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Polymeric nanoparticle-based delivery of TRAIL DNA for cancer-specific killing.

ABSTRACT: Lack of specificity in cancer therapeutics severely limits the efficacy of many existing treatment modalities. The use of Tumor Necrosis Factor-related Apoptosis-Inducing Ligand (TRAIL) is of interest to the field due to this protein's ability to cause cell death specifically in cancer cells without harming the surrounding healthy tissue. Here, we report that polymeric nanoparticles, based on synthetic poly(beta-amino ester)s (PBAEs) and containing DNA, are able to selectively transfect cancer cells in vitro over healthy cells of the same tissue type. Moreover, PBAE-based nanoparticles containing TRAIL DNA are able to transfect several human cancer cell cultures in vitro and cause cell death. While certain cell types, including human glioblastoma (GBM), showed resistance to TRAIL, we found that the expression of TRAIL-binding surface proteins was predictive of each cell type's resistance to TRAIL therapy. We demonstrate a non-viral nanomedicine approach to cancer gene therapy that can improve cancer specificity via both biomaterial selection and through the use of cancer-targeting genetic cargo.

SUBMITTER: Tzeng SY

PROVIDER: S-EPMC5365091 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Polymeric nanoparticle-based delivery of TRAIL DNA for cancer-specific killing.

Tzeng Stephany Y SY Wilson David R DR Hansen Sarah K SK Quiñones-Hinojosa Alfredo A Green Jordan J JJ

Bioengineering & translational medicine 20160601 2

Lack of specificity in cancer therapeutics severely limits the efficacy of many existing treatment modalities. The use of Tumor Necrosis Factor-related Apoptosis-Inducing Ligand (TRAIL) is of interest to the field due to this protein's ability to cause cell death specifically in cancer cells without harming the surrounding healthy tissue. Here, we report that polymeric nanoparticles, based on synthetic poly(beta-amino ester)s (PBAEs) and containing DNA, are able to selectively transfect cancer c ...[more]

PMID: 28349127

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Project description:Hepatocellular carcinoma (HCC) is the third most deadly cancer in the US, with a meager 5-year survival rate of <20%. Such unfavorable numbers are closely related to the heterogeneity of the disease and the unsatisfactory therapies currently used to manage patients with invasive HCC. Outside of the clinic, gene therapy research is evolving to overcome the poor responses and toxicity associated with standard treatments. The inadequacy of gene delivery vectors, including poor intracellular delivery and cell specificity, are major barriers in the gene therapy field. Herein, we described a non-viral strategy for effective and cancer-specific DNA delivery to human HCC using biodegradable poly(beta-amino ester) (PBAE) nanoparticles (NPs). Varied PBAE NP formulations were evaluated for transfection efficacy and cytotoxicity to a range of human HCC cells as well as healthy human hepatocytes. To address HCC heterogeneity, nine different sources of human HCC cells were utilized. The polymeric NPs composed of 2-((3-aminopropyl)amino) ethanol end-modified poly(1,5-pentanediol diacrylate-co-3-amino-1-propanol) ('536') at a 25 polymer-to-DNA weight-to-weight ratio led to high transfection efficacy to all of the liver cancer lines, but not to hepatocytes. Each individual HCC line had a significantly higher percentage of exogenous gene expression than the healthy liver cells (P<0.01). Notably, this biodegradable end-modified PBAE gene delivery vector was not cytotoxic and maintained the viability of hepatocytes above 80%. In a HCC/hepatocyte co-culture model, in which cancerous and healthy cells share the same micro-environment, 536 25 w/w NPs specifically transfected cancer cells. PBAE NP administration to a subcutaneous HCC mouse model, established with one of the human lines tested in vitro, confirmed effective DNA transfection in vivo. PBAE-based NPs enabled high and preferential DNA delivery to HCC cells, sparing healthy hepatocytes. These biodegradable and liver cancer-selective NPs are a promising technology to deliver therapeutic genes to liver cancer.

Dataset Information

Polymeric nanoparticle-based delivery of TRAIL DNA for cancer-specific killing.

Publications

Polymeric nanoparticle-based delivery of TRAIL DNA for cancer-specific killing.

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