RGD-modified polymeric micelles as potential carriers for targeted delivery to integrin-overexpressing tumor vasculature and tumor cells.

Integrins alphavbeta3 and alphavbeta5 are overexpressed in angiogenic tumor endothelial cells and malignant tumor cells, making them attractive targets for cancer therapy. In this study, an integrin alphavbeta3 and alphavbeta5 binding tripeptide, RGD (Arg-Gly-Asp), was conjugated with the surface of poly(ethylene glycol)-block-poly(D,L-lactide) (PEG-PLA) micelles. A lipophilic fluorescent probe, DiI, was loaded into both the nontargeted methoxy PEG-PLA (mPEG-PLA) micelles and the targeted RGD-modified PEG-PLA micelles. The DiI-loaded targeted micelles had a size of 24.2 nm. The targeted micelles were stable in phosphate buffered saline and exhibited a negligible leakage in culture medium. Transmission electron microscopy analysis showed that targeted micelles were spherical in shape. Cell uptake of DiI-labeled targeted micelles by human umbilical vein endothelial cells and melanoma B16 cells was investigated by spectrophotofluorometry and confocal microscopy techniques. Results revealed that RGD-modified micelles significantly facilitated the intracellular delivery of the encapsulated agents via integrin-mediated endocytosis. This study suggests that RGD-modified PEG-PLA micelles are promising drug carriers for targeted delivery to both angiogenic tumor endothelial cells and tumor cells and that the targeted micelles may be attractive carriers for combination cancer therapy against both targets.