纳米载体
体内分布
聚合物囊泡
小岛
药理学
西罗莫司
PI3K/AKT/mTOR通路
免疫抑制
移植
乙二醇
化学
癌症研究
医学
药品
免疫学
胰岛素
信号转导
内科学
生物化学
体外
两亲性
有机化学
共聚物
聚合物
作者
Jacqueline A. Burke,Xiaomin Zhang,Sharan Bobbala,Molly Frey,Carolina Bohorquez Fuentes,Helena Haddad,Shannon A. Allen,Reese AK Richardson,Guillermo A. Ameer,Evan A. Scott
标识
DOI:10.1038/s41565-021-01048-2
摘要
Standard oral rapamycin (that is, Rapamune) administration is plagued by poor bioavailability and broad biodistribution. Thus, this pleotropic mammalian target of rapamycin (mTOR) inhibitor has a narrow therapeutic window and numerous side effects and provides inadequate protection to transplanted cells and tissues. Furthermore, the hydrophobicity of rapamycin limits its use in parenteral formulations. Here, we demonstrate that subcutaneous delivery via poly(ethylene glycol)-b-poly(propylene sulfide) polymersome nanocarriers significantly alters rapamycin's cellular biodistribution to repurpose its mechanism of action for tolerance, instead of immunosuppression, and minimize side effects. While oral rapamycin inhibits T cell proliferation directly, subcutaneously administered rapamycin-loaded polymersomes modulate antigen presenting cells in lieu of T cells, significantly improving maintenance of normoglycemia in a clinically relevant, major histocompatibility complex-mismatched, allogeneic, intraportal (liver) islet transplantation model. These results demonstrate the ability of a rationally designed nanocarrier to re-engineer the immunosuppressive mechanism of a drug by controlling cellular biodistribution.
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