Arg-Gly-Asp (RGD) peptide conjugated poly (lactic acid)-poly(ethylene oxide) micelle for targeted drug delivery

摘要

In this study, a new poly(lactic acid)-poly (eth-ylene oxide)-Arg-Gly-Asp (PLA-PEO-RGD) derivative was synthesized, and paclitaxel-loaded PLA-PEO-RGD micelles were prepared by this derivative. The solubility assay showed that micelles mixed with Pluronic F-68 as surfactant could increase the solubility of this hydrophobic paclitaxel in aqueous solution. The cell-binding assay showed that PLA-PEO-RGD micelle (IC_(50) = 11.13 + - 1.38 nmol/L) had about 3.6-fold higher integrin avidity than PLA-PEO-RGD conjugates (IC_(50) = 40.33 + - 3.12 nmol/L). The avidity of micelle was also higher than RGD4C peptide (IC_(50) = 24.44 + -1.21 nmol/L). The in vitro drug release profile of drug-loaded PLA-PEO-RGD micelles exhibited initial burst release to 37 percent + - 2 percent (w/w) during the first 12 h, and then the release rate became steady in a controlled release manner. Furthermore, treatment of the MDA-MB-435 breast cancer cell line with paclitaxel-loaded PLA-PEO-RGD micelles yielded cytotoxicities, with EC_(50) values of approx 30 mu mol/L. The paclitaxel-loaded PLA-PEO-RGD micelles treated group showed the most dramatic tumor reduction in MDA-MB-435 tumor-bearing nude mice, and the final mean tumor load was 31 + - 16 mm~3 (mean + - SD; n = 8). ~(125)I-labeled micelles administration resulted in significant (p < 0.001) higher tumor uptake (2.68 percent + - 0.14 percent, ID/g) of PLA-PEO-RGD micelles compared to PLA-PEO micelles (0.84 percent + - 0.09 percent, ID/g) after 2.5 h postinjection. Biodistribution study showed the best blood clearance of PLA-PEO-RGD micelles after 4.5 h postinjection. The results of this study suggest that paclitaxel-loaded PLA-PEO-RGD micelles based on the specific recognition of alpha_V beta_3 integrin represent a potential and powerful target delivery technology.