Aromatic Thioacetal-Bridged ROS-Responsive Nanoparticles as Novel Gene Delivery Vehicles

Abstract

In this report, a series of polycations are designed and synthesized by conjugating reactive oxygen species (ROS)-responsive thioacetal-linkers to low molecular weight (LMW) polyethylenimine (PEI) via ring-opening polymerization. Their structure–activity relationships (SARs) as gene delivery vectors are systematically studied. Although the MWs of the target polymers are only ~9 KDa, they show good DNA binding ability. The formed polyplexes, which are stable toward serum but decomposed under ROS-conditions, have appropriate sizes (180~300 nm) and positive zeta-potentials (+35~50 mV). In vitro experiments reveal that these materials have low cytotoxicity, and higher transfection efficiency (TE) than controls. Furthermore, the title polymers exhibit excellent serum tolerance. With the present of 10% serum, the TE of the polymers even increases up to 10 times higher than 25 KDa PEI and 9 times higher than Lipofectamine 2000. The SAR studies also reveal that electron-withdrawing groups on the aromatic ring in 4a may benefit to balance between the DNA condensation and release for efficient gene transfection.

Synthesis of ROS-responsive poly(thioacetal)s with narrow molecular weight distributions via lactone ring-opening polymerization

“…The concentration looks significantly higher than the physiological concentration of H 2 O 2 , 3 but we could estimate the degradability of the thioacetal polymers we developed in the presence of various ROS including superoxides, hydroxyl radicals, hypochlorite and H 2 O 2 , which are produced by ROS-generating systems in the body, 40 similar to the previous reports of ROS responsive degradation of thioketal/thioacetal polymers in ROS-rich physiological conditions. 22,23,41 After incubation at 37 °C, the SEC trace of the H 2 O 2 -treated polymeric samples showed significant peak shifts to low-molecular-weight regions, which indicates degradation in the backbone, unlike the water-treated samples showing only small changes (Fig. 4).…”

Nanoformulations in Pharmaceutical and Biomedical Applications: Green Perspectives

“…Biopolymers such as alginate and gelatin are also used as probiotic carriers. The encapsulation of Propionibacterium freudenreichii in alginate–gelatin capsules participates in delivering probiotic bacteria to the intestine [ 181 ]. An alginate hydrogel microsphere encapsulating Bifidobacterium (Bac) and drug-modified nanoscale dietary fibers (NDFs) is responsible for protecting drugs from acidic and multi-enzymatic environments and delivering drugs to the colorectum [ 182 ].…”

Stimuli-Responsive Polymer-Based Nanosystems for Cancer Theranostics

“…Thioketal, which was obtained by dehydrating two thiols and ketone, has also been widely utilized as monomers to form ROS-sensitive polymers in various drug delivery applications. − This is due to the fact that ketone thioacetal can be readily decomposed by oxidizing agents or Lewis bases such as OH•, O 2 – , etc . An excellent example is demonstrated by D. Scott Wilson et al, who developed a thioketal nanoparticle (TKN) system for the targeted delivery of siRNA to inflamed intestinal tissue with high levels of ROS .…”