes). The fabricated liposomes had smaller particle size < 200 nm and higher drug loading (~ 4.26 ± 0.18%). In-vitro release displayed pH-dependent sustained release for up to 48 h. Cellular internalization revealed maximal uptake via clathrin-mediated endocytosis. The cytotoxicity assay showed reduced IC₅₀ in the 4T1 (~ 1.559-fold) and MDA-MB-231 (~ 1.539-fold) cell lines than free OXA-CBL. In-vivo efficacy in 4T1-induced TNBC model revealed a marked increase in % tumor inhibition rate, while diminished % tumor burden in OXA-CBL/BSA-NPs treated animals. Toxicity assessment displayed no signs of systemic and hemolytic toxicity. Overall, delivery of Pt (IV) prodrug as a pH-sensitive PEGylated liposomes offers a safer and efficient system to manage TNBC.

Graphical Abstract