An intravenous micellar formulation of clopidogrel (CLP/PM) achieved rapid hepatic bioactivation with a short Tmax of 22.5 ± 8.2 min, resulting in potent and rapid-onset antiplatelet efficacy.
An intravenous micellar formulation of clopidogrel enables rapid hepatic bioactivation, offering a potential strategy for rapid-onset antiplatelet therapy in emergency PCI.
Rapid platelet inhibition is essential for effective management during emergency percutaneous coronary intervention (PCI) in patients with acute coronary syndrome (ACS). However, the oral dosage form of clopidogrel (CLP) commonly used in clinical practice shows a delayed onset due to gastrointestinal absorption, first-pass metabolism, and the requirement for hepatic cytochrome P450 (CYP450)-mediated bioactivation, which limits its applications in urgent scenarios and complicating post-PCI bleeding management. To address these challenges, we developed an intravenous micellar formulation (CLP/PM) using FDA-approved mPEG-PLA copolymers to promote rapid hepatic exposure and metabolic activation. By tuning the PLA chain length, micellar core density and PEG conformation were modulated, thereby influencing protein corona (PC) formation and liver-affinity interactions. Proteomic profiling revealed that micelles with intermediate PLA length selectively recruited liver-affinity apolipoproteins (ApoM, ApoH, ApoA1, and ApoB), which are known ligands of LDLR and SR-BI, while minimizing adsorption of inflammatory and opsonization proteins. The optimized CLP/PM (3.9 k) exhibited a hepatotropic-like PC that was associated with hepatocyte-enriched uptake in primary liver cell analyses. In vivo biodistribution showed rapid liver-level signal, and pharmacokinetic studies supported enhanced CYP450-mediated activation, achieving a higher Cmax of the active metabolite and shorter Tmax of 22.5 ± 8.2 min. This translated into rapid-onset and potent antiplatelet efficacy, as reflected by prolonged bleeding time, diminished platelet reactivity, and reduced thrombus formation. Overall, these findings highlight a structure-corona-function framework for designing micelles that enhance hepatic prodrug bioactivation. By tuning PLA chain length, PC composition can be rationally modulated to optimize hepatic interaction and prodrug activation, providing a translational platform for rapid-onset and reversible platelet inhibition.
Chen et al. (Fri,) conducted a other in Acute coronary syndrome (ACS) requiring emergency PCI. Intravenous micellar formulation of clopidogrel (CLP/PM) was evaluated on Tmax of the active metabolite. An intravenous micellar formulation of clopidogrel (CLP/PM) achieved rapid hepatic bioactivation with a short Tmax of 22.5 ± 8.2 min, resulting in potent and rapid-onset antiplatelet efficacy.