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Adv Healthc Mater. 2018 Aug;7(16):e1800052. doi: 10.1002/adhm.201800052. Epub 2018 Jun 10.

Bacterial tRNase-Based Gene Therapy with Poly(β-Amino Ester) Nanoparticles for Suppressing Melanoma Tumor Growth and Relapse.

Author information

1
Department of Biotechnology, Yonsei University, Seoul, 03722, Republic of Korea.
2
Department of Chemical and Biochemical Engineering, Dongguk University-Seoul, Seoul, 04620, Republic of Korea.
3
Department of Biomedical Engineering, Translational Tissue Engineering Center, Institute for Nanobiotechnology, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA.

Abstract

Here, a novel anticancer gene therapy with a bacterial tRNase gene, colicin D or virulence associated protein C (VapC), is suggested using biodegradable polymeric nanoparticles, such as poly(β-amino esters) (PBAEs) as carriers. These genes are meticulously selected, aiming at inhibiting translation in the recipients by hydrolyzing specific tRNA species. In terms of nanoparticles, out of 9 PBAE formulations, a leading polymer, (polyethylene oxide)4 -bis-amine end-capped poly(1,4-butanediol diacrylate-co-5-amino-1-pentanol) (B4S5E5), is identified that displays higher gene delivery efficacy to cancer cells compared with the leading commercial reagent Lipofectamine 2000. Interestingly, the B4S5E5 PBAE nanoparticles complexed with colicin D or VapC plasmid DNA induce significant toxicity highly specific to cancer cells by triggering apoptosis. In contrast, the PBAE nanoparticles do not induce these cytotoxic effects in noncancerous cells. In a mouse melanoma model of grafted murine B16-F10 cells, it is demonstrated that treatment with PBAE nanoparticles complexed with these tRNase genes significantly reduces tumor growth rate and delays tumor relapse. Moreover, increased stability of PBAE by PEGylation further enhances the therapeutic effect of tRNase gene treatment and improves survival of animals. This study highlights a nonviral gene therapy that is highly promising for the treatment of cancer.

KEYWORDS:

PEGylation; anticancer therapy; bacterial tRNase; nonviral gene delivery; poly(β-amino ester)

PMID:
29888531
DOI:
10.1002/adhm.201800052

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