T₁-Positive Mn²⁺-Doped Multi-Stimuli Responsive poly(L-DOPA) Nanoparticles for Photothermal and Photodynamic Combination Cancer Therapy

In this study, we designed near-infrared (NIR)-responsive Mn²⁺-doped melanin-like poly(L-DOPA) nanoparticles (MNPs), which act as multifunctional nano-platforms for cancer therapy. MNPs, exhibited favorable π-π stacking, drug loading, dual stimuli (NIR and glutathione) responsive drug release, photothermal and photodynamic therapeutic activities, and T₁-positive contrast for magnetic resonance imaging (MRI). First, MNPs were fabricated via KMnO₄ oxidation, where the embedded Mn²⁺ acted as a T₁-weighted contrast agent. MNPs were then modified using a photosensitizer, Pheophorbide A, via a reducible disulfide linker for glutathione-responsive intracellular release, and then loaded with doxorubicin through π-π stacking and hydrogen bonding. The therapeutic potential of MNPs was further explored via targeted design. MNPs were conjugated with folic acid (FA) and loaded with SN38, thereby demonstrating their ability to bind to different anti-cancer drugs and their potential as a versatile platform, integrating targeted cancer therapy and MRI-guided photothermal and chemotherapeutic therapy. The multimodal therapeutic functions of MNPs were investigated in terms of T₁-MR contrast phantom study, photothermal and photodynamic activity, stimuli-responsive drug release, enhanced cellular uptake, and in vivo tumor ablation studies.