Lytic peptide-grafted beta-cyclodextrin polymer based nano-scaled drug delivery system with enhanced camptothecin anti-cancer efficacy

摘要

The aqueous solubility of drug molecules is closely related to its bioactivity like bioavailability and subsequent therapeutic index, especially in the case of hydrophobic drugs like camptothecin (CPT), a potential broad-spectrum anti-cancer agent. Enhanced anti-cancer activity and selectivity of CPT are equally important. Inspired by host-guest effect and drug combination regimen, we developed a novel tumor lytic peptide incorporated drug delivery system by forming beta-cyclodextrin polymer (BCDp) based inclusion complex in nano-scaled size. In this study, BCDp formed inclusion complex with CPT and then a lytic-type peptide (ZH) was grafted. The resulting combinational formulation of BCDp, CPT and ZH, named as ZH-BCDp-CPT inclusion complex, demonstrated greater solubility resulting from its nano-scaled size, amorphous solid state and inclusion structure. Moreover, ZH facilitated quick internalization of conjugated drug via cell membrane lysis, leading to efficient intracellular drug delivery. This novel drug formulation was featured with prolonged circulation, enhanced anti-cancer efficacy, selectivity, anti-cell migration activity and better biocompatibility in comparison with crude CPT and binary BCDp-CPT inclusion complex, all of which were attributed to a cooperative action between ZH and BCDp-CPT inclusion complex. Our results suggested ZH-BCDp-CPT inclusion complex induced cell apoptosis by up-regulation of Bax and P53 and down-regulation of Bcl-2, primarily involved in the mitochondrial pathways.