US/MR Bimodal Imaging-Guided Bio-Targeting Synergistic Agent for Tumor Therapy.

Purpose: Breast cancer is detrimental to the health of women due to the difficulty of early diagnosis and unsatisfactory therapeutic efficacy of available breast cancer therapies. High intensity focused ultrasound (HIFU) ablation is a new method for the treatment of breast tumors, but there is a problem of low ablation efficiency. Therefore, the improvement of HIFU efficiency to combat breast cancer is immediately needed. This study aimed to describe a novel anaerobic bacteria-mediated nanoplatform, comprising synergistic HIFU therapy for breast cancer under guidance of ultrasound (US) and magnetic resonance (MR) bimodal imaging. Methods: The PFH@CL/Fe3O4 nanoparticles (NPs) (Perfluorohexane (PFH) and superparamagnetic iron oxides (SPIO, Fe3O4) with cationic lipid (CL) NPs) were synthesized using the thin membrane hydration method. The novel nanoplatform Bifidobacterium bifidum-mediated PFH@CL/Fe3O4 NPs were constructed by electrostatic adsorption. Thereafter, US and MR bimodal imaging ability of B. bifidum-mediated PFH@CL/Fe3O4 NPs was evaluated in vitro and in vivo. Finally, the efficacy of HIFU ablation based on B. bifidum-PFH@CL/Fe3O4 NPs was studied. Results: B. bifidum combined with PFH@CL/Fe3O4 NPs by electrostatic adsorption and enhanced the tumor targeting ability of PFH@CL/Fe3O4 NPs. US and MR bimodal imaging clearly displayed the distribution of the bio-targeting nanoplatform in vivo. It was conducive for accurate and effective guidance of HIFU synergistic treatment of tumors. Furthermore, PFH@CL/Fe3O4 NPs could form microbubbles by acoustic droplet evaporation and promote efficiency of HIFU ablation under guidance of bimodal imaging. Conclusion: A bio-targeting nanoplatform with high stability and good physicochemical properties was constructed. The HIFU synergistic agent achieved early precision imaging of tumors and promoted therapeutic effect, monitored by US and MR bimodal imaging during the treatment process.

Potential Application of Low-Intensity Focused Ultrasound in Rapidly Relieving Delayed-Onset Muscle Soreness Induced by High-Intensity Exercise.

OBJECTIVES: To evaluate the efficacy of low-intensity focused ultrasound (LIFU) treatment on rapid relief of delayed-onset muscle soreness (DOMS) triggered by high-intensity exercise. METHODS: A total of 16 healthy male college students were randomly divided into two groups: the LIFU group (n = 8) and the Sham group (n = 8). After the exercise protocol, the LIFU group received treatment, which parameters included that the power output was 2.5 W/cm2 , the frequency was 1 MHz, and the treating time was 20 minutes. The Sham group was treated with LIFU without energy output. Visual analog scale was used to evaluate the level of DOMS in every participant. The activities of plasma creatine kinase, lactate dehydrogenase, and the plasma concentration were measured by spectrophotometry. Tumor necrosis factor-α and interleukin-6 of serum were analyzed by enzyme-linked immunosorbent assay. RESULTS: The visual analog scale of quadriceps femoris and/or calf muscles in the LIFU group decreased significantly at 24 hours (P < 0.01) and 48 hours (P < .01) after the exercise protocol. Both the accumulation of lactic acid (P < .01) in muscle and the activity of lactate dehydrogenase (P < .01) reduced immediately after LIFU treatment. The activities of tumor necrosis factor-α and interleukin-6 24 hours lowered in the LIFU group (P < .01). CONCLUSIONS: LIFU treatment could relieve muscle soreness rapidly and effectively in the early stages of DOMS. The application of LIFU may provide a potential strategy for clinical treatment for DOMS.

Bifidobacterium bifidum-Mediated Specific Delivery of Nanoparticles for Tumor Therapy.

