TPGS-Decorated Lipopolymersomes Encapsulating Piperine for Myocardial Infarction: Response Surface Optimization, In Vivo Cardioprotection, and Physiologically Based Pharmacokinetic Modeling

Piperine, derived from black pepper, exhibits powerful cardioprotective activity. However, its poor solubility limits its clinical translation for myocardial infarction (MI) management. This study aims to develop piperine-loaded lipopolymersomes for MI, to assess systemic and cardiac exposure.Lipopolymersomes were prepared using emulsification-solvent evaporation method, followed by surface coating with TPGS. The lipid-to-polymer ratio and nanoparticles-to-drug ratio were optimized for ideal particle size, zeta potential, and encapsulation efficiency. Oral pharmacokinetics and physiologically based pharmacokinetic (PBPK) modeling were conducted to evaluate bioavailability enhancement and predict cardiac exposure. Cardioprotective efficacy was assessed using an isoprenaline-induced mouse model of MI.TPGS-decorated lipoloymerosomes (O1-TPGS) exhibited a size of 188.56 ± 8.33 nm, a zeta potential of –19.67 ± 2.81 mV, and 98.67 ± 4.80%. entrapment efficiency. The formulation provided sustained piperine release over 72 hours. Piperine oral systemic exposure was increased by 1.5-fold. PBPK simulation predicted a three-fold increase in cardiac concentration and area under the curve for O1-TPGS versus unformulated piperine. O1-TPGS normalized heart rate, reduced creatinine kinase-MB and troponin-I, and suppressed NLRP3, mTOR, NF-κB, and IL-6 than standard piperine, with superior preservation of myocardial architecture.TPGS-modified lipopolymersomes markedly enhanced the systemic and cardiac bioavailability of piperine, translating this pharmacokinetic improvement into superior cardioprotective effects in isoprenaline-induced MI.