Design and therapeutic application of trans‐sodium crocetinate‐loaded cyclodextrin metal–organic frameworks as an enteric preparation for treating chronic heart failure

Abstract

Chronic heart failure (CHF) arises from structural and functional changes in the myocardial tissue attributable to various etiologies. Crocetin and its derivative trans‐sodium crocetinate (TSC) have exhibited cardioprotective attributes; however, their poor aqueous solubility and bioavailability impede clinical development. This study aimed to construct a cyclodextrin metal–organic frameworks (CDMOFs)‐based oral delivery system to enhance the pharmacokinetic profile and therapeutic efficacy of TSC for CHF treatment. TSC was loaded into the synthesized γ‐CDMOFs via vacuum adsorption. The CDMOFs@TSC formulation was characterized and evaluated in vitro. Pharmacokinetic and pharmacodynamic analyses were performed in beagle dogs and CHF rats induced by coronary artery ligation, respectively. Both TSC and CDMOFs@TSC elicited no discernible toxicity or pathological changes in major organs of rats, providing preliminary evidence for their biosafety. Pharmacokinetic study in beagle dogs demonstrated that CDMOFs@TSC capsules markedly increase the relative oral bioavailability by 198% versus free TSC capsules. In rats afflicted with CHF, the administration of CDMOFs@TSC yielded notable enhancements in cardiac function. Additionally, it precipitated a reduction in biomarkers linked to myocardial injury, manifested anti‐inflammatory and antifibrotic effects, and induced alterations in myocardial energy metabolism. This is the first report of CDMOFs‐based oral delivery to improve the TSC bioavailability and efficacy. The utilization of CDMOFs@TSC resulted in superior therapeutic outcomes in comparison to standalone TSC by optimizing pharmacokinetics and precise targeted delivery. These results highlight the clinical potential of CDMOF as porous carriers to enable oral delivery of natural products for CHF therapy.