Abstract
Microbubbles have been widely used as ultrasound (US) contrast agents. However, their short lifetime, low drug payload and micron-sized restricted their applications. Mesoporous silica nanoparticles (MSNPs) have the properties of high porosity, high payload and tunable pore sizes. Thus, we proposed superhydrophobic MSNPs adsorbing air bubbles to prevent drug leakage from MSNPs and to be served as cavitation nuclei to initiate inertial cavitation (IC) repeatedly and efficiently by US sonication. In this study, anti-vascular therapy and reactive oxygen species (ROS) generated by means of IC (sonodynamic therapy) and chemotherapy were combined to achieve synthetic tumor therapeutics by applying the drug-loaded superhydrophobic MSNPs. MCM-48 MSNPs were modified with perfluorodecyltriethoxysilane to obtain the F48-ext. F48-ext-dox were accomplished after loading DOX. A 15-MHz transducer was used as a passive cavitation detector to measure inertial cavitation dose (ICD) by MSNPs with HIFU sonications. Then, DCFH-DA assay was used to measure ROS caused by MSNPs under the same setup. Alamar Blue® assay was used to test the cell viability. The subcutaneous prostate tumor xenograft mice were established to evaluate the anti-vascular,,ROS generation effect, and treatment efficiency. The sizes of MCM48 and F48-ext were 253.1 ± 92.5 nm and 289.1 ± 96.2 nm, respectively. The contact angles were increased from 10.9° (hydrophilic) to 159º (superhydrophobic) after fluoridation. The amount of 0.5 g Dox can be loaded into 0.5 g F48-ext. The ICD of superhydrophobic F48-ext was 3.9±0.03 times larger than that of hydrophilic MCM48, and the amount of ROS also was increased 10.9±1.3 times accordingly. The cell viability results showed that the IC and Dox release inhibited 40±4 % and 20±3 % cell viability, respectively. Finally, ultrasound contrast-perfused imaging showed that F48-ext-dox combined with US decreased 50% of the tumor blood perfusion, and DHE staining showed that 17 times more ROS were produced than that of control group. The F48-ext and F48-ext-dox with US stimulus inhibited 58.2±3.0 % and 49.2±3.8 % tumor volume growth with respect to control group, respectively, while F48-ext-dox without ultrasound irradiation inhibited only 25.7±9 % tumor growth. In this study, the occurrence of IC of superhydrophobic NPs both in vitro and vivo were observed, and the combination of anti-vascular, sonodynamic therapy by ROS, and chemotherapy obviously promoted the tumor treatment efficacy. Future work included to establish a superhydrophobic active drug-release system to improve the efficiency of chemotherapy.