Heavy-Atom-Free Aza-BODIPY Polymeric Nanoparticles for Theranostic-Guided Photodynamic Cancer Therapy

Abstract

Photodynamic therapy (PDT) presents a noninvasive method for cancer treatment, characterized by high spatial selectivity and reduced side effects. However, conventional photosensitizers containing heavy atoms often pose risks of cellular toxicity, limiting their clinical translation. To address this, we developed a heavy-atom-free aza-BODIPY derivative (AB–OH) with a donor–acceptor–donor (D–A–D) structure, conjugated to poly(ethylene glycol)-succinic acid (mPEG-SA) to form amphiphilic mPEG-SA-AB. This conjugate self-assembles into stable nanoparticles (NPs) that can generate reactive oxygen species (ROS) and produce mild heat upon irradiation with 660 nm red light from an LED. In vitro studies on 4T1 breast cancer cells revealed that mPEG-SA-AB NPs maintain high biocompatibility under dark conditions and induce significant photocytotoxicity upon irradiation, as confirmed by intracellular ROS detection, live/dead staining assays, and apoptosis by flow cytometry. Confocal microscopy revealed increased cellular uptake and accumulation of NPs in endocytic compartments in both 2D and 3D culture models, compared to the free dye. Moreover, optical coherence tomography (OCT) enabled real-time, noninvasive monitoring of PDT efficacy in 3D cultures, supporting the platform’s translational potential. Finally, in vivo fluorescence imaging in 4T1 tumor-bearing BALB/c mice confirmed the targeted tumor accumulation and superior antitumor performance of the NPs, achieving 2.5-fold greater therapeutic efficacy than the parent AB–OH molecule. The NPs also exhibited excellent hemocompatibility and systemic biocompatibility. Overall, mPEG-SA-AB NPs represent a safe and potent nanotheranostic platform, offering synergistic photodynamic and mild photothermal effects for enhanced cancer diagnosis and therapy. © 2025 The Authors. Published by American Chemical Society