Orally delivered thioketal nanoparticles loaded with TNF-α–siRNA target inflammation and inhibit gene expression in the intestines

Abstract

Gene silencing via orally delivered small interfering RNAs (siRNAs) represents a promising treatment strategy for numerous gastrointestinal (GI) diseases associated with chronic intestinal inflammation; however, the oral delivery of siRNA to inflamed isntestinal tissues remains a major challenge. Here, we present a delivery vehicle for siRNA, termed thioketal nanoparticles (TKNs), that can localize orally deliver siRNA to sites of intestinal inflammation, and thus inhibit gene expression in diseased intestinal tissue. TKNs are formulated from a new polymer, poly-(1,4-phenyleneacetone dimethylene thioketal) (PPADT), that degrades selectively in response to reactive oxygen species (ROS). Therefore, when delivered orally, TKNs release siRNA in response to the abnormally high levels of ROS specific to sites of intestinal inflammation1–3. Using a murine model of ulcerative colitis (UC), we demonstrate that orally administered TKNs loaded with siRNA against the proinflammatory cytokine tumor necrosis factor-alpha (TNFα) diminish TNFα messenger RNA (mRNA) levels in the colon and protect mice from UC.

Reactive Oxygen Species (ROS) Responsive Polymers for Biomedical Applications

“…Poly(propylene sulfi de) [19][20][21][22] Selenium-containing polymers [26,28,29] [ 25,30] Telluriumcontaining polymers [35][36][37] Poly(thioketal) [38][39][40]46] [ [41][42][43][44][45]55] Phenylboronic acid/ ester containing polymers Poly(L-methionine) [49] Poly(L-proline) [53,54] Macromolecular Bioscience www.mbs-journal.de and SN38 resulted in enhanced proliferation inhibition of tumor cells via inducing cell apoptosis. In addition to drug carrier, the thioether-containing particles themselves can also show inherent therapeutic properties against oxidative stress.…”

“…[ 38,39 ] Xia and co-workers developed a ROScleavable polymer for targeted gene delivery in cancer cells. [ 40 ] The unique physiological environments of intracellular space or tumor sites are usually used as specifi c biological triggers for smart drug delivery systems, such as weakly acidic pH value in tumor sites.…”

Nanotherapeutics for the treatment of inflammatory bowel disease

“…Most of the current oral formulations for IBD therapy, which include pellets, capsules, and tablets, are based on pH-, pressure-, or bacteria-responsive mechanisms [17], and can only perform organ-level targeting. NPs, in contrast, have the potential to accumulate in inflamed colon tissues passively, and studies have shown that reactive oxygen species (ROS)-sensitive formulations can induce active targeted drug delivery at the tissue level [18]. For cell-level delivery of NPs, receptormediated drug delivery is a promising approach for achieving target specificity and avoiding nonspecific interactions.…”

Punica granatum flower extract mediated synthesis of Copper oxide Nanoparticle and evolution of its antibacterial activity

“…In pharmaceuticals, it has been applied to cure infection [2], cancer [3], allergy [4], diabetes [5] and inflammation [6].…”