Oral nucleic acid therapy using multicompartmental delivery systems

Abstract

Nucleic acid-based therapeutics has the potential for treating numerous diseases by correcting abnormal expression of specific genes. Lack of safe and efficacious delivery strategies poses a major obstacle limiting clinical advancement of nucleic acid therapeutics. Oral route of drug administration has greater delivery challenges, because the administered genes or oligonucleotides have to bypass degrading environment of the gastrointestinal (GI) tract in addition to overcoming other cellular barriers preventing nucleic acid delivery. For efficient oral nucleic acid delivery, vector should be such that it can protect encapsulated material during transit through the GI tract, facilitate efficient uptake and intracellular trafficking at desired target sites, along with being safe and well tolerated. In this review, we have discussed multicompartmental systems for overcoming extracellular and intracellular barriers to oral delivery of nucleic acids. A nanoparticles-in-microsphere oral system-based multicompartmental system was developed and tested for in vivo gene and small interfering RNA delivery for treating colitis in mice. This system has shown efficient transgene expression or gene silencing when delivered orally along with favorable downstream anti-inflammatory effects, when tested in a mouse model of intestinal bowel disease. WIREs Nanomed Nanobiotechnol 2018, 10:e1478. doi: 10.1002/wnan.1478 This article is categorized under: Biology-Inspired Nanomaterials > Nucleic Acid-Based Structures Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Emerging Technologies.

The Nano–Intestine Interaction: Understanding the Location‐Oriented Effects of Engineered Nanomaterials in the Intestine

“…Interestingly, the multi functional nanodelivery system containing nucleic acid showed effective antiinflammatory effects through downregulating or silencing the gene expression associated with inflammation in the IBD mice. [94] Aside from above effects, nanomaterials can also improve the therapeutic effect of oral vaccines for intes tinal autoimmune diseases as immune adjuvants. Moreover, NMs with different modification can also resist the invasion of Salmonella enteritis and prevent anaphylactic shock through modulating immune responses through enhancing Th1 effect, the release of Treg cytokines, and immune memory.…”

Pharmacokinetics and Biodistribution Analysis of Small Interference RNA for Silencing Tissue Transglutaminase-2 in Celiac Disease After Oral Administration in Mice Using Gelatin-Based Multicompartmental Delivery Systems

“…The multicompartmental systems evaluated in this study, TG2-NiE and TG2-NiMOS, were specifically designed to evade these extra-and intracellular barriers to facilitate oral nucleic acid delivery. 25,26 Prior in vitro evaluations with GNPs showed that GNPs were capable of efficiently encapsulating siRNA, delivering siRNA to the cellular cytoplasm, and enabling functional RISC loading of delivered siRNA. Further, when tested in an in vitro model of CD, the knockdown of IL-15, either specific or an adjunct with TG2, showed significant downregulation in the expression of proinflammatory cytokines-TNF-a and IFN-c. 22 Our current objective was to develop an oral siRNA delivery system that is capable of inhibiting expression of target proteins in the small intestine, aimed at developing a potential treatment for patients with CD.…”

Oligonucleotide Delivery across the Caco-2 Monolayer: The Design and Evaluation of Self-Emulsifying Drug Delivery Systems (SEDDS)

“…In addition to the size of carriers, negative surface charge and hydrophilic surface decoration are also strategies utilized for passive targeting to the inflamed intestinal tissue [ 9 , 10 , 11 ]. The local delivery of OND has been investigated using many kinds of polymeric nanoparticles [ 12 ], lipid nanoparticles [ 13 ], microencapsulated nanogel [ 14 ], thioketal nanoparticles [ 15 ] and nanoparticles-in-microspheres multicompartment systems [ 16 ].…”