Fang Huapan, Chen Linfu, Deng Zheng, Gao Yunxuan, Yang Yang, Chen Qian, Liu Zhuang
Institute of Functional Nano and Soft Materials, Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou 215123, China.
Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China.
ACS Nano. 2023 Jan 3. doi: 10.1021/acsnano.2c08434.
Oral administration of protein drugs has always been challenging owing to various intestinal barriers. Herein, we developed an efficient oral protein delivery strategy by using polymerization of zwitterions to encapsulate proteins, which were then loaded into enteric coated capsules for oral feeding. After oral administration of such capsules, the enteric coating would be degraded once the capsule enters the intestine, releasing polyzwitterion/protein nanocomplexes. With the help of polyzwitterion modification, such nanocomplexes were able to pass through the mucus and cellular barriers, likely by the proton-assisted amino acid transporter 1 (PAT1) pathway. Such a polyzwitterion-based protein encapsulation strategy could allow for effective oral delivery of different proteins, including bovine serum albumin (BSA), insulin, and antibodies. Using this strategy, the oral bioavailabilities of insulin and immunoglobin G (IgG) were measured to be as high as 16.9% and 12.5%, respectively. Notably, oral feeding of polyzwitterion/insulin capsules could effectively lower the blood glucose level of diabetic animals (mice, rats, and pigs). Moreover, polyzwitterion/antiprogramed death-1 (αPD-1) capsules were able to induce efficient antitumor immune responses, showing significant tumor inhibition effects toward B16F10- and 4T1-tumor bearing mouse models after oral administration. No significant toxic effect was observed for such oral protein formulations in the treated animals. Our work presents a strategy for the efficient oral delivery of protein drugs, including those with large molecular weights (.., antibodies) that can hardly be orally delivered using existing technologies.
由于存在各种肠道屏障，蛋白质药物的口服给药一直具有挑战性。在此，我们开发了一种高效的口服蛋白质递送策略，即利用两性离子聚合来包裹蛋白质，然后将其装入肠溶胶囊中进行口服。口服此类胶囊后，一旦胶囊进入肠道，肠溶衣就会降解，释放出聚两性离子/蛋白质纳米复合物。借助聚两性离子修饰，此类纳米复合物能够穿过黏液和细胞屏障，可能是通过质子辅助氨基酸转运体1（PAT1）途径。这种基于聚两性离子的蛋白质包裹策略能够实现不同蛋白质的有效口服递送，包括牛血清白蛋白（BSA）、胰岛素和抗体。使用该策略，测得胰岛素和免疫球蛋白G（IgG）的口服生物利用度分别高达16.9%和12.5%。值得注意的是，口服聚两性离子/胰岛素胶囊能够有效降低糖尿病动物（小鼠、大鼠和猪）的血糖水平。此外，聚两性离子/抗程序性死亡蛋白1（αPD - 1）胶囊能够诱导有效的抗肿瘤免疫反应，在口服给药后对携带B16F10和4T1肿瘤的小鼠模型显示出显著的肿瘤抑制作用。在接受治疗的动物中，未观察到此类口服蛋白质制剂有明显的毒性作用。我们的工作提出了一种高效口服递送蛋白质药物的策略，包括那些使用现有技术难以口服递送的大分子药物（如抗体）。
