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

Stephany Y Tzeng,Jordan J Green,David R Wilson,Sarah K Hansen,Alfredo Quiñones‐Hinojosa

doi:10.1002/btm2.10019

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.

Highlights

The ability to deliver DNA is attractive for clinical applications, including cancer therapy
Using the leading poly(beta-amino ester)s (PBAEs)/DNA formulations for each of the human-derived cell types in Table 1 found from the initial experiments with GFP, nanoparticles were formed with DNA coding for GFP-Tumor Necrosis Factor-related Apoptosis-Inducing Ligand (TRAIL) fusion protein and used to transfect cells using the protocol described above
We examined four cell types spanning the spectrum of responsiveness to TRAIL, including H446 cells, on which TRAIL is highly effective; MDA and JHGBM-965 cells, which show low to moderate response to TRAIL; and JHGBM-276 cells, which showed no significant response to TRAIL

Summary

| INTRODUCTION

The ability to deliver DNA is attractive for clinical applications, including cancer therapy. The field of nanomedicine has recently produced many non-viral gene delivery agents based on biomaterials that are capable of facilitating intracellular delivery of DNA and can be engineered for high transfection efficacy in relevant cells while minimizing toxicity.[11,12,13] Poly (b-amino ester)s (PBAEs), a class of synthetic, cationic polymers, have been found to be effective as non-viral gene delivery agents. They are easy to synthesize, effective at binding to DNA, and hydrolytically degradable under physiological conditions, which decreases their cytotoxicity. We examined mechanisms of resistance in cancer cells lines that were less responsive to TRAIL treatment

| MATERIALS AND METHODS

| RESULTS

Findings

| DISCUSSION