Targeting Intestinal Inflammation With CD98 siRNA/PEI–loaded Nanoparticles

Abstract

Intestinal CD98 expression plays a crucial role in controlling homeostatic and innate immune responses in the gut. Modulation of CD98 expression in intestinal cells therefore represents a promising therapeutic strategy for the treatment and prevention of inflammatory intestinal diseases, such as inflammatory bowel disease. Here, the advantages of nanoparticles (NPs) are used, including their ability to easily pass through physiological barriers and evade phagocytosis, high loading concentration, rapid kinetics of mixing and resistance to degradation. Using physical chemistry characterizations techniques, CD98 siRNA/polyethyleneimine (PEI)-loaded NPs was characterized (diameter of ~480 nm and a zeta potential of -5.26 mV). Interestingly, CD98 siRNA can be electrostatically complexed by PEI and thus protected from RNase. In addition, CD98 siRNA/PEI-loaded NPs are nontoxic and biocompatible with intestinal cells. Oral administration of CD98/PEI-loaded NPs encapsulated in a hydrogel reduced CD98 expression in mouse colonic tissues and decreased dextran sodium sulfate-induced colitis in a mouse model. Finally, flow cytometry showed that CD98 was effectively downregulated in the intestinal epithelial cells and intestinal macrophages of treated mice. Finally, the results collectively demonstrated the therapeutic effect of "hierarchical nano-micro particles" with colon-homing capabilities and the ability to directly release "molecularly specific" CD98 siRNA in colonic cells, thereby decreasing colitis.

Genetic Deletion of Klf4 in the Mouse Intestinal Epithelium Ameliorates Dextran Sodium Sulfate–induced Colitis by Modulating the NF-κB Pathway Inflammatory Response

“…For in vivo use, to overcome the low penetration of naked siRNA across cell membranes, 58 we resorted to NPs that have previously shown high potential in binding and delivering siRNA. 39,41,59–61 Here, we used biodegradable noncytotoxic NPs for targeting of Klf4-siRNA with the aim to inhibit Klf4 expression in the colonic epithelium. This method has been used successfully before to target the colonic epithelial cells for load delivery.…”

Nanosponge-Mediated Drug Delivery Lowers Intraocular Pressure

“…29 Recently, nanoparticles have been used for targeted drug delivery in chemotherapeutics and their use in the treatment of other diseases, such as Alzheimer's disease, inflammatory intestinal disease, and lupus, has been promising. [30][31][32][33][34][35] Given the issues with patient compliance in glaucoma, the use of nanoparticles to deliver a controlled, sustained release of therapeutics to the retina or other ocular structures via topical drops, contact lenses, and intravitreal injection could drastically reduce the number of patients who have progression to vision loss in this disease. [36][37][38][39] To address the need for extended-release treatments that minimize patient nonadherence and discomfort, we examined the efficacy of four types of nanoparticleencapsulated compounds, or nanosponges (NS), administered intravitreally to lower IOP in mice with microbead-induced ocular hypertension.…”

Strategist PLGA Nano-capsules to Deliver siRNA for Inhibition of Carcinoma and Neuroblastoma Cell Lines by Knockdown of MYC Proto-oncogene using CPPs and PNA

“…Flow cytometry measurements were taken at fluorescence emissions of 530 nm and 575 nm [40]. Same procedure was carried on normal cells to determine the effect of NPs.…”