Hollow Manganese-Doped Calcium Phosphate Nanoparticles Treated with Melanin Nanoparticles and Thalidomide for Photothermal and Anti-angiogenic Cancer Therapy

Photothermal therapy (PTT) integrated with anti-angiogenic therapy has aroused great interest as a combined tumor treatment with enhanced therapeutic efficacy. Herein, biodegradable hollow nanosystems manganese-doped calcium phosphate (MnCaP)-MNP-Thd (MMT) were developed based on hollow MnCaP nanoparticles (NPs) treated with melanin NPs (MNPs) as photothermal agents and thalidomide (Thd) as an anti-cancer drug for photothermal and anti-angiogenesis combination therapy. Dual-responsive drug release stimulated by weakly acidic tumor conditions and near-infrared (NIR) laser irradiation was demonstrated. Under co-stimulation of low pH and NIR laser irradiation, the hollow MMT NPs showed excellent biodegradability and released MNPs, Thd, and Ca2+ and Mn2+ ions in situ in the tumor. The released MNPs, as endogenous natural biopolymers, can be applied for photoacoustic imaging (PAI) and PTT. As an angiogenesis inhibitor drug, Thd can block the energy supplement of cancer cells and further enhance the PTT's anti-tumor effect. Besides, the released Ca2+ ions from MMT NPs could trigger mitochondrial dysfunction, suppress cellular respiration, and block intracellular ATP production, further enhancing the tumor-killing effect. Magnetic resonance imaging derived from Mn2+ ions combined with PAI was used to monitor the therapeutic effect. The in vivo and in vitro investigations indicated outstanding tumor inhibition effects of MMT NPs through a combination of anti-angiogenic therapy and PTT. With the characteristics of safety, low-toxic side effects, and easy metabolism after degradation, hollow MMT NPs provide a perspective for clinical tumor treatment.