The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY, USA.
Shifa Biomedical Corporation, Malvern, PA, USA.
Nanomedicine. 2022 Feb;40:102480. doi: 10.1016/j.nano.2021.102480. Epub 2021 Nov 5.
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 (C) 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.
前蛋白转化酶枯草溶菌素 9 是一种由肝脏分泌的蛋白酶，通过与 LDLR 结合并将其伴侣蛋白运送到溶酶体进行降解，从而下调肝脏的低密度脂蛋白受体（LDLR），导致高胆固醇血症。抗 PCSK9 治疗的发展引起了人们对心血管疾病风险管理的极大关注。然而，只有皮下注射的 PCSK9 单克隆抗体获得了 FDA 的批准。如果能够实现，口服小分子 PCSK9 抑制剂有可能成为一种实用的治疗选择。在本工作中，我们使用纳米技术方法开发了首个口服小分子纳米肝脏靶向抗 PCSK9。通过高通量优化和一系列评估，合成并表征了一种稳定的水溶性 150-200nm 纳米包裹药物（命名为 P-4），该药物与肝脏靶向部分缀合（命名为 P-21）。使用高脂肪饮食诱导的高胆固醇血症小鼠模型进行了药效学（PD）、药代动力学（PK）和生物利用度研究，以评估 P-21 作为抗 PCSK9 LDL-胆固醇降低肝脏靶向纳米药物的疗效。PD 结果表明，P-21 以剂量依赖性方式有效降低 LDL-C 达 50-90%。PK 结果表明，P-4 的最大血浆浓度（C）在给药 30 分钟后达到，口服生物利用度为 31%，半衰期延长至 24 小时。在大鼠体内安全性研究中，不同递增剂量的 P-21 治疗组均未显示明显的不良反应，化学标志物正常，组织病理学未见异常。与 FDA 批准的单克隆抗体相比，P-21 提供了一种更有效、更实用的治疗方案，用于靶向控制不佳的高胆固醇血症，降低心血管疾病风险。本研究介绍了一种针对 PCSK9/LDLR 拮抗剂的纳米靶向药物递送方法。
