Oligoproline-derived nanocarrier for dual stimuli-responsive gene delivery

Abstract

Gene therapy is a promising method for the treatment of vascular disease; however, successful strategies depend on the development of safe and effective delivery technologies with specific targeting to a diseased point of vasculature. Reactive oxygen species (ROS) are overproduced by vascular smooth muscle cells (VSMCs) at critical stages of atherosclerosis progression. Therefore, ROS were exploited as a stimulus for vascular targeted gene delivery in this study. A combination of bio-conjugation methods and controlled reverse addition-fragmentation chain-trasfer (RAFT) polymerization was utilized to synthesize a new ROScleavable, pH-responsive mPEG 113 -b-CP 5 K-b-PDMAEMA 42 -b-P(DMAEMA 22 -co-BMA 40 -co-PAA 24 ) (PPDDBP) polymer as a nanocarrier for plasmid DNA (pDNA) delivery. The ros degradability of PPDDBP polymers was confirmed by SIN-1-mediated cleavage of CP 5 K peptide linkers through a shift in GPC chromatogram with an appearance of mPEG shoulder peak and an increase in zeta potential (z). The polyplex nanocarrier also demonstrated effective PDNA loading, serum stability, and hemocompatibility, indicating its excellent performance under physiological conditions. The polyplexes demonstrated ideal pH responsiveness for endosomal escape and effective ROS responsiveness for improved targeting in an in vitro model of pathogenic VSMCs in terms of both uptake and expression of reporter gene. These data suggest this novel nanocarrier polyplex system is a promising gene delivery tool for preventing or treating areas of high ROS, such as atherosclerotic lesions.

Oxidation‐Responsive Materials: Biological Rationale, State of the Art, Multiple Responsiveness, and Open Issues

“…However, when ROS‐degradable (and angiogenic) scaffolds have been obtained via cross‐linking PEG‐PCL bearing side‐chain carboxylic groups with amine‐terminated PEG‐oligo(proline) of five to ten amino acid residues, no clear difference in degradability (taking place within a week) could be highlighted . Of note, pentaproline was employed in the preparation of pDNA carriers based on PEG and N , N ‐dimethylaminoethyl methacrylate (DMAEMA) blocks, and pentaproline‐PEG constructs have been grafted on chitosan for an ROS‐responsive release of radioprotectant proteins …”

Atherosclerosis Treatment with Stimuli‐Responsive Nanoagents: Recent Advances and Future Perspectives

“…Fluorescent agents for visible fluorescence imaging and NIR fluorescence imaging are commonly combined with other stimuli‐sensitive materials, owing to their advantages of cost‐effectiveness, sensitivity, innate biological safety, and relative simplicity of use . For instance, the Cy5 dye has been widely used as a fluorescent imaging agent in ROS‐, enzyme‐, and pH‐responsive nanoplatforms . Meanwhile, ICG is an example of NIR fluorescent imaging agents that not only can be used for imaging but also for PTT and PDT .…”

“…Gupta et al developed oligoproline peptide‐derived nanocarriers for plasmid DNA (pDNA) delivery targeting VSMCs in plaque lesions. The nanocarriers were made of a pH‐responsive (PPDDBP) polymer consisting of a P(DMAEMA‐ co ‐BMA‐ co ‐PAA) core‐stabilizing block and PEG coating to efficiently entrap plasmid DNAs.…”

“…Conversely, multi‐stimuli‐responsive OR‐based nanosystems have successfully been developed by Gupta et al for pDNA delivery to VSMCs in atherosclerosis lesions. The nanocarriers were made of a pH‐responsive (PPDDBP) polymer consisting of a P(DMAEMA‐ co ‐BMA‐ co ‐PAA) core‐stabilizing block and PEG coating to efficiently entrap pDNAs.…”

“…Illustration of extracellular ROS‐mediated dePEGylation of polyplexes and delivery of pDNA triggered by endosomal pH (5.0). Reproduced with permission . Copyright 2015, The Royal Society of Chemistry.…”