Therapeutic Ultrasound Irradiation Research Articles

Sonoinduced Tumor Therapy and Metastasis Inhibition by a Ruthenium Complex with Dual Action: Superoxide Anion Sensitization and Ligand Fracture.

Photoresponsive ruthenium(II) complexes have recently emerged as a promising tool for synergistic photodynamic therapy and chemotherapy in oncology, as well as for antimicrobial applications. However, the limited penetration power of photons prevents the treatment of deep-seated lesions. In this study, we introduce a sonoresponsive ruthenium complex capable of generating superoxide anion (O2•-) via type I process and initiating a ligand fracture process upon ultrasound triggering. Attaching hydroxyflavone (HF) as an "electron reservoir" to the octahedral-polypyridyl-ruthenium complex resulted in decreased highest occupied molecular orbital (HOMO)-lowest unoccupied molecular orbital (LUMO) energy gaps and triplet-state metal to ligand charge transfer (3MLCT) state energy (0.89 eV). This modification enhanced the generation of O2•- under therapeutic ultrasound irradiation at a frequency of 1 MHz. The produced O2•- rapidly induced an intramolecular cascade reaction and HF ligand fracture. As a proof-of-concept, we engineered the Ru complex into a metallopolymer platform (PolyRuHF), which could be activated by low-power ultrasound (1.5 W cm-2, 1.0 MHz, 50% duty cycle) within a centimeter range of tissue. This activation led to O2•- generation and the release of cytotoxic ruthenium complexes. Consequently, PolyRuHF induced cellular apoptosis and ferroptosis by causing mitochondrial dysfunction and excessive toxic lipid peroxidation. Furthermore, PolyRuHF effectively inhibited subcutaneous and orthotopic breast tumors and prevented lung metastasis by downregulating metastasis-related proteins in mice. This study introduces the first sonoresponsive ruthenium complex for sonodynamic therapy/sonoactivated chemotherapy, offering new avenues for deep tumor treatment.

Investigating the effect of therapeutic ultrasound irradiation on the liver and kidney function of male albino mice

Investigating the effect of therapeutic ultrasound irradiation on the liver and kidney function of male albino mice

Theranostic Multilayer Capsules for Ultrasound Imaging and Guided Drug Delivery.

Despite the accessibility of ultrasound, the clinical potential of ultrasound-active theranostic agents has not been fully realized because it requires combining sufficient imaging contrast, high encapsulation efficiency, and ultrasound-triggered release in one entity. We report on theranostic polymer microcapsules composed of hydrogen-bonded multilayers of tannic acid and poly(N-vinylpyrrolidone) that produce high imaging contrast and deliver the anticancer drug doxorubicin upon low-power diagnostic or high-power therapeutic ultrasound irradiation. These capsules exhibit excellent imaging contrast in both brightness and harmonic modes and show prolonged contrast over six months, unlike commercially available microbubbles. We also demonstrate low-dose gradual and high-dose fast release of doxorubicin from the capsules by diagnostic (∼100 mW/cm2) and therapeutic (>10 W/cm2) ultrasound irradiation, respectively. We show that the imaging contrast of the capsules can be controlled by varying the number of layers, polymer type (relatively rigid tannic acid versus more flexible poly(methacrylic acid)), and polymer molecular weight. In vitro studies demonstrate that 50% doxorubicin release from ultrasound-treated capsules induces 97% cytotoxicity to MCF-7 human cancer cells, while no cytotoxicity is found without the treatment. Considering the strong ultrasound imaging contrast, high encapsulation efficiency, biocompatibility, and tunable drug release, these microcapsules can be used as theranostic agents for ultrasound-guided chemotherapy.

Antimicrobial Effect of Biocompatible Silicon Nanoparticles Activated Using Therapeutic Ultrasound.

In this study, we report a method for the suppression of Escherichia coli (E. coli) vitality by means of therapeutic ultrasound irradiation (USI) using biocompatible silicon nanoparticles as cavitation sensitizers. Silicon nanoparticles without (SiNPs) and with polysaccharide (dextran) coating (DSiNPs) were used. Both types of nanoparticles were nontoxic to Hep 2 cells up to a concentration of 2 mg/mL. The treatment of bacteria with nanoparticles and application of 1 W/cm2 USI resulted in the reduction of their viabilities up to 35 and 72% for SiNPs and DSiNPs, respectively. The higher bacterial viability reduction for DSiNPs as compared with SiNPs can be explained by the fact that the biopolymer shell of the polysaccharide provides a stronger adhesion of nanoparticles to the bacterial surface. Transmission electron microscopy (TEM) studies showed that the bacterial lipid shell was partially perforated after the combined treatment of DSiNPs and USI, which can be explained by the lysis of bacterial membrane due to the cavitation sensitized by the SiNPs. Furthermore, we have shown that 100% inhibition of E. coli bacterial colony growth is possible by coupling the treatments of DSiNPs and USI with an increased intensity of up to 3 W/cm2. The observed results reveal the application of SiNPs as promising antimicrobial agents.

