Attarwala Husain Z, Suri Kanika, Amiji Mansoor M
Department of Pharmaceutical Sciences, School of Pharmacy Northeastern University, Boston, Massachusetts, USA.
Department of Bioengineering, Northeastern University, Boston, Massachusetts, USA.
Bioelectricity. 2020 Jun 1;2(2):167-174. doi: 10.1089/bioe.2020.0008. Epub 2020 Jun 17.
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). 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). 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) 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. 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.
RNA干扰（RNAi）疗法在治疗以基因过表达为特征的疾病方面具有巨大潜力。然而，利用该疗法面临的最大挑战是设计出能够将小干扰RNA（siRNA）有效转运至合适靶点的递送系统。我们在本研究中的目标是开发并评估用于口服递送siRNA的多室系统，该siRNA靶向小肠中过表达的转谷氨酰胺酶2基因（TG2-siRNA），用于治疗乳糜泻（CD）。我们开发并评估了两种类型的多室系统：（1）一种固-固多室系统，即“微球口服系统中的纳米颗粒（NiMOS）”，其中含有TG2-siRNA的B型明胶纳米颗粒（TG2-NiMOS）被包裹在聚己内酯（PCL）基微球内；（2）一种固-液多室系统，即“纳米颗粒-乳液（NiE）”，由含有TG2-siRNA的B型明胶纳米颗粒包裹在含有水包油包水（W/O/W）多重乳液的红花油内组成（TG2-NiE）。对C57BL/6小鼠单次口服含siRNA的多室系统后的生物分布和药代动力学（PK）评估表明，通过TG2-NiE和TG2-NiMOS系统，TG2-siRNA均可被递送至小肠（十二指肠、空肠和回肠）以及结肠，且全身暴露最小。相对于TG2-NiE制剂，TG2-NiMOS制剂在十二指肠、空肠、回肠和结肠中的TG2-siRNA暴露量（AUC）分别高56.4倍、34.3倍、85.5倍和35.5倍。本研究结果表明，TG2-NiMOS制剂在通过口服途径促进siRNA的肠道递送方面比TG2-NiE制剂更具优势，并且有可能用于治疗乳糜泻。
