Co-delivery of d-(KLAKLAK)2 peptide and doxorubicin using a pH-sensitive nanocarrier for synergistic anticancer treatment

Abstract

Currently, one of the most important challenges in the development of nanotechnology-based anticancer treatments is the failure of nanoparticles to escape from the endo-lysosomal compartment and the resulting elimination of endocytosed nanoparticles via the exocytosis pathway without drug release. A pH-sensitive nanoparticle composed of poly(ethylene glycol)-poly(l-lysine)(-grafted 2,3 dimethyl maleic anhydride)-poly(lactic acid) triblock copolymer (PEG-PLL(-g-DMA)-PLA) with a pro-apoptotic peptide (d-(KLAKLAK)2) and an anticancer drug doxorubicin (Dox) (DTM(Pep, Dox)) was prepared and evaluated for its antiproliferative activity against tumor cells. Due to the membrane-lytic ability of the peptide and the proton sponge effect of the pH-sensitive nanocarrier, DTM(Pep, Dox) accelerated the disruption of the endo-lysosomal membrane and displayed enhanced anticancer activities, arising from strong synergism, under in vitro and in vivo conditions. The prepared formulations are anticipated to be of potential use in nanotechnology-based combination therapy and it is believed that this novel formulation will have new applications in advanced tumor therapy. © 2019 The Royal Society of Chemistry.