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As a non-invasive therapeutic, radiotherapy (RT) has been extensively used for solid tumor treatment. However, intratumoral hypoxia leads to severe RT resistance or failure. Moreover, damage from RT to normal tissues limits the application of high doses of radiation to eliminate cancer cells. Therefore, simultaneously improving the curative efficacy while minimizing the side effects of RT is in pressing need. Hence, the purpose of this study is to use oxygen-based microbubbles (O2 @MBs) combined with ultrasound (US) targeting microbubble destruction (UTMD) technology to overcome hypoxia prior to RT, evaluate the effects of O2 @MBs on contrast-enhanced ultrasound (CEUS) imaging enhancement, investigate the optimum delivery route of O2 @MBs, and evaluate the therapeutic efficacy. In this study, O2 @MBs were injected intravenously or locally and the distribution of O2 @MBs in tumors or regions surrounding the tumors are compared by US imaging. The hypoxic status of tumors and their sensitivity to RT were investigated. Our findings suggest that O2 @MBs combined with UTMD can significantly enhance the effects of RT. In addition, the in vivo biosafety assay demonstrates good biocompatibility, indicating great potential for clinical translation.

Background: As one of the most effective triggers with high tissue-penetrating capability and non-invasive feature, ultrasound shows great potential for controlling the drug release and enhancing the chemotherapeutic efficacy. In this study, we report, for the first time, construction of a phase-changeable drug-delivery nanosystem with programmable low-intensity focused ultrasound (LIFU) that could trigger drug-release and significantly enhance anticancer drug delivery. Methods: Liquid-gas phase-changeable perfluorocarbon (perfluoropentane) and an anticancer drug (doxorubicin) were simultaneously encapsulated in two kinds of nanodroplets. By triggering LIFU, the nanodroplets could be converted into microbubbles locally in tumor tissues for acoustic imaging and the loaded anticancer drug (doxorubicin) was released after the microbubble collapse. Based on the acoustic property of shell materials, such as shell stiffness, two types of nanodroplets (lipid-based nanodroplets and PLGA-based nanodroplets) were activated by different acoustic pressure levels. Ultrasound irradiation duration and power of LIFU were tested and selected to monitor and control the drug release from nanodroplets. Various ultrasound energies were introduced to induce the phase transition and microbubble collapse of nanodroplets in vitro (3 W/3 min for lipid nanodroplets; 8 W/3 min for PLGA nanodroplets). Results: We detected three steps in the drug-releasing profiles exhibiting the programmable patterns. Importantly, the intratumoral accumulation and distribution of the drug with LIFU exposure were significantly enhanced, and tumor proliferation was substantially inhibited. Co-delivery of two drug-loaded nanodroplets could overcome the physical barriers of tumor tissues during chemotherapy. Conclusion: Our study provides a new strategy for the efficient ultrasound-triggered chemotherapy by nanocarriers with programmable LIFU capable of achieving the on-demand drug release.

To determine whether combining microbubbles (MBs) with diagnostic ultrasound (US) at a high mechanical index (MI) could enhance the microwave (MW) ablation of tumours.Five therapeutic MW adjuvant protocols were studied: MW, MW + US, MW + US + MB, MW + US + NS (saline) and MW + MB. In 30 normal rabbit livers, the synergistic effects were evaluated via temperature, necrosis volume and histology. In 90 VX2 rabbit hepatic tumours, residual cells in the peripheral ablated tumours were examined via immunohistochemical assay and tumour growth. Additional 40 VX2 hepatic tumours were evaluated for ablation safety via blood assay and weight and for survival to 105 days. Results were compared using analysis of variance.Compared with the other protocols, the ablation volumes in normal rabbit livers were significantly larger using the MW + US + MB protocol (p .001). The histological examination was consistent with more efficient ablation in that protocol. In detecting residual cells, the apoptotic index was higher, the proliferating index was lower (p .05), tumour growth was significantly smaller (p .001), and the rabbits of the MW + US + MB T-Group survived longer (p .05) than those of the other groups. Additionally, no damage to the liver function or blood cells was found in any of the protocols after ablation (p .05).MBs in combination with diagnostic US at a high MI showed potential synergy in the MW ablation of tumours in rabbits.

Theranostics is a new trend in the tumor research field, which involves the integration of diagnostic and therapeutic functions using imageable nanoparticles coupled with therapeutic drugs. Imaging-guided targeted delivery of therapeutics and diagnostics using nanocarriers hold great promise to minimize the side effects of conventional chemotherapy. Ultrasound microbubbles have been employed as theranostic agents over the last decade, which provide both real-time dynamic imaging for diagnosis and precise control for targeted tumor therapy. However, the intrinsic defects of microbubbles such as poor tissue penetration, short circulation time and instability hinder microbubble-based theranostic applications. In recent years, liquid-to-gas transitional perfluorocarbon nanoparticles have been developed as promising diagnostic and therapeutic nanoagents to solve the abovementioned problems. In this study, phase-changeable, folate-targeted perfluoropentane nanodroplets loaded with 10-hydroxycamptothecin (HCPT) and superparamagnetic Fe3O4 (denoted as FA-HCPT-Fe3O4-PFP NDs) are prepared and investigated for multimodal tumor imaging and targeted therapy. After intravenous administration into nude mice bearing SKOV3 ovarian cancer, FA-HCPT-Fe3O4-PFP NDs exhibit the ability to enhance MR and PA imaging. Furthermore, after the phase transition activated by low-intensity focused ultrasound (LIFU) sonication, FA-HCPT-Fe3O4-PFP NDs remarkably enhance US imaging at the tumor location. Meanwhile, the HCPT released from FA-HCPT-Fe3O4-PFP NDs during the liquid-to-gas transition provides a therapeutic effect on tumor cells with relatively low side effects to normal tissue. Therefore, the combination of LIFU and FA-HCPT-Fe3O4-PFPNDs presents an ideal modality for tumor-targeted theranostics.

High-intensity focused ultrasound (HIFU) is deemed to be a promising noninvasive therapeutic modality for cancers as well as non-neoplastic diseases. However, the accuracy of the technique in the diagnosis and treatment of tumors remains unsatisfactory. HIFU, when combined with multifunctional synergistic agents (SAs), has the potential to be of greater diagnostic and therapeutic efficacy. Here we describe a smart and multifunctional hollow mesoporous Prussian blue (HMPBs) theranostic nanoplatform, the hollow structure of which is capable of encapsulating doxorubicin (DOX) and perfluorohexane (HMPBs-DOX/PFH). In vitro and in vivo studies validated that HMPBs-DOX/PFH can be used as an amplifiable dual-mode imaging contrast agent, which can simultaneously enhance ultrasound (US) and photoacoustic (PA) imaging for guiding and monitoring tumor therapy. When exposed to HIFU, this versatile HMPBs-DOX/PFH agent could increase the cavitation effect and use lower HIFU intensity to achieve coagulative necrosis. Furthermore, it significantly accelerated the release of DOX thereby enhancing chemotherapeutic efficacy and avoiding systemic side effects of the drug. Such a novel theranostic nanoplatform is expected to integrate dual-mode guided imaging with greater therapeutic efficacy and fewer side effects and is very promising for the noninvasive synergistic tumor therapy.