fulltext.study @t Gmail

Biodegradable polyamino acid-based polycations as safe and effective gene carrier minimizing cumulative toxicity

Paper ID Volume ID Publish Year Pages File Format Full-Text
9725 643 2010 8 PDF Available
Title
Biodegradable polyamino acid-based polycations as safe and effective gene carrier minimizing cumulative toxicity
Abstract

Gene delivery using cationic polymers has attracted much attention due to their potential advantages, such as large DNA loading capacity, ease of large-scale production, and reduced immunogenicity. We recently reported that polyplexes from poly[N-[N-(2-aminoethyl)-2-aminoethyl]aspartamide] (P[Asp(DET)]), having an efficient endosomal escape due to pH-selective membrane destabilization, showed high transfection efficiency with minimal toxicity. Pharmacogenomic analysis demonstrated that P[Asp(DET)] also provided long-term security after transfection. We hypothesized that the biodegradability of P[Asp(DET)] played a significant role in achieving effective transfection. Gel permeation chromatography (GPC) and electrospray ionization mass spectrometry (ESI-MS) measurements of P[Asp(DET)] revealed their ability to undergo rapid degradation. In contrast, a derivative polycation, N-substituted polyglutamide (P[Glu(DET)]), showed no degradability, indicating that the degradation of P[Asp(DET)] was induced by a specific self-catalytic reaction between the PAsp backbone and the side-chain amide nitrogen. Degradation products of P[Asp(DET)] caused no cytotoxicity, even at high concentrations in the culture medium. Repeated transfection by administering the polyplexes for every 24 h showed that biodegradable P[Asp(DET)] provided a continuous increase in transgene expression, while non-degradable P[Glu(DET)] showed a decrease in transgene expression after 48 h, coupled with fluctuations in expression profiles of endogenous genes. In vivo intraperitoneal injection of P[Asp(DET)] induced minimal inflammatory cytokine induction to a level comparable to that of normal saline. These results indicate that the biodegradability of P[Asp(DET)] played a key role in achieving safe and sustained transgene expression, by minimizing cumulative toxicity caused by polycations remaining in cells or in the body.

Keywords
Non-viral gene carrier; Cationic polymer; Biodegradable polycation; Polyplex; Cumulative toxicity
First Page Preview
Biodegradable polyamino acid-based polycations as safe and effective gene carrier minimizing cumulative toxicity
Publisher
Database: Elsevier - ScienceDirect
Journal: Biomaterials - Volume 31, Issue 13, May 2010, Pages 3707–3714
Authors
, , , ,
Subjects
Physical Sciences and Engineering Chemical Engineering Bioengineering