Targeted delivery of calcium antagonist by side-chain selenium containing polymer for cardiac hypertrophy therapy

Sustained stress overload results in pathological hypertrophy, which is characterized by fibrosis and excessive calcium ion accumulation in the heart. This calcium overload subsequently induces a surge of reactive oxygen species (ROS) in cardiomyocytes, further aggravating cardiac fibrosis and accelerating the progression of cardiac remodeling. Fortunately, the calcium channel blocker amlodipine possesses antihypertrophic and antifibrotic properties. Given these features, nano-formulating common calcium channel blockers offers potential for treating myocardial hypertrophy in the absence of specific drugs. Hence, a side-chain selenium-containing polymer was constructed (PSe@Amd-TAG) modified with CREKA loaded with the amlodipine to achieve targeted accumulation and localized release in hypertrophic myocardium. The results showed that the PSe@Amd-TAG improved cardiac function in transverse aortic constriction (TAC) mice, and effectively suppressed the expression of myocardial hypertrophy markers ANP, BNP, and MYH7. PSe@Amd-TAG inhibited the enlargement of cardiomyocyte, inhibited cardiac fibrosis, and suppressed the production of calmodulin in the heart. Additionally, PSe@Amd-TAG effectively suppressed intracellular calcium levels and inhibited the NFκB signaling pathway. Therefore, this study provides a novel strategy for targeted inhibition of calcium level in cardiomyocytes to treat TAC-induced myocardial hypertrophy.