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

Husain Z Attarwala; Kanika Suri; Mansoor M Amiji

doi:10.1089/bioe.2020.0008

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

Bioelectricity. 2020 Jun 1;2(2):167-174. doi: 10.1089/bioe.2020.0008. Epub 2020 Jun 17.

Authors

Husain Z Attarwala¹, Kanika Suri², Mansoor M Amiji¹

Affiliations

¹ Department of Pharmaceutical Sciences, School of Pharmacy Northeastern University, Boston, Massachusetts, USA.
² Department of Bioengineering, Northeastern University, Boston, Massachusetts, USA.

Abstract

Background: RNA interference (RNAi) therapy has tremendous potential in treating diseases that are characterized by overexpression of genes. However, the biggest challenge to utilize the therapy is to engineer delivery systems that can efficiently transport small interfering RNA (siRNA) to appropriate target sites. Our objective in this study was to develop and evaluate multi-compartmental systems for the oral delivery of siRNA that targets the overexpressed TG2 gene (TG2-siRNA) in the small intestine for the treatment of celiac disease (CD). Materials and Methods: Two types of multicompartmental systems were developed and evaluated: (1) a solid-in-solid multicompartmental system featuring "nanoparticle in microsphere oral system (NiMOS)" where type B gelatin nanoparticles containing TG2-siRNA (TG2-NiMOS) were encapsulated within poly(ɛ-caprolactone) (PCL) based microspheres, and (2) a solid-in-liquid multicompartmental system, "Nanoparticle-in-Emulsion (NiE)" consisting of type-B gelatin nanoparticles containing TG2-siRNA encapsulated within safflower oil containing water-in-oil-in-water (W/O/W) multiple emulsion (TG2-NiE). Results: Evaluation of the biodistribution and pharmacokinetics (PK) after a single oral dose of siRNA containing multicompartmental systems to C57BL/6 mice showed that TG2-siRNA was delivered to the small intestine (duodenum, jejunum and ileum), and colon with minimal systemic exposure via both TG2-NiE and TG2-NiMOS systems. TG2-siRNA exposure (AUC_0-t) in the duodenum, jejunum, ileum and colon was 56.4-, 34.3-, 85.5- and 35.5-fold greater for the TG2-NiMOS formulation, relative to the TG2-NiE formulation. Conclusion: The results of this study suggest that TG2-NiMOS formulation was more superior than TG2-NiE formulation in facilitating intestinal delivery of siRNA via the oral route of administration and can be potentially used in the treatment of CD.

Keywords: gelatin nanoparticles; multicompartmental delivery; oral administration; pharmacokinetic and biodistribution; small interference RNA.