Multimodal Nanobubbles Carrying Indocyanine Green and VCAM-1 Targeting Peptide for Molecular Imaging of DOX-Induced Cardiotoxicity

Purpose: Doxorubicin is an effective chemotherapeutic agent for numerous cancers; however, its clinical utility remains severely limited by cumulative dose-dependent cardiotoxicity, which is a critical challenge in cardioprotective strategies of cardio-oncology. Therefore, real-time dynamic and accurate diagnosis of DOX-induced cardiotoxicity (DIC) is essential to improve patient prognosis. We aimed to integrate the high spatial resolution and deep tissue penetration of ultrasound with the strong optical contrast of photoacoustic imaging (PAI) and the high sensitivity of fluorescence imaging (FLI) to construct an ICG-loaded targeted nanobubble platform for visualized monitoring of DIC.

Materials and methods: A novel nanosystem for multimodal (ultrasonic, fluorescence, and photoacoustic) imaging of DIC was developed. The nanobubbles (NBs) were functionalized with indocyanine green (ICG@ NBs), and then modified with vascular cellular adhesion molecule-1 (VCAM-1) targeting peptide, enabling targeting capability (ICG@VCAM-1 NBs). We described their basic characteristics and targeting capability and then evaluated VCAM-1 expression in mouse DIC models. Multimodal imaging both in vitro and in vivo were conducted.

Results: ICG@VCAM-1 NBs exhibited excellent biocompatibility and superior stability. Western blotting results showed the significant upregulation of the VCAM-1 expression in DIC mice, and the overexpression persisted. ICG@VCAM-1 NBs possess ultrasound, fluorescence, and photoacoustic multimodal imaging capabilities both in vitro or in vivo, and can be precisely located by targeting the myocardial injury, thus realizing real-time dynamic monitoring in DIC mice.

Conclusion: We used VCAM-1 targeting peptide and ICG to establish a noninvasive and diagnostic NB platform (ICG@VCAM-1 NBs) for real-time imaging. This investigation exhibits the potential for visualized monitoring of DIC.