Study summary · research use only
Novel oral nano-hepatic targeted anti-PCSK9 in hypercholesterolemia
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
This study developed an orally administered, nano-encapsulated small-molecule anti-PCSK9 compound (P-4/P-21) targeted to the liver and tested it in a high fat diet-induced hypercholesterolemia mouse model, with additional testing in rats. The abstract reports P-21 was 150-200 nm in size and, in a dose-dependent manner, lowered LDL-cholesterol by 50-90%. Pharmacokinetic results showed a maximum plasma concentration (Cmax) at 30 min after administration, 31% oral bioavailability, and a half-life of up to 24 h. In rats, no adverse effects, and normal chemical biomarkers and histopathology, were reported across escalating P-21 doses. The authors describe P-21 as a nano-targeted drug-delivery approach for a PCSK9/LDLR antagonist, compared with FDA-approved monoclonal antibodies.
Abstract
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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