PEG-farnesylthiosalicylate conjugate as a nanomicellar carrier for delivery of paclitaxel.

Abstract

S-trans, trans-farnesylthiosalicylic acid (FTS) is a synthetic small molecule that acts as a potent and especially nontoxic Ras antagonist. It inhibits both oncogenically activated Ras and growth factor receptor-mediated Ras activation, resulting in the inhibition of Ras-dependent tumor growth. In this work, an FTS conjugate with poly(ethylene glycol) (PEG) through a labile ester linkage, PEG5K-FTS2(L), was developed. PEG5K-FTS2 conjugate readily forms micelles in aqueous solutions with a critical micelle concentration of 0.68 μM, and hydrophobic drugs such as paclitaxel (PTX) could be effectively loaded into these particles. Both drug-free and PTX-loaded micelles were spherical in shape with a uniform size of 20-30 nm. The release of PTX from PTX-loaded PEG5K-FTS2 micelles was significantly slower than that from Taxol formulation. In vitro cytotoxicity studies with several tumor cell lines showed that PEG5K-FTS2(L) was comparable to FTS in antitumor activity. Western immunoblotting showed that total Ras levels were downregulated in several cancer cell lines treated with FTS or PEG5K-FTS2(L). The micellar formulation of PTX exhibited more in vitro cytotoxic activity against several tumor cell lines compared with free PTX, suggesting a possible synergistic effect between the carrier and the codelivered drug. The antitumor activity of the PTX loaded PEG5K-FTS2(L) micelles in a syngeneic murine breast cancer model was found to be significantly higher than that of Taxol, which may be attributed to their preferential tumor accumulation and a possible synergistic effect between PEG5K-FTS2 carrier and loaded PTX.

• Authors: Xiaolan Zhang, Jianqin Lu, Yixian Huang, Wenchen Zhao, Yichao Chen, Jiang Li, Xiang Gao, Raman Venkataramanan, Ming Sun, Donna Beer Stolz, Lin Zhang, Song Li
• Journal: Bioconjugate chemistry (Bioconjug Chem) Vol. 24 Issue 3 Pg. 464-72 (Mar 20 2013) ISSN: 1520-4812 [Electronic] United States
• PMID: 23425093 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents, Phytogenic
• Micelles
• Salicylates
• farnesylthiosalicylic acid
• Polyethylene Glycols
• Farnesol
• Paclitaxel

Topics

• Animals
• Antineoplastic Agents, Phytogenic (administration & dosage, chemistry)
• Breast Neoplasms (drug therapy)
• Cell Line, Tumor
• Drug Delivery Systems (methods)
• Farnesol (administration & dosage, analogs & derivatives, chemistry)
• Female
• HCT116 Cells
• Humans
• Mice
• Mice, Inbred BALB C
• Micelles
• Paclitaxel (administration & dosage, chemistry)
• Polyethylene Glycols (administration & dosage, chemistry)
• Random Allocation
• Rats
• Salicylates (administration & dosage, chemistry)