Porous silicon nanoparticles as efficient sensitizers for sonodynamic therapy of cancer

Luminescent porous silicon nanoparticles with mean size of about 100 nm were covered by biodegradable polymer (dextran) and were investigated as potential sensitizers for ultrasound-assisted therapy. Luminescent confocal microscopy revealed an efficient uptake of the nanoparticles by cancer cells in vitro. The nanoparticles were found to be almost nontoxic up to the concentration of 0.1 mg/mL and doses of 30 mg/kg as it was confirmed by in vitro and in vivo experiments, respectively. A strong suppression of the cancer cell proliferation was observed after a combined treatment by the nanoparticles and therapeutic ultrasound irradiation with frequencies of 1–3 MHz and intensities of 1–2 W/cm2. The obtained results are discussed in view of potential applications of biocompatible and biodegradable silicon-based nanoparticles in sonodynamic therapy of cancer.

CO2 bubbling-based 'Nanobomb' System for Targetedly Suppressing Panc-1 Pancreatic Tumor via Low Intensity Ultrasound-activated Inertial Cavitation.

Noninvasive and targeted physical treatment is still desirable especially for those cancerous patients. Herein, we develop a new physical treatment protocol by employing CO2 bubbling-based 'nanobomb' system consisting of low-intensity ultrasound (1.0 W/cm2) and a well-constructed pH/temperature dual-responsive CO2 release system. Depending on the temperature elevation caused by exogenous low-intensity therapeutic ultrasound irradiation and the low pH caused by the endogenous acidic-environment around/within tumor, dual-responsive CO2 release system can quickly release CO2 bubbles, and afterwards, the generated CO2 bubbles waves will timely explode before dissolution due to triggering by therapeutic ultrasound waves. Related bio-effects (e.g., cavitation, mechanical, shock waves, etc) caused by CO2 bubbles' explosion effectively induce instant necrosis of panc-1 cells and blood vessel destruction within panc-1 tumor, and consequently inhibit the growth of panc-1 solid tumor, simultaneously minimizing the side effects to normal organs. This new physiotherapy employing CO2 bubbling-based 'nanobomb' system promises significant potentials in targetedly suppressing tumors, especially for those highly deadly cancers.

Os efeitos do ultra-som terapêutico nas lesões por esmagamento do nervo ciático de ratos: análise funcional da marcha

Background: The effects of therapeutic ultrasound irradiation on peripheral nerve regeneration are not well known, particularly regarding functional recovery. However, in rats, footprint evaluation is a well-systematized method for measuring the Sciatic Functional Index (SFI), showing close correlation with morphological regeneration of damaged sciatic nerves. Objective: To analyze the influence of therapeutic ultrasound on sciatic nerve regeneration in rats subjected to controlled crushing. Method: 20 Wistar rats (mean body weight: 300 g) were divided into two experimental groups: 1) crushing only (n=10); 2) crushing followed by ultrasound irradiation (n=10). Under general anesthesia, a 5-mm segment of sciatic nerve proximal to its bifurcation in the right thigh was exposed and crushed with constant loading of 15 kg for 10 minutes, using a specially-built device. Low-intensity pulsed ultrasound irradiation (1:5, 0.4 W/cm2, 1 MHz, 2 minutes) was started on the first postoperative day and administered for ten consecutive days. Footprints were obtained weekly (postoperative weeks 13) using a specially-designed walkway, and evaluated using specifically-developed software, according to a previously-tested method, with automatic SFI calculation. Results: The SFI progressively increased in both groups: Group 2, from 101 in the first week to 59.21 (second) and 26.68 (third), i.e. 73% improvement overall; Group 1, from 98.2 (first) to 79.5 (second) and 44 (third), i.e. 55% improvement overall. The differences between the groups were significant for the second and third weeks (p=0.02 and p=0.002, respectively). Conclusion: Low-intensity therapeutic ultrasound accelerates the regeneration of crushed sciatic nerves in rats, as demonstrated by its functional recovery.

