Department of Chemical Engineering, National Tsing Hua University, Hsinchu, Taiwan (ROC).
Acc Chem Res. 2012 Apr 17;45(4):619-29. doi: 10.1021/ar200234q. Epub 2012 Jan 11.
Despite advances in drug-delivery technologies, successful oral administration of protein drugs remains an elusive challenge. When protein drugs are administered orally, they can rapidly denature or degrade before they reach their targets. Such drugs also may not absorb adequately within the small intestine. As a protein drug for treating diabetes, insulin is conventionally administered via subcutaneous (SC) injection, yet often fails to achieve the glucose homeostasis observed in nondiabetic subjects. Some of this difference may relate to insulin transport: normally, endogenously secreted insulin moves to the liver via portal circulation. When administered subcutaneously, insulin moves through the body via peripheral circulation, which can produce a peripheral hyperinsulinemia. In addition, because SC treatment requires multiple daily injections of insulin, patients often do not fully comply with treatment. Oral administration of exogenous insulin would deliver the drug directly into the liver through portal circulation, mimicking the physiological fate of endogenously secreted insulin. This characteristic may offer the needed hepatic activation, while avoiding hyperinsulinemia and its associated long-term complications. This Account demonstrates the feasibility of using chitosan nanoparticles for oral insulin delivery. Nanoparticle (NP) delivery systems may provide an alternative means of orally administering protein drugs. In addition to protecting the drugs against a harmful gastric environment, the encapsulation of protein drugs in particulate carriers can avert enzymatic degradation, while controlling the drug release and enhancing their absorption in the small intestine. Our recent study described a pH-responsive NP system composed of chitosan (CS) and poly(γ-glutamic acid) for oral delivery of insulin. As a nontoxic, soft-tissue compatible, cationic polysaccharide, CS also adheres to the mucosal surface and transiently opens the tight junctions (TJs) between contiguous epithelial cells. Therefore, drugs made with CS NPs would have delivery advantages over traditional tablet or powder formulations. This Account focuses on the premise that these CS NPs can adhere to and infiltrate the mucus layer in the small intestine. Subsequently, the infiltrated CS NPs transiently open the TJs between epithelial cells. Because they are pH-sensitive, the nanoparticles become less stable and disintegrate, releasing the loaded insulin. The insulin then permeates through the opened paracellular pathway and moves into the systemic circulation.
尽管药物输送技术取得了进步，但成功将蛋白质药物口服给药仍然是一个难以实现的挑战。当蛋白质药物口服给药时，它们在到达靶标之前可能会迅速变性或降解。此类药物在小肠内也可能不能充分吸收。作为一种用于治疗糖尿病的蛋白质药物，胰岛素通常通过皮下 (SC) 注射给药，但通常无法达到非糖尿病患者观察到的葡萄糖内稳态。这种差异的部分原因可能与胰岛素转运有关：正常情况下，内源性分泌的胰岛素通过门静脉循环移动到肝脏。当皮下给药时，胰岛素通过体循环移动，这会导致外周高胰岛素血症。此外，由于 SC 治疗需要每天多次注射胰岛素，患者通常不能完全遵守治疗方案。外源性胰岛素的口服给药将通过门静脉循环将药物直接递送到肝脏，从而模拟内源性分泌的胰岛素的生理命运。这一特征可能提供所需的肝激活，同时避免高胰岛素血症及其相关的长期并发症。本说明演示了使用壳聚糖纳米粒子进行口服胰岛素递送的可行性。纳米粒子 (NP) 递送系统可能为口服给予蛋白质药物提供替代方法。除了保护药物免受有害的胃环境影响外，将蛋白质药物包封在颗粒载体中可以避免酶降解，同时控制药物释放并增强其在小肠中的吸收。我们最近的研究描述了一种由壳聚糖 (CS) 和聚 (γ-谷氨酸) 组成的 pH 响应型 NP 系统，用于口服递送胰岛素。作为一种无毒、软组织相容的阳离子多糖，CS 还能黏附在黏膜表面并瞬时打开相邻上皮细胞之间的紧密连接 (TJ)。因此，用 CS NPs 制成的药物在给药方面优于传统的片剂或粉末制剂。本说明侧重于这些 CS NPs 可以黏附和渗透到小肠中的粘液层这一前提。随后，渗透的 CS NPs 瞬时打开上皮细胞之间的 TJ。由于它们对 pH 敏感，纳米颗粒变得不太稳定并崩解，释放负载的胰岛素。胰岛素然后通过打开的细胞旁途径渗透，并进入全身循环。
