Dual-function nanoparticles for oral treatment of inflammatory bowel disease

 描述(申请人提供)：炎症性肠病(IBD)是一种慢性复发性胃肠道炎症，目前尚无根治方法。传统的IBD治疗依赖于全身作用的抗炎和免疫抑制药物。目前的治疗方法面临一系列问题，涉及成本、全身免疫抑制和癌症风险增加。新的治疗方法有很大的需求和潜力，特别是如果这些治疗方法可以通过口服途径局部给药到肠道炎症部位的话。炎症性肠病的特征之一是免疫细胞的激活和促炎细胞因子的产生，如肿瘤坏死因子α。此外，趋化因子受体CXCR4在炎症性肠黏膜中普遍过度表达。炎症性肠病患者肿瘤坏死因子α和CXCR4水平均升高，代表了局部联合治疗的一个令人兴奋的组合靶点。这项提案的目的是开发和测试用于联合口服治疗的新型双功能颗粒，旨在安全地减少结肠炎。中心假设是，由于抗肿瘤坏死因子CXCR4siRNA和聚合物α拮抗剂(PCXA)对CXCR4的抑制，建议的联合方法将改善IBD的治疗。这一假说是基于(I)现有证据表明，阻断肿瘤坏死因子α可以减少炎症性肠病的局部炎症，以及(Ii)我们目前的研究表明，多氯联苯单独作用可以促进实验性炎症性肠病小鼠的愈合。本应用程序的总体目标将通过追求两个具体目标来实现：1)设计 2)评估联合应用肿瘤坏死因子α沉默和CXCR4拮抗PCXA/siRNA在IBD小鼠模型中的有效性。独立于所传递的治疗剂而展示其自身药理活性的传递载体的设计代表了IBD联合治疗的创新方法。这项研究具有重要意义，因为它将为同时靶向CXCR4拮抗剂和抗炎siRNA的局部传递建立一个新的平台，以改善传递，从而更好地治疗IBD和改善预后。

 DESCRIPTION (provided by applicant): Inflammatory bowel disease (IBD) is a chronic relapsing inflammation of the gastrointestinal tract with no available permanent cure. Conventional IBD treatment relies on systemically acting anti-inflammatory and immunosuppressive agents. The current treatments face a range of problems related to their cost, systemic immune suppression and increased cancer risk. There is a great need and potential for novel treatments, especially if those treatments can be delivered locally to the site of intestinal inflammation by oral route. One of the hallmarks of IBD is the activation of immune cells and the production of proinflammatory cytokines such as TNFα. Furthermore, the chemokine receptor CXCR4 is ubiquitously overexpressed in inflamed intestinal mucosa. Both TNFα and CXCR4 levels are increased in IBD and represent an exciting putative combination target for local combination therapy. The objective of this proposal is to develop and test novel dual-function particles for combination oral treatment designed to safely reduce colonic inflammation. The central hypothesis is that the proposed combined approach will result in improved treatment of IBD as a result of decreased inflammation due to anti-TNFα siRNA and inhibition of CXCR4 by polymeric CXCR4 antagonists (PCXA). The hypothesis is based on (i) available evidence that blockade of TNFα reduces local inflammation in IBD and (ii) our current studies, which demonstrate that PCXA alone enhances healing of experimental IBD in mice. The overall objective of this application will be achieved by pursuing two specific aims: 1) design PCXA capable of oral delivery of siRNA; and 2) evaluate effectiveness of the combined TNFα silencing and CXCR4 antagonism of PCXA/siRNA in a mouse model of IBD. Design of delivery vectors that exhibit their own pharmacologic activity independent of the delivered therapeutic agent represents innovative approach to combination therapies of IBD. The proposed research is significant because it will establish a novel platform for simultaneous targeted local delivery f CXCR4 antagonists and anti-inflammatory siRNA to improve delivery for better treatment and outcome of IBD.