Low-frequency Ultrasound With Microbubbles Combined With Doxorubicin-loaded Hollow Mesoporous Silica Nanoparticles In The Treatment Of Prostate Cancer

It is well established that prostate cancer is exposed to fluctuating oxygen tensions and both acute and chronic hypoxia exist,and these conditions can upregulate angiogenesis-associated proteins such as hypoxia-inducible factor-1?(HIF-1?)and vascular endothelial growth factor A.Low-frequency low-intensity ultrasound with microbubbles(LFUM)can induce obvious microvessel damage in tumors,cause cell necrosis or apoptosis.Here we investigated the impact of different LFUM radiation times on prostate tumors,observed the change in theHIF-1?and VEGFA protein levels,as well as cell proliferation,apoptosis,and tumor volume.We try to prepare a kind of hollow mesoporous silica materials-HMONs in a simple synthetic process,the effect to treat prostate cancer in vitro.And we investigate the therapeutic efficacy of LFUM combined with DOX-HMONs in treating metastatic hormone-refractory prostate cancer.The results of this work demonstrated that under the same conditions,different radiation times of LFUM affect the hypoxia response differently,and the effect at least partly stimulates or inhibits tumor growth.HMONs were spherical,like raspberries,because its surface were coated with silicon nanoparticles.HMONs had pore and hollow structure,its dispersion performance was good,the size was about 289.4nm,the specific surface area of about204204m~2/g.HMONs show the excellent performances in echogenic behavior in vitro,and could be degraded within cells.The results showed that there was no obvious toxicity within the concentration of 100?g/mL for cells and 200?g for nude mouse.Doxorubicin loading capacity was 34.58±4.1%,Drug release in 2 hours was 46±1.93wt%at pH 5.0.In vitro experiments showed that the cell inhibition rate of DOX-HMONs was 18.0%higher than that of DOX,when the content of DOX in two groups was equally(10?g/mL).The location of DOX-HMONs in tumor could be seen using ultrasound in clinical condition,and it was consistent with the distribution of DOX.Tumor volum:LFUM+DOX-HMONs group<DOX-HMONs group<DOX group<control group;cell apoptotic rate:LFUM+DOX-HMONs group>DOX-HMONs group>DOX group>control group;cell proliferation rate:LFUM+DOX-HMONs group<DOX-HMONs group<DOX group<control group.The mice survival time were extended in LFUM+DOX-HMONs group and DOX-HMONs group,and the time was longer in LFUM+DOX-HMONs group.HMONs had the potential to be ultrasound contrast agent.LFUM could enhance the therapeutic effect of drug-loaded HMONs in treating prostate cancer,and extended the animal survival time.