Interfacial activity assisted surface functionalization: a novel approach to incorporate maleimide functional groups and cRGD peptide on polymeric nanoparticles for targeted drug delivery.

Nanoparticles formulated using poly(d,l-lactide-co-glycolide) (PLGA) copolymer have emerged as promising carriers for targeted delivery of a wide variety of payloads. However, an important drawback with PLGA nanoparticles is the limited types of functional groups available on the surface for conjugation to targeting ligands. In the current report, we demonstrate that the interfacial activity assisted surface functionalization (IAASF) technique can be used to incorporate reactive functional groups such as maleimide onto the surface of PLGA nanoparticles. The surface maleimide groups were used to conjugate cRGD peptide to nanoparticles. The cRGD peptide targets alpha(v)beta(3) integrins overexpressed on tumor vasculature and some tumor cells, and was used as model targeting ligand in this study. Incorporation of biologically active cRGD peptide on the surface of nanoparticles was confirmed by in vitro cell uptake studies and in vivo tumor accumulation studies. Functionalization of nanoparticles with cRGD peptide increased the cellular uptake of nanoparticles 2-3-fold, and this enhancement in uptake was substantially reduced by the presence of excess cRGD molecules. In a syngeneic mouse 4T1 tumor model, cRGD functionalization resulted in increased accumulation and retention of nanoparticles in the tumor tissue (nearly 2-fold greater area under the curve), confirming the in vivo activity of cRGD functionalized nanoparticles. In conclusion, the IAASF technique enabled the incorporation of reactive maleimide groups on PLGA nanoparticles, which in turn permitted efficient conjugation of biologically active cRGD peptide to the surface of PLGA nanoparticles.