Evaluation of folate-PAMAM for the delivery of antisense oligonucleotides to rat C6 glioma cells in vitro and in vivo.

Abstract

In the current study, we evaluated the efficiency of folate-polyamidoamine dendrimers conjugates (FA-PAMAM) for the in situ delivery of therapeutic antisense oligonucleotides (ASODN) that could inhibit the growth of C6 glioma cells. Folic acid was coupled to the surface amino groups of G5-PAMAM dendrimer (G5D) through a 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide bond, and ASODNs corresponding to rat epidermal growth factor receptor (EGFR) were then complexed with FA-PAMAM. At an ASODN to PAMAM ratio of 16:1, agarose electrophoresis indicated that antisense oligonucleotides were completely complexed with PAMAM or FA-PAMAM. The ASODN transfection rates mediated by FA-PAMAM and PAMAM were superior to oligofectamine, resulting in greater suppression of EGFR expression and glioma cell growth. Stereotactic injection of EGFR ASODN:FA-PAMAM complexes into established rat C6 intracranial gliomas resulted in greater suppression of tumor growth and longer survival time of tumor-bearing rats compared with PAMAM and oligofectamine-mediated EGFR-ASODN therapy. The current study demonstrates the suitability of folate-PAMAM dendrimer conjugates for efficient EGFR ASODN delivery into glioma cells, wherein they release the ASODN from the FA-PAMAM to knock down EGFR expression in C6 glioma cells, both in vitro and in vivo. FA-PAMAM may thus represent a novel delivery system for short oligonucleotides in glioma-targeted therapy.

• Authors: Chunsheng Kang, Xubo Yuan, Fei Li, Peiyu Pu, Shizhu Yu, Changhong Shen, Zhiyong Zhang, Yunting Zhang
• Journal: Journal of biomedical materials research. Part A (J Biomed Mater Res A) Vol. 93 Issue 2 Pg. 585-94 (May 2010) ISSN: 1552-4965 [Electronic] United States
• PMID: 19591231 (Publication Type: Evaluation Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2009 Wiley Periodicals, Inc.

Chemical References

• Biocompatible Materials
• Dendrimers
• Oligonucleotides, Antisense
• PAMAM Starburst
• Folic Acid
• ErbB Receptors

Topics

• Animals
• Apoptosis
• Biocompatible Materials (chemistry, metabolism)
• Cell Cycle
• Cell Line, Tumor
• Dendrimers (chemistry, metabolism)
• Drug Delivery Systems (instrumentation, methods)
• ErbB Receptors (genetics)
• Female
• Flow Cytometry (methods)
• Folic Acid (chemistry, metabolism)
• Genetic Therapy (methods)
• Glioma (drug therapy, genetics)
• Humans
• Materials Testing
• Neoplasm Transplantation
• Oligonucleotides, Antisense (chemistry, metabolism, therapeutic use)
• Rats
• Rats, Sprague-Dawley