Pleiotropic Multi-Drug Co-Assembled Nanocomposites Offer Protection Against Doxorubicin-Induced Cardiotoxicity

Doxorubicin (DOX) is a first-line chemotherapeutic agent, yet its clinical utility is limited by doxorubicin-induced cardiotoxicity (DIC), a dose-dependent side effect. Current drug delivery strategies fail to prevent off-target accumulation of DOX in cardiac tissue, necessitating innovative therapeutic approaches that protect the heart without compromising antitumor efficacy through targeted cardioprotection.

We developed a multifunctional self-assembled nanoplatform (PGPP/NPs) via co-assembly of ginsenoside Rb1, probucol (PB), and a phosphoinositide 3-kinase gamma (PI3Kγ) inhibitor (PI), with surface modification using PCM peptide for cardiomyocyte-targeted delivery. In vitro and in vivo models of DIC were used to evaluate targeting specificity and therapeutic efficacy. Mechanistic investigations included ROS detection (DCFH-DA assay), inflammatory phenotype analysis (immunohistochemistry for CD68 and CD206), and autophagy flux assessment (immunofluorescence for LC3-II).

PGPP/NPs demonstrated selective accumulation in cardiomyocytes compared to non-targeted GPP/NPs (p<0.05). This nanocomposite significantly alleviated DIC through antioxidative, anti-inflammatory, and autophagy-promoting mechanisms. Notably, it reduced DIC severity while preserving the antitumor efficacy of DOX.

This novel therapeutic strategy shows great promise for mitigating chemotherapy-induced cardiotoxicity and may be extended to other chemotherapeutic agents with cardiac side effects.