Hydroxyapatite and doxorubicin-laden nanotherapeutics for effective multimodality cancer treatment boosted via mitochondrial calcium overload

What is it about?

A new nanotherapeutic system comprising palladium-deposited bismuth sulfide (Pd/Bi2S3) nanoparticles (NPs) as the primary component, loaded with doxorubicin (DOX) and coated with PEG-modified hydroxyapatite/mesoporous silica (HAP/MPS) layers, was developed for the treatment of triple-negative breast cancer. In addition to chemotherapy using DOX, the nanotherapeutic system was characterized by pronounced photothermal properties through in situ Pd growth at NP interfaces and stimulus-responsive intracellular calcium release by HAP decoration. The acid-triggered calcium release from HAP of the NPs within cancer cells resulted in intracellular calcium overload, thereby inducing prolonged opening of mitochondrial permeability transition pores and mitochondrial dysfunction and sensitizing cancer cells to both chemo- and photothermal therapies. The cell viability of 4 T1 breast cancer cells, when treated by either chemotherapy or photothermal therapy in combination with calcium overload treatment, was significantly reduced compared to the single modality regimens lacking the calcium overload effect. The combined photothermal/chemotherapy efficacy was boosted with calcium overload as demonstrated by a more pronounced reduction in cell viability against 4 T1 breast cancer cells. The in vivo data indicated an almost complete eradication of orthotopic breast cancer in the 4 T1 tumor-bearing mice treated with the NP-based calcium-mediated chemo/photothermal combined therapy, along with a significant reduction in lung metastasis as compared to the appreciable tumor nodules observed in the lungs from the combined therapy in the absence of calcium aid. The results indicate that the NP-based calcium overload strategy is an effective and essential auxiliary modality for sensitizing cancer cells to both chemo- and photothermal therapies.

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Photo by Marcel Strauß on Unsplash

Photo by Marcel Strauß on Unsplash

Why is it important?

We have demonstrated that functionalized semiconductor heterojunction nanotherapeutics featuring calcium-mediated photothermal/chemotherapy exhibit a profound effect on cancer treatment. The intracellular calcium overload prolongs the opening of mitochondrial permeability transition pores, leading to mitochondrial dysfunction and sensitizing cancer cells to chemo/photothermal therapy, as demonstrated by almost full eradication of orthotopic breast cancer in tumor-bearing mice.