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.

Biodegradable nanoparticles composed of dendrigraft poly-l-lysine for gene delivery

“…In addition, the electrostatic compaction of DNA by dendrimers was found to protect it from degradation by nucleases and to enhance the cellular uptake of dendrimer-based DNA-containing particles via adsorptive endocytosis or phagocytosis. Polyamidoamine (PAMAM) dendrimers are commercially available macromolecules that can be used as carriers for plasmid DNA, antisense oligonucleotides, and siRNA [5][6][7][8]. However, PAMAM dendrimers are not biodegradable and exhibit strong cytotoxicity [9,10].…”

Folic Acid-Decorated Polyamidoamine Dendrimer Mediates Selective Uptake and High Expression of Genes in Head and Neck Cancer Cells

“…Therefore, it can be targeted for developing active tumor-targeting therapies [9][10][11]. Although FR-targeted drug and gene delivery systems have been developed on the basis of dendrimers [12][13][14][15][16][17] and many other types of nanoparticle carriers [18][19][20][21][22][23], few nonviral vectors have been developed for HNSCC [24,25]. Given the scarcity of nonviral vectors for gene therapy of HNSCC and limited clinical outcomes, it is highly desirable to develop and evaluate vectors under the context of HNSCC.…”

Inhibition of C6 glioma in vivo by combination chemotherapy of implantation of polymer wafer and intracarotid perfusion of transferrin-decorated nanoparticles

“…The binding of the endogenous and chimeric ligands renders the NPs capable of selectively recognizing brain capillary endothelial cells and cerebral tumoral cells, improving both the selective brain targeting and the tumor uptake of therapeutic molecules (30). Different ligands have been used to functionalize the nanoparticles, include Tf (31), RGD (32) and folic acid (33). Tf has been used as a tumor-targeting ligand for several drug delivery systems to the brain (34)(35)(36)(37).…”