PURPOSE: Hypoxia is considered to be obstructive to tumor treatment, but the reduced oxygen surroundings provide a suitable habitat for Bifidobacterium bifidum (BF) to colonize. The anaerobe BF selectively colonizes into tumors following systemic injection due to its preference for the hypoxia in the tumor cores. Therefore, BF may be a potential targeting agent which could be used effectively in tumor treatment. We aimed to determine whether a novel BF-mediated strategy, that was designed to deliver AP-PFH/PLGA NPs (aptamers CCFM641-5-functionalized Perfluorohexane (PFH) loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles) by aptamer-directed approach into solid tumor based on the tumor-targeting ability of BF, could improve efficiency of high intensity focused ultrasound (HIFU) treatment of breast cancer. METHODS: We synthesized AP-PFH/PLGA NPs using double emulsion method and carbodiimide method. Then, we evaluated targeting ability of AP-PFH/PLGA NPs to BF in vivo. Finally, we studied the efficacy of HIFU ablation based on BF plus AP-PFH/PLGA NPs (BF-mediated HIFU ablation) in tumor. RESULTS: The elaborately designed AP-PFH/PLGA NPs can target BF colonized in tumor to achieve high tumor accumulation, which can significantly enhance HIFU therapeutic efficiency. We also found that, compared with traditional chemotherapy, this therapy not only inhibits tumor growth, but also significantly prolongs the survival time of mice. More importantly, this treatment strategy has no obvious side effects. CONCLUSION: We successfully established a novel therapy method, BF-mediated HIFU ablation, which provides an excellent platform for highly efficient and non-invasive therapy of tumor.

Polyethylenimine (PEI)-modified poly (lactic-co-glycolic) acid (PLGA) nanoparticles conjugated with tumor-homing bacteria facilitate high intensity focused ultrasound-mediated tumor ablation.

The acoustic propagation characteristic of ultrasound determines that the energy of ultrasound beam will decrease with the increase of its propagation depth in the body. Similarly, the energy of High Intensity Focused Ultrasound (HIFU) will be attenuated with the increase of HIFU propagation depth in the body. Ensuring sufficient ultrasound energy deposition in the HIFU ablation region for tumor ablation is usually achieved by increasing the ultrasound irradiation power or prolonging the ultrasound ablation time. However, these two methods may damage the normal tissue adjacent to the HIFU ablation region. Herein, we constructed the nanoparticles conjugated with tumor-homing bacteria as the biological tumor-homing synergist to facilitate HIFU-mediated tumor ablation avoiding the potential safety risk. In our strategy, Bifidobacterium bifidum (B.bifidum) was selectively colonized in the hypoxic region of solid tumors after been injected into 4T1 breast cancer bearing-BALB/c mice via the tail vein due to its anaerobic growth characteristic. The amount of B. bifidum with negative surface potential in the hypoxic region of solid tumors was increased by its anaerobic proliferation. Polyethylenimine (PEI) -modified Poly (lactic-co-glycolic) acid nanoparticles loaded sodium bicarbonate (PEI-PLGA-NaHCO3-NPs) with positive surface potential injected into 4T1 breast cancer bearing-BALB/c mice via the tail vein displayed the tumor-homing ability by the electrostatic adsorption with B. bifidum colonized solid tumors. PEI-PLGA-NaHCO3-NPs could release NaHCO3 to produce carbon dioxide (CO2) as cavitation nuclei inside the acidic microenvironment of solid tumors. When HIFU irradiated solid tumors contained with more cavitation nuclei, the ultrasound energy deposition at the tumor region was increased to destroy the tumors more effectively. Meanwhile, the improved efficiency of HIFU-mediated tumor ablation reduced the dependence of the tumor ablation on the ultrasound energy dose, which improved the safety of HIFU-mediated tumor ablation to the non-targeted ablation tissue. This tumor-homing synergist shows the potential application value on the HIFU-mediated tumor ablation in the clinical.

Genetically Engineered Bacterial Protein Nanoparticles for Targeted Cancer Therapy.

PURPOSE: Cancer treatment still faces big challenges in the clinic, which is raising concerns over the world. In this study, we report the novel strategy of combing bacteriotherapy with high-intensity focused ultrasound (HIFU) therapy for more efficient breast cancer treatment. METHODS: The acoustic reporter gene (ARG) was genetically engineered to be expressed successfully in Escherichia coli (E. coli) to produce the protein nanoparticles-gas vesicles (GVs). Ultrasound was utilized to visualize the GVs in E. coli. In addition, it was injected intravenously for targeted breast cancer therapy by combing the bacteriotherapy with HIFU therapy. RESULTS: ARG expressed in E. coli can be visualized in vitro and in vivo by ultrasound. After intravenous injection, E. coli containing GVs could specifically target the tumor site, colonize consecutively in the tumor microenvironment, and it could obviously inhibit tumor growth. Meanwhile, E. coli which contained GVs could synergize HIFU therapy efficiently both in vitro and in vivo as the cavitation nuclei. Furthermore, the tumor inhibition rate in the combination therapy group could be high up to 87% compared with that in the control group. CONCLUSION: Our novel strategy of combing bacteriotherapy with HIFU therapy can treat breast cancers more effectively than the monotherapies, so it can be seen as a promising strategy.