Journal
INTERNATIONAL JOURNAL OF PHARMACEUTICS
Volume 356, Issue 1-2, Pages 29-36Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ijpharm.2007.12.030
Keywords
liposomes; targeted drug delivery; folate receptor; nanotechnology; doxorubicin; cancer
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Funding
- NCI NIH HHS [R01 CA095673-05, R01 CA095673] Funding Source: Medline
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Folate receptors (FRs) have been identified as cellular surface markers for cancer and leukemia. Liposomes containing lipophilic derivatives of folate have been shown to effectively target FR-expressing cells. Here, we report the synthesis of a novel lipophilic folate derivative, folate-polyethylene glycol-cholesterol hemisuccinate (F-PEG-CHEMS), and its evaluation as a targeting ligand for liposomal doxorubicin (L-DOX) in FR-expressing cells. Liposomes containing F-PEG-CHEMS, with a mean diameter of 120 +/- 20 nm, were synthesized by polycarbonate membrane extrusion and were shown to have excellent colloidal stability. The liposomes were taken up selectively by KB cells, which overexpress FR-alpha. Compared to folate-PEG-cholesterol (F-PEG-Chol), which contains a carbamate linkage, F-PEG-CHEMS better retained its FR-targeting activity during prolonged storage. In addition, F-PEG-CHEMS containing liposomes loaded with DOX (F-L-DOX) showed greater cytotoxicity (IC50 = 10.0 mu M) than non-targeted control L-DOX (IC50 = 57.5 mu M) in KB cells. In ICR mice, both targeted and non-targeted liposomes exhibited long circulation properties, although F-L-DOX (t(1/2) = 12.34 h) showed more rapid plasma clearance than L-DOX (t(1/2) = 17.10 h). These results suggest that F-PEG-CHEMS is effective as a novel ligand for the synthesis of FR-targeted liposomes. Published by Elsevier B.V.
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