RGD-fatty alcohol-modified docetaxel liposomes improve tumor selectivity in vivo.

Abstract The tripeptidearginine-glycine-aspartate (RGD) was conjugated with various fatty alcoholsto obtain RGDOC n H 2 n + 1 ( n = 8, 10, 12, 14, 16, 18), which were incorporated into the bilayer of docetaxelliposomes to improve their tumor specificity. The fatty alcoholswere accepted as linking groupsto insert the tetrapeptideRGDX (X = amino acid) into the bilayer of liposomes. RGDX was previously shown to be a potent ligand to target tumor cell-surface integrin receptors, whereas RGD was not shown to have this ability. We hypothesized that RGD- fatty alcoholconjugates lacking the fourth amine X can guide liposomes to tumors without reducing their binding affinity to integrins. Antitumor activity, pharmacokinetics and biodistribution studies were evaluated in mice inoculated with S 180 sarcoma. Compared with unmodified liposomes, RGD- fatty alcohol-modified liposomes successfully delivered significantly more docetaxelto tumors, which led to significant tumor weight loss and increased tumor docetaxelconcentrations accompanied by reduced liver accumulation. Improved affinity of RGD- fatty alcoholsto integrins was also confirmed on A375 cell model. Further comparisons among the tumor-targeting capacities of liposomes containing RGD- fatty alcohols, RGDF- fatty alcoholsand RGDV-fatty acids demonstrated that RGD- fatty alcoholswere as effective as the other two tetrapeptidederivatives. Therefore, a simplified tumor-targeting delivery system using RGD- fatty alcoholswas developed.