Treatment of prostate carcinoma with (galectin-3)-targeted HPMA copolymer-(G3-C12)-5-Fluorouracil conjugates.

Abstract

Galectin-3 (Gal-3), over-expressed on a variety of human tumor cells, is a potential binding site for targeted metastatic prostate cancer therapy. The aim of this study was to develop a G3-C12-mediated drug delivery system based on N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers targeting to Gal-3-expressed human PC-3 prostate carcinoma cells. 5-Fluorouracil (5-Fu), an anti-tumor agent, was selected as a model drug. G3-C12, a binding peptide, which specifically binds to the carbohydrate-recognition domain (CRD) of Gal-3, was attached to HPMA copolymers as a targeting moiety. Compared with non-targeted conjugates (P-Fu), Gal-3-targeted HPMA copolymer-(G3-C12)-5-Fu conjugates (P-(G3-C12)-Fu) displayed a superior intracellular internalization followed by enhanced cytotoxicity and apoptosis-induction. Subsequently, the in vitro migration study on PC-3 cells indicated that P-(G3-C12)-Fu was able to efficiently inhibit the cell migration ability after wounding. On PC-3 tumor-bearing mice model, G3-C12-modified copolymers showed a higher tumor accumulation coupled with a faster clearance from blood circulation than non-modified ones. Finally, Gal-3-targeted conjugates significantly improved the anti-tumor activity of 5-Fu in nude mice bearing PC-3 tumor xenografts. Consequently, G3-C12 would be a promising targeting moiety for cell-specific prostate cancer therapy in future.

• Authors: Yang Yang, Zhou Zhou, Shuang He, Tingting Fan, Yun Jin, Xi Zhu, Chunhui Chen, Zhi-rong Zhang, Yuan Huang
• Journal: Biomaterials (Biomaterials) Vol. 33 Issue 7 Pg. 2260-71 (Mar 2012) ISSN: 1878-5905 [Electronic] Netherlands
• PMID: 22189143 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• Antimetabolites, Antineoplastic
• Drug Carriers
• Galectin 3
• Methacrylates
• Polymers
• Fluorouracil
• hydroxypropyl methacrylate

Topics

• Animals
• Antimetabolites, Antineoplastic (chemistry, metabolism, therapeutic use)
• Cell Line, Tumor
• Drug Carriers (chemistry, metabolism)
• Drug Delivery Systems
• Endocytosis (physiology)
• Fluorouracil (chemistry, metabolism, therapeutic use)
• Galectin 3 (metabolism)
• Humans
• Male
• Materials Testing
• Methacrylates (chemistry, metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Molecular Structure
• Neoplasm Transplantation
• Polymers (chemistry, metabolism, therapeutic use)
• Prostatic Neoplasms (drug therapy, metabolism, pathology)
• Tissue Distribution