Arg-Gly-Asp (RGD) peptide conjugated poly(lactic acid)-poly(ethylene oxide) micelle for targeted drug delivery.
In this study, a new poly(lactic acid)-poly (ethylene 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% +/- 2% (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 approximately 30 mumol/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% +/- 0.14%, ID/g) of PLA-PEO-RGD micelles compared to PLA-PEO micelles (0.84% +/- 0.09%, 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.
Hu
Zhiyuan
Z
Department of Biomedical Engineering, Xiangya Hospital, Central South University, Changsha 410008, China.
Luo
Fang
F
Pan
Yifeng
Y
Hou
Can
C
Ren
Lifeng
L
Chen
Jiji
J
Wang
Jiwei
J
Zhang
Yangde
Y
D000818:Animals; D001665:Binding Sites; D001682:Biological Availability; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D004852:Epoxy Compounds / Q000737:chemistry; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008823:Micelles; D009842:Oligopeptides / Q000737:chemistry*; D011091:Polyesters / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012995:Solubility
D004852:Epoxy Compounds; D039302:Integrin alphaVbeta3; D008823:Micelles; D009842:Oligopeptides; C402662:PEO-poly(lactide); D011091:Polyesters; C047981:arginyl-glycyl-aspartic acid