Dan Yin,1,2 Can Li,3 Jiajin Li,1 Jieying Zeng,4 Mengjie Jia,4 Wenjing Yuan,1 Lingjuan Liu,1 Yi Tang,2 Yi Wang,4 Jie Tian1 

1National Clinical Key Cardiovascular Specialty, Key Laboratory of Children’s Important Organ Development and Diseases of Chongqing Municipal Health Commission, Chongqing, People’s Republic of China; 2Department of Ultrasound, Children’s Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 3Department of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 4School of Basic Medical Science, Chongqing Medical University, Chongqing, 400016, People’s Republic of China

Correspondence: Jie Tian; Yi Wang, Email jietian@cqmu.edu.cn; wangyi@cqmu.edu.cn

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

Keywords: doxorubicin, cardiotoxicity, detoxification, self-assembled nanoparticles, antioxidative