Sonodynamic Cancer Therapy Research Articles

New Developments in Photodynamic and Sonodynamic Cancer Therapy

Background: Photodynamic therapy (PDT) is already widely used for the treatment of superficial tumors. Due to technological developments in the field of low-level laser therapy it can now also be used to treat various kinds of internal cancers, including breast, lung, prostate, bladder, rectal and other cancers. The principle is the photoactivation of a light sensitive substance (photosensitizer) which is injected into the bloodstream or directly into the tumor. After a certain amount of time the photosensitizer will be taken up by cancer cells by endocytosis. The cancerous area is then irradiated by laser light of appropriate wavelength, according to the absorption spectra of the photosensitizer. The emitted photons are absorbed by the photosensitizer which is thereby shifted to a highly reactive state. As a consequent, it interacts with tissue oxygen, leading to the development of reactive singlet oxygen radicals which are cytotoxic for cancer cells. Additional sonodynamic cancer therapy (SDT) improves the clinical outcomes. Aim: We describe a broad number of case studies to demonstrate the outstanding potential of the treatment protocols. Methods: We used indocyanine green, curcumin and hypericin as photosensitizing agents. Upon light activation, the agents react with oxygen, leading to the development of oxygen radicals which induce irreparable damage on cancer cells. Results: In the vast majority of all cases, significant reductions of tumor mass up to complete remissions could be achieved. Conclusion: Protocols consisting of photodynamic and sonodynamic cancer therapies have the potential to become mainstream cancer therapies in the next couple of years.

Ultrasound powers tumor-killing particles

Metal-organic frameworks (MOFs) can store and separate gases, but there is growing interest in their potential medical applications. Chinese researchers have now converted a MOF into nanoparticles that harness the power of ultrasound to kill tumor cells in mice (Adv. Mater. 2018, DOI: 10.1002/adma.201800180). This so-called sonodynamic cancer therapy relies on compounds that are activated by a targeted burst of ultrasound. The sound waves prompt the compