PCSK9
可欣
生物利用度
低密度脂蛋白受体
药代动力学
药理学
前蛋白转化酶
口服
最大值
体内
医学
脂蛋白
化学
胆固醇
内科学
生物
生物技术
作者
Taher A. Salaheldin,Kavitha Godugu,Dhruba J. Bharali,Kazutoshi Fujioka,Nabil A. Elshourbagy,Shaker A. Mousa
标识
DOI:10.1016/j.nano.2021.102480
摘要
Proprotein convertase subtilisin/kexin type 9 is a protease enzyme secreted by liver that downregulates hepatic low-density lipoprotein receptor (LDLR) by binding and chaperoning LDLR to lysosomes for degradation, causing hypercholesteremia. The development of anti-PCSK9 therapeutics attracted considerable attention for the management of cardiovascular disease risk. However, only subcutaneous injectable PCSK9 monoclonal antibodies have been FDA approved. Oral administration of small-molecule PCSK9 inhibitors has the potential to become a practical therapeutic option if achievable. In the present work, we used nanotechnological approaches to develop the first small oral molecule nano-hepatic targeted anti-PCSK9. Using high-throughput optimization and a series of evaluations, a stable water-dispersible 150-200 nm nano-encapsulated drug (named P-4) conjugated with hepatic targeting moiety was synthesized and characterized (named P-21). Pharmacodynamic (PD), pharmacokinetic (PK) and bioavailability studies were conducted using a high fat diet nutritionally induced hypercholesterolemia mouse model to evaluate the efficacy of P-21 as an anti-PCSK9 LDL-cholesterol lowering hepatic targeted nanodrug. The PD results demonstrate that P-21 in a dose-dependent manner is highly effective in lowering LDL-C by 50-90%. PK results show the maximum plasma concentration (Cmax) of P-4 was observed after 30 min of administration with 31% oral bioavailability and had a sustained longer half-life up to 24 h. In vivo safety studies in rats showed no apparent adverse effects, normal chemical biomarkers and normal histopathological findings in all P-21 treated groups at different escalating doses. Compared to the FDA-approved monoclonal antibodies, P-21 offers a more efficient, and practical treatment protocol for targeting uncontrolled hypercholesterolemia in reducing the risk of cardiovascular diseases. The present study introduced a nano-targeted drug delivery approaches for PCSK9/LDLR antagonist.
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