Mitochondria-Targeted Mesoporous Titanium Dioxide Nanoplatform for Synergistic Nitric Oxide Gas-Sonodynamic Therapy of Breast Cancer

Abstract

Background Sonodynamic therapy (SDT) has rapidly advanced as a promising alternative to conventional photodynamic therapy owing to its preferable therapeutic depth. However, single-modal SDT exhibits limited efficacy due to the long-term hypoxia in tumors. Method and Results To address these issues, we proposed a synergistic SDT strategy that integrates mitochondrial targeting with nitric oxide (NO) gas therapy by using multifunctional nanoplatforms. The nanoplatform, which was named as T-mTNPs@L-Arg, was composed of mesoporous titanium dioxide loaded with the NO donor precursor L-arginine (L-Arg) and modified with triphenyl phosphonium (TPP), a mitochondria-targeting ligand. Therefore, T-mTNPs@L-Arg could efficiently concentrate into mitochondria and release NO gas as well as generate reactive oxygen species (ROS) with ultrasound stimulus. Importantly, the released NO gas exerted multiple synergies with SDT, including inducing NO poisoning, generating more lethal reactive nitrogen species (RNS) by reaction with ROS, and alleviating hypoxia through NO-mediated mitochondrial respiration inhibition. On account of the synergistic effects, T-mTNPs@L-Arg showed an outstanding SDT efficacy and a reduced side effect. Conclusion This work designed a nanoplatform to integrate mitochondria targeting, SDT and NO gas therapy, providing a new strategy for highly efficient breast cancer therapy.

Nitric Oxide and Tumors: From Small-Molecule Donor to Combination Therapy

“…The majority of scientific researchers are interested in nanoparticle-based drug delivery systems as a means of drugassisted treatment, because they can precisely control the time and space distribution and release time of drugs in the body, thereby increasing the efficacy of drug treatment and decreasing side effects. Nanoparticles of various forms and compositions, including liposomes, 59 polymer nanoparticles, 60 metal oxide nanoparticles, 61 silica nanoparticles, 62 nano- tubes, 63 and up-conversion nanoparticles, 64 have been used extensively in drug delivery. 65 NO donors or NO prodrugs were recently paired with intelligent nanocarriers to accomplish steady NO transport to tumor cells in vivo and minimize systemic toxicity caused by NO circulating in the body.…”

The crosstalk between sonodynamic therapy and autophagy in cancer

“…To date, several gases, such as nitrogen (N 2 ), and nitric oxide (NO), carbon oxide (CO), carbon dioxide (CO 2 ), have been involved in these therapeutic approaches ( Chen et al, 2019 ). When SDT is combined with gas therapy for tumor treatment, the US triggers gas donors to release and produce highly toxic products or change the disease condition to promote the tumor suppression effects ( An et al, 2020b ; Cheng et al, 2022 ; Zhu et al, 2022 ; Zuo et al, 2022 ). The generated gas bubbles could be used as a powerful US contrast agent that greatly enhances the US contrast to guide cancer therapy.…”

Gold nanoplatform for near-infrared light-activated radio-photothermal gas therapy in breast cancer

“…Nitric oxide (NO) is the first gasotransmitter in the gas family and has various physiological and pathological activities, including blood vessel relaxation, NO poisoning, and macrophage activation (Yu et al, 2018;Ding et al, 2019). Furthermore, NO can react with reactive oxygen species (ROS) to produce more lethal reactive nitrogen species (RNS), which improves the effectiveness of radiotherapy as the treatment effect of radiotherapy is mainly due to ROS produced by the interaction between radiation and water (Zuo et al, 2022). Therefore, combining radiotherapy with NO therapy promises a synergistic effect with low side effects for the treatment of TNBC.…”