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

描述(申请人提供)：口服生物制剂，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带来的生理障碍。这些问题包括极端的pH环境，酶降解，以及肠道上皮通透性差。将生物制剂封装在聚合物纳米颗粒中，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道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存在于肠道的新生儿Fc受体(FcRN)来克服这一障碍。FcRN负责通过细胞穿透过程，通过肠道上皮主动运输免疫球蛋白抗体。我们推测，使用免疫球蛋白的Fc部分将生物包裹的纳米颗粒靶向FcRN，将允许Fc靶向的纳米颗粒在口服后通过肠道上皮主动转运并进入体循环。在这项提案中，以胰岛素作为生物模型，糖尿病作为疾病模型，我们的目标是开发胰岛素包裹和FcRN靶向的纳米颗粒，以有效地口服胰岛素。可生物降解和生物相容的聚合物将被用于开发尺寸小于100 nm的纳米颗粒，这种纳米颗粒能够以超过5%的负载量包裹胰岛素，释放生物活性大于90%的胰岛素，并通过免疫球蛋白Fc片段进行表面功能化。这些纳米粒子将在体外的人类上皮细胞模型中进行测试，以证实FcRN特别引起的跨细胞增强作用，并在体内测试，以评估口服胰岛素后胰岛素包裹和FcRN靶向纳米粒子的疗效，目标生物利用度为20%的胰岛素。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障碍，使生物制剂能够有效地口服给药。

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.