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PEG-farnesylthiosalicylate conjugate as a nanomicellar carrier for delivery of paclitaxel.
Bioconjug Chem 2013; 24(3):464-72BC

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+Show Affiliations

Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, PA 15261, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

23425093

Citation

Zhang, Xiaolan, et al. "PEG-farnesylthiosalicylate Conjugate as a Nanomicellar Carrier for Delivery of Paclitaxel." Bioconjugate Chemistry, vol. 24, no. 3, 2013, pp. 464-72.
Zhang X, Lu J, Huang Y, et al. PEG-farnesylthiosalicylate conjugate as a nanomicellar carrier for delivery of paclitaxel. Bioconjug Chem. 2013;24(3):464-72.
Zhang, X., Lu, J., Huang, Y., Zhao, W., Chen, Y., Li, J., ... Li, S. (2013). PEG-farnesylthiosalicylate conjugate as a nanomicellar carrier for delivery of paclitaxel. Bioconjugate Chemistry, 24(3), pp. 464-72. doi:10.1021/bc300608h.
Zhang X, et al. PEG-farnesylthiosalicylate Conjugate as a Nanomicellar Carrier for Delivery of Paclitaxel. Bioconjug Chem. 2013 Mar 20;24(3):464-72. PubMed PMID: 23425093.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - PEG-farnesylthiosalicylate conjugate as a nanomicellar carrier for delivery of paclitaxel. AU - Zhang,Xiaolan, AU - Lu,Jianqin, AU - Huang,Yixian, AU - Zhao,Wenchen, AU - Chen,Yichao, AU - Li,Jiang, AU - Gao,Xiang, AU - Venkataramanan,Raman, AU - Sun,Ming, AU - Stolz,Donna Beer, AU - Zhang,Lin, AU - Li,Song, Y1 - 2013/03/01/ PY - 2013/2/22/entrez PY - 2013/2/22/pubmed PY - 2013/12/18/medline SP - 464 EP - 72 JF - Bioconjugate chemistry JO - Bioconjug. Chem. VL - 24 IS - 3 N2 - 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. SN - 1520-4812 UR - https://www.unboundmedicine.com/medline/citation/23425093/PEG_farnesylthiosalicylate_conjugate_as_a_nanomicellar_carrier_for_delivery_of_paclitaxel_ L2 - https://dx.doi.org/10.1021/bc300608h DB - PRIME DP - Unbound Medicine ER -