Knipe Jennifer M, Strong Laura E, Peppas Nicholas A
Department of Chemical Engineering, C0400, The University of Texas at Austin , Austin, Texas 78712, United States.
Institute for Biomaterials, Drug Delivery, and Regenerative Medicine, The University of Texas at Austin , Austin, Texas 78712, United States.
Biomacromolecules. 2016 Mar 14;17(3):788-97. doi: 10.1021/acs.biomac.5b01518. Epub 2016 Feb 11.
Inflammatory bowel diseases (IBD) manifest from excessive intestinal inflammation. Local delivery of siRNA that targets these inflammatory cytokines would provide a novel treatment approach. Microencapsulated nanogels are designed and validated as platforms for oral delivery of siRNA targeting TNF-α, a common clinical target of IBD treatments. The preferred platform was designed to (i) protect siRNA-loaded nanogels from the harsh acidic environment of the upper GI tract and (ii) enzymatically degrade and release the nanogels once the carrier has reached the intestinal region. This platform consists of microgels composed of poly(methacrylic acid-co-N-vinyl-2-pyrrolidone) (P[MAA-co-NVP]) cross-linked with a trypsin-degradable peptide linker. The P(MAA-co-NVP) backbone is designed to collapse around and protect encapsulated nanogel from degradation at the low pH levels seen in the stomach (pH 2-4). At pH levels of 6-7.5, as typically observed in the intestine, the P(MAA-co-NVP) matrix swells, potentially facilitating diffusion of intestinal fluid and degradation of the matrix by intestinal enzymes such as trypsin, thus "freeing" the therapeutic nanogels for delivery and cellular uptake within the intestine. TNF-α siRNA-loaded nanogels released from this platform were capable of inducing potent knockdown of secreted TNF-α levels in murine macrophages, further validating the potential for this approach to be used for the treatment of IBD.
炎症性肠病（IBD）由过度的肠道炎症引起。局部递送靶向这些炎症细胞因子的小干扰RNA（siRNA）将提供一种新的治疗方法。微囊化纳米凝胶被设计并验证为用于口服递送靶向肿瘤坏死因子-α（TNF-α）的siRNA的平台，TNF-α是IBD治疗的常见临床靶点。优选的平台设计为：（i）保护负载siRNA的纳米凝胶免受上消化道恶劣酸性环境的影响；（ii）一旦载体到达肠道区域，纳米凝胶通过酶促降解并释放。该平台由与可被胰蛋白酶降解的肽接头交联的聚（甲基丙烯酸-co-N-乙烯基-2-吡咯烷酮）（P[MAA-co-NVP]）组成的微凝胶构成。P（MAA-co-NVP）主链设计为在胃中所见的低pH水平（pH 2-4）下围绕并保护包封的纳米凝胶不被降解。在肠道中通常观察到的pH 6-7.5水平下，P（MAA-co-NVP）基质膨胀，可能促进肠液扩散并被诸如胰蛋白酶的肠道酶降解基质，从而“释放”治疗性纳米凝胶以便在肠道内递送和细胞摄取。从该平台释放的负载TNF-α siRNA的纳米凝胶能够有效降低小鼠巨噬细胞中分泌的TNF-α水平，进一步验证了这种方法用于治疗IBD的潜力。
