Intracellularly Disintegratable Polysulfoniums for Efficient Gene Delivery

Abstract

Amine-based cationic polymers have been extensively explored as nonviral carriers for gene delivery, but inefficient intracellular unpacking of polymer/ DNA complexes (polyplexes) to release plasmids is still a key limiting step to high transfection efficiency. Furthermore, the amine-resulting cationic charges in the polymer chains, and even their degraded fragments, inherently interfere with transgene expression. A cationic polymer capable of converting to uncharged fragments once inside cells would not only quickly release the DNA, but also not interfere with the gene transcription process for efficient gene expression and low toxicity. A new class of polysulfoniums that can degrade into neutral thioether fragments triggered by reactive oxygen species (ROS) is reported. The polysulfoniums condense DNA into nanosized polyplexes, which can be quickly internalized and efficiently escape from endo/lysosomes. In cancer cells, the oxidation of the boronic acid/ester by the elevated ROS levels triggers polysulfonium to break down into neutral thioether fragments, efficiently releasing DNA for gene expression. More importantly, the polyplexes have excellent serum resistance; in vivo, they efficiently deliver the suicide gene pTRAIL to intraperitoneal tumors eliciting effective anticancer activity.

Cationic micelle: A promising nanocarrier for gene delivery with high transfection efficiency

“…Intracellular signaling ROS, including H 2 O 2 , superoxide anions (O 2− ) and hydroxyl radicals, are known to be elevated in cancerous cells and are capable of oxidizing benzylboronic acid/esters to trigger drug release, activation of prodrugs and fluorescence . ROS responsive vectors in recent studies show effective gene delivery, which can efficiently deliver a cancer suicide gene, pTRAIL, to different tumors and achieve high antitumor activity …”

“…91,92 ROS responsive vectors in recent studies show effective gene delivery, which can efficiently deliver a cancer suicide gene, pTRAIL, to different tumors and achieve high antitumor activity. 93,94 Low generation PAMAM-based micelles conjugating ROS-and GSH-responsive poly (propylenesulfide) (PPS) as a core were prepared, which showed a very strong binding ability towards DNA, fully condensing the plasmid DNA even at very low N/P ratios. The thioether cores of the micelles were ROS-responsive, which facilitated the disassembly of polyplexes and the release of the entrapped DNA ( Figure 6).…”

Advances in Stimulus‐Responsive Polymeric Materials for Systemic Delivery of Nucleic Acids

“…This resulted in up-regulation of the expression of the death ligand TRAIL and achieved a greater anti-tumor efficacy than carriers loaded with anticancer drug doxorubicin only. Another ROS-responsive NADS was developed by the Shen group [59]. They synthesized a new class of disintegrable polysulfoniums with boronic acid/ester moieties that respond to intracellular ROS by degrading into thioether fragments, thus accelerating the release of DNA in tumor cells (Figure 6).…”

“…Another ROS-responsive NADS was developed by Shen and co-workers. [59] They synthesized a new class of disintegrable polysulfoniums with boronic acid/ester moieties that respond to intracellular ROS by degrading into thioether fragments, thus accelerating the release of DNA in tumor cells (Figure 6). The polysulfoniums efficiently complexed DNA into small uniform polyplexes in an aqueous medium.…”

“…Reproduced with permission. [59] Copyright 2017, Wiley. key component of an enzyme-sensitive material is the enzymeresponsive moiety, which is an enzyme substrate or a substrate mimic.…”