Dendrimeric anticancer prodrugs for targeted delivery of ursolic acid to folate receptor-expressing cancer cells: synthesis and biological evaluation.

Abstract

The anticancer efficacy of ursolic acid (UA) was limited by poor water solubility, non-specific tumor distribution, and low bioavailability. To overcome this problem, polyamidoamine (PAMAM) conjugated with UA and folic acid (FA) as novel dendrimeric prodrugs were designed and successfully synthesized by a concise one-pot synthetic approach. Both FA and UA were covalently conjugated to the surface of PAMAM through acid-labile ester bonds and the covalently linked UA could be hydrolysed either in acidic (pH 5.4) or in neutral (pH 7.4) PBS solution. The cellular uptake study indicated that the presence of FA enhanced uptake of the dendrimeric prodrugs in folate receptor (FR) over-expressing Hela cells. The enhanced cellular uptake could be due to the electrostatic absorptive endocytosis and FR-mediated endocytosis. In contrast, for HepG2 cells, a FR-negative cell line, FA conjugation on the surface of the dendrimer showed no effect on the cellular uptake. In MTT assay and cell cycle analysis, FA-modified dendrimeric prodrugs showed significantly enhanced toxicity than non-FA-modified ones in Hela cells. These results suggested that FA-modified dendrimeric UA prodrugs have the potential for targeted delivery of UA into cancer cells to improve its anti-tumor efficacy.

• Authors: Yu Gao, Zhihong Li, Xiaodong Xie, Chaoqun Wang, Jiali You, Fan Mo, Biyu Jin, Jianzhong Chen, Jingwei Shao, Haijun Chen, Lee Jia
• Journal: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences (Eur J Pharm Sci) Vol. 70 Pg. 55-63 (Apr 05 2015) ISSN: 1879-0720 [Electronic] Netherlands
• PMID: 25638419 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier B.V. All rights reserved.

Chemical References

• Antineoplastic Agents
• Dendrimers
• Folate Receptors, GPI-Anchored
• PAMAM Starburst
• Prodrugs
• Triterpenes
• ursolic acid

Topics

• Antineoplastic Agents (administration & dosage, chemical synthesis, metabolism)
• Cell Survival (drug effects, physiology)
• Dendrimers (administration & dosage, chemical synthesis, metabolism)
• Drug Delivery Systems (methods)
• Drug Evaluation, Preclinical (methods)
• Folate Receptors, GPI-Anchored (metabolism)
• Gene Expression Regulation, Neoplastic
• HeLa Cells
• Hep G2 Cells
• Humans
• Prodrugs (administration & dosage, chemical synthesis, metabolism)
• Triterpenes (administration & dosage, chemical synthesis, metabolism)