title: 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: Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors: Xiaolan
authors: X
authors: Zhang
authors: Jianqin
authors: J
authors: Lu
authors: Yixian
authors: Y
authors: Huang
authors: Wenchen
authors: W
authors: Zhao
authors: Yichao
authors: Y
authors: Chen
authors: Jiang
authors: J
authors: Li
authors: Xiang
authors: X
authors: Gao
authors: Raman
authors: R
authors: Venkataramanan
authors: Ming
authors: M
authors: Sun
authors: Donna Beer
authors: DB
authors: Stolz
authors: Lin
authors: L
authors: Zhang
authors: Song
authors: S
authors: Li
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000737:chemistry; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods*; D005204:Farnesol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008823:Micelles; D017239:Paclitaxel / Q000008:administration & dosage* / Q000737:chemistry; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000737:chemistry; D011897:Random Allocation; D051381:Rats; D012459:Salicylates / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D008823:Micelles; D012459:Salicylates; C093323:farnesylthiosalicylic acid; D011092:Polyethylene Glycols; D005204:Farnesol; D017239:Paclitaxel