Development of Long-Circulating Zwitterionic Cross-Linked Micelles for Active-Targeted Drug Delivery.

Blood stability, active targeting, and controlled drug release are the most important features to design desirable drug carriers. Here, we demonstrate a zwitterionic biodegradable cross-linked micelle based on a penta-block copolymer, which utilizes poly(carboxybetaine methacrylate) as hydrophilic segment, poly(ε-caprolactone) as biodegradable hydrophobic segment, poly(S-2-hydroxyethyl-O-ethyl dithiocarbonate methacrylate) (PSODMA) block as thiol protecting segment for cross-linking, and cyclic Arg-Gly-Asp-d-Tyr-Lys [c(RGDyK)] as targeting ligand. As a result, this micelle possessed excellent colloidal stability at high dilution and in 50% fetal bovine serum. In vitro drug release experiment showed no burst release under physiological conditions but accelerated drug release in mimicking tumor tissue environment. In vivo tests showed that the drug-loaded micelles had prolonged half-life in bloodstream, enhanced therapeutic efficiency, and reduced cardiac toxicity and biotoxicity compared with free drug formulation. Taken together, the reported c(RGDyK)-modified zwitterionic interfacially cross-linked micelle has emerged as an appealing platform for cancer therapy.