Combinatorial targeting polymeric micelles for anti-tumor drug delivery

Polymeric micelles of amphiphilic block copolymers have been studied for decades for their application as a targeting delivery agent of anti-tumor drugs. However, the targeting micelles may cause an immunological response because of the surface distributed ligands. In this work, mixed micelles were developed to improve the specificity of cancer cell uptake under tumor-acidic conditions. This was achieved by the co-assembly of an active targeting amphiphilic polymer, i.e. cyclic (Arg-Gly-Asp-D-Phe-Lys) c(RGDfK) functionalized poly(ethylene oxide)-b-poly(epsilon-caprolactone) (cRGD-PEO-b-PCL), and a pH sensitive drug conjugate, i.e. benzoic-imine linked PEGylated doxorubicin (PEG-DOX). Because the PEG-DOX is cleavable at the extracellular pH of a solid tumor, the characteristics of the mixed micelles turn from "stealthy" to cancer cell-affinitive due to the detachment of PEG from the micelle surface and hence allow the action of the c(RGDfK) in the cRGD-PEO-b-PCL with the cancer cell membrane. Besides, the mixed micelles exhibited the capacity for encapsulating hydrophobic drugs such as paclitaxel to form a combination formulation. Our results indicate that co-assembly is a facile but efficient strategy to coordinate the characteristics of each individual component and thus provide combinatorial functions to the delivery system.