Diclofenac phonophoresis in human volunteers

A quantitative study of sodium diclofenac (Voltaren Emulgel®, Novartis) phonophoresis was undertaken in humans. Fourteen healthy human volunteers were submitted to ultrasound irradiation on two 225-cm 2 areas on the dorsum (group A), followed by the application of the medication gel, and the plasma diclofenac mass was measured at 1, 2 and 3 h later by high performance liquid chromatography. The same procedure was repeated one month later with the same volunteers but with the ultrasound equipment switched off for the control group (group B). The plasma diclofenac mass was significantly higher in group A than in group B at 1 h (0.0987 μg/mL as opposed to 0.0389 μg/mL; p = 0.01) and 2 h (0.0724 μg/mL as opposed to 0.0529 μg/mL; p = 0.01), but not at 3 h (0.0864 μg/mL as opposed to 0.0683 μg/mL; p = 0.16). The authors conclude that previously applied therapeutic ultrasound irradiation enhances the percutaneous penetration of the topical diclofenac gel, although the mechanism remains unclear. (E-mail: chbarbie@fmrp.usp.br)

Cellular Alterations in Cultured Endothelial Cells Exposed to Therapeutic Ultrasound Irradiation

Restoration of blood supply to tissue with impaired perfusion depends on spontaneous or mediated angiogenesis, which among other mechanisms includes stimulation, migration, and proliferation of endothelial cells (ECs). Therapeutic ultrasound (US) irradiation is known as an inducer of cellular modifications and is used to accelerate wound healing. An in vitro setup was developed in order to allow for a comprehensive investigation of cellular alterations induced in cultured ECs after exposure to different modes of therapeutic US irradiation. Viability assays revealed a higher rate of proliferation in the sonicated groups, although cell death was not observed. Visualization of actin stress fibers demonstrated partial disassembly of the fibers immediately after US sonication, with a maximum after about 2 h. However, 24 h following sonication the fibers regain normal appearance. A similar behavior was observed with the microtubules and focal adhesion complexes. Utilizing a wound healing assay revealed that migration rate of ECs is enhanced by US irradiation. These findings hint that therapeutic US sonication of ECs results in temporarily cellular alterations, which may induce tissue remodeling via stimulation of EC proliferation and migration.

Therapeutic ultrasound irradiation in combination with photodynamic therapy drugs to colon cancer: In vitro and early clinical study

Therapeutic ultrasound irradiation in combination with photodynamic therapy drugs to colon cancer: In vitro and early clinical study

Evaluation of high-intensity therapeutic ultrasound irradiation in the treatment of experimental hepatoma.

A study evaluating the efficacy of high-intensity therapeutic ultrasound (HITU) as a treatment modality in experimental hepatoma is reported. Morris hepatoma (3924) 1 x 10(6) cells were transferred subcutaneously into 40 male ACI rats (weight, 150 to 200 g). Animals were divided into four experimental groups: group 1 (n = 10) consisted of untreated controls; group 2 (n = 10) received intraperitoneal cyclophosphamide 50 mg/kg as a single dose; group 3 (n = 10) underwent HITU only; and group 4 (n = 10) received both chemotherapy (as in group 2) and HITU (as in group 3). HITU was administered with a 5.5-cm diameter 4-MHz quartz transducer creating a continuous wave with 400 W/cm2 focal intensity. The entire tumor was irradiated in 1-mm increments (horizontal and vertical) using treatment cycles of 4 seconds on and 11 seconds off. Total body weight and tumor volume were measured on the day of treatment, and 4 weeks later. At 4 weeks, the animals were killed, the tumor was excised and weighed, and tumor volume was determined. Tumor volume in all treated animals (groups 2, 3 and 4) was significantly smaller than in controls (P less than .001) at 4 weeks, and tumor volume for animals in group 4 was significantly smaller than for those in groups 2 and 3 (P less than .01). These data indicate that HITU significantly reduces tumor size when compared with control rats with Morris hepatoma. A synergistic effect of chemotherapy and HITU was observed and resulted in an enhanced tumor response and reduction of tumor size.(ABSTRACT TRUNCATED AT 250 WORDS)

Interaction of ultrasound with neoplastic tissue IV. Alteration of biologic activity in cells derived from rat wilms' tumor sonicated in vivo

Paired Wistar-Furth male rats were implanted subcutaneously with the Furth-Columbia rat Wilms' tumor. Seven days after implantation the tumors were either subjected to therapeutic ultrasound irradiation or were left as untreated controls. On the ninth day after implantation the animals were sacrificed, and suspensions of cells were made from the excised tumors by trypsinization. The cells were counted using trypan blue dye as an indicator of viability. New rats were then implanted with cells either from sonicated tumors or cells from controls. In half the recipient animals the suspensions were matched by total cell count. In the other half of the rats cell counts were matched for viability by the dye exclusion test. Tumors developed in a total of 8 of 11 rats receiving control cells and they died. A palpable tumor did not develop in any rat receiving cells from sonicated tumors during the ninety-day study period. Surviving rats were challenged with Wilms' tumor by trocar implant. Tumor developed in all recipients, and they died.