Journal
INTERNATIONAL JOURNAL OF PHARMACEUTICS
Volume 468, Issue 1-2, Pages 133-141Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ijpharm.2014.04.001
Keywords
RGD; Fatty alcohol; Docetaxel liposomes; Tumor targeting; Pharmacokinetics; In vivo
Categories
Funding
- National Natural Science Foundation of China [81202486]
- Beijing Natural Science Foundation [7133228]
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The tripeptide arginine-glycine-aspartate (RGD) was conjugated with various fatty alcohols to obtain RGDOC(n)H(2n) + 1 (n = 8, 10, 12, 14, 16, 18), which were incorporated into the bilayer of docetaxel liposomes to improve their tumor specificity. The fatty alcohols were accepted as linking groups to insert the tetrapeptide RGDX (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 alcohol conjugates 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 S180 sarcoma. Compared with unmodified liposomes, RGD-fatty alcohol-modified liposomes successfully delivered significantly more docetaxel to tumors, which led to significant tumor weight loss and increased tumor docetaxel concentrations accompanied by reduced liver accumulation. Improved affinity of RGD-fatty alcohols to integrins was also confirmed on A375 cell model. Further comparisons among the tumor-targeting capacities of liposomes containing RGD-fatty alcohols, RGDF-fatty alcohols and RGDV-fatty acids demonstrated that RGD-fatty alcohols were as effective as the other two tetrapeptide derivatives. Therefore, a simplified tumor-targeting delivery system using RGD-fatty alcohols was developed. (C) 2014 Elsevier B. V. All rights reserved.
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