Cyclic RGD-Peptide-Functionalized Polylipopeptide Micelles for Enhanced Loading and Targeted Delivery of Monomethyl Auristatin E

Monomethyl auristatin E (MMAE) is an extremely potent peptide drug that is currently used in the form of antibody drug conjugates (ADCs) for treating different cancers. ADCs are, however, associated with low drug conjugation, immunogenicity, small scale production, and high costs. Here, cRGD-functionalized polylipopeptide micelles (cRGD-Lipep-Ms) were explored for enhanced loading and targeted delivery of MMAE to HCT-116 colorectal tumor xenografts. Interestingly, cRGD-Lipep-Ms achieved an MMAE loading content of 5.5 wt %, which was 55-fold higher than that of poly(ethylene glycol)-b-poly(d,l-lactide) micelles. MMAE-loaded cRGD-Lipep-Ms (MMAE-cRGD-Lipep-Ms) showed a small hydrodynamic size of 59 nm, minimal drug leakage in 10% FBS, and efficient uptake and superb antiproliferative activity in αvβ5-overexpressing HCT-116 tumor cells. Remarkably, MMAE-cRGD-Lipep-Ms displayed over 10-fold better toleration than free MMAE in mice and completely suppressed growth of HCT-116 colorectal tumor xenografts. These polylipopeptide micelles have appeared to be an attractive alternative to ADCs for targeted delivery of potent peptide drugs.