Small-Sized and Robust Chimaeric Lipopepsomes: A Simple and Functional Platform with High Protein Loading for Targeted Intracellular Delivery of Protein Toxin in Vivo

How to chaperone protein drugs into target tumor cells in vivo is a big challenge. Here, we report on small-sized and robust chimaeric vesicles (lipopepsomes) constructed with asymmetric poly(ethylene glycol)-b-poly(a-aminopalmitic acid)b-poly(L-aspartic acid) triblock copolypeptide as a simple and functional platform for high loading and targeted intracellular delivery of saporin, a protein toxin, in vivo. Cyclic RGD peptide decorated chimaeric lipopepsomes (cRGD-CLP) following loading 2.0-9.4 wt % of model protein FITC-labeled cytochrome C showed a small hydrodynamic size of 81-86 nm, enhanced internalization by alpha(v)beta(3)-overexpressing A549 lung tumor cells, as well as remarkable accumulation of 7.73% ID/g in the cancerous lung in mice. Saporin-loaded cRGD-CLP displayed a low half maximal inhibitory concentration of 16.3 nM to A549 cancer cells. Intriguingly, saporin-loaded cRGD-CLP at 16.7 nmol saporin equiv/kg showed a high potency in treating orthotopically xenografted A549 lung tumors, suppressed tumor progression, and remarkably improved survival rate. These chimaeric lipopepsomes provide a versatile and potential means for targeted protein therapy of various malignancies.