Development of FcRn-Targeted Nanoparticles for Efficient Oral Delivery of Insulin

描述（由申请人提供）：口服给药生物制剂（如激素、抗体、生长因子、酶和疫苗）的一个关键挑战是克服胃肠道出现的生理障碍。这些包括极端pH环境、酶降解和肠上皮渗透性差。将生物制剂封装在聚合纳米颗粒内，可以使治疗剂免受低pH环境和胃肠道酶的影响。然而，目前还没有有效和安全地克服肠上皮运输障碍的策略。我们建议通过将生物包裹的纳米颗粒靶向于存在于肠道中的新生儿Fc受体（FcRn）来克服这一障碍。FcRn通过胞吞作用过程负责IgG抗体在肠上皮上的主动转运。我们假设，使用IgG的Fc部分将生物包膜纳米颗粒靶向FcRn，将允许Fc靶向纳米颗粒在口服给药后通过肠道上皮积极运输并进入体循环。在本研究中，我们以胰岛素为模型生物，糖尿病为模型疾病，旨在开发胰岛素包封和fcrn靶向的纳米颗粒，用于有效的口服胰岛素递送。可生物降解和生物相容性聚合物将用于开发尺寸小于100纳米的纳米颗粒，这些纳米颗粒能够包封胰岛素的负荷大于5%，释放胰岛素的生物活性大于90%，并且具有IgG Fc片段的表面功能化。这些纳米颗粒将在体外人上皮细胞模型中进行测试，以证明FcRn特异性地增强了胞吞作用，并在体内评估胰岛素包封和FcRn靶向纳米颗粒口服后的胰岛素靶生物利用度为20%的功效。这项研究的成功完成将对许多疾病的治疗产生重大影响，因为它克服了一个关键的障碍，使口服生物制剂成为可能。

DESCRIPTION (provided by applicant): A key challenge in the oral administration of biologics such as hormones, antibodies, growth factors, enzymes, and vaccines is overcoming the physiological barriers presented by the gastrointestinal tract. These include extreme pH environments, enzymatic degradation, and poor permeability across the intestinal epithelium. Encapsulation of biologics inside polymeric nanoparticles allows the therapeutic agent to be shielded from the low pH environment and enzymes of the GI tract. However, there are currently no strategies that efficiently and safely overcome the intestinal epithelium transport barrier. We propose to overcome this barrier by targeting biologic-encapsulated nanoparticles to the neonatal Fc receptor (FcRn) present in the intestines. The FcRn is responsible for active transport of IgG antibodies across the intestinal epithelium through the process of transcytosis. We hypothesize that using the Fc portion of IgG to target biologic-encapsulated nanoparticles to the FcRn will allow Fc-targeted nanoparticles to be actively transported across the intestinal epithelium and enter systemic circulation after oral administration. In this proposal, using insuli as a model biologic and diabetes as a model disease, we aim to develop insulin-encapsulated and FcRn-targeted nanoparticles for efficient oral delivery of insulin. Biodegradable and biocompatible polymers will be used to develop nanoparticles with sizes less than 100 nm that are able to encapsulate insulin with a load greater than 5%, release insulin with bioactivity greater than 90%, and are surface functionalized with IgG Fc fragments. The nanoparticles will be tested in an in vitro human epithelium cell model to demonstrate enhanced transcytosis due specifically to the FcRn and in vivo to evaluate the efficacy of insulin-encapsulated and FcRn-targeted nanoparticles after oral administration with a target bioavailability of 20% for insulin. Successful completion of this study will have a significant impact on the treatment of many diseases by overcoming a critical barrier and enabling efficient oral delivery of biologics. PUBLIC HEALTH RELEVANCE: Oral administration is considered a more favorable route of administration than injection because of improved convenience and compliance by patients, resulting in improved treatment efficacy. In this project, we will develop a novel nanoparticle delivery system designed to overcome all of the barriers of the gastrointestinal tract and provide efficient oral delivery of biologics such as insulin. This technology may have a significant impact on diseases that are currently limited to injection-based therapies, such as diabetes.