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

描述（由申请方提供）：生物制剂（如激素、抗体、生长因子、酶和疫苗）口服给药的一个关键挑战是克服胃肠道的生理屏障。这些包括极端pH环境、酶降解和穿过肠上皮的渗透性差。将生物制剂封装在聚合物纳米颗粒内允许治疗剂免受低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转运屏障的策略。我们建议通过将生物封装的纳米颗粒靶向肠道中的新生儿Fc受体（FcRn）来克服这一障碍。FcRn负责IgG抗体通过胞吞转运过程主动转运穿过肠上皮。我们假设使用IgG的Fc部分将生物封装的纳米颗粒靶向FcRn将允许Fc靶向纳米颗粒主动转运穿过肠上皮并在口服给药后进入体循环。在这项提案中，使用胰岛素作为模型生物和糖尿病作为模型疾病，我们的目标是开发胰岛素封装和FcRn靶向纳米颗粒，用于有效的口服胰岛素递送。生物可降解和生物相容性聚合物将用于开发尺寸小于100 nm的纳米颗粒，其能够以大于5%的负载包封胰岛素，释放生物活性大于90%的胰岛素，并且用IgG Fc片段进行表面功能化。纳米颗粒将在体外人上皮细胞模型中进行测试，以证明特异性归因于FcRn的增强的胞吞作用，并在体内评估胰岛素包封和FcRn靶向纳米颗粒在口服给药后的疗效，胰岛素的目标生物利用度为20%。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，使生物制剂能够有效地口服给药。 公共卫生相关性：口服给药被认为是比注射给药更有利的给药途径，因为方便性和患者依从性得到改善，从而改善了治疗疗效。在这个项目中，我们将开发一种新型的纳米颗粒递送系统，旨在克服胃肠道的所有障碍，并提供生物制剂如胰岛素的有效口服递送。这项技术可能会产生重大影响 目前仅限于注射疗法的疾病，如糖尿病。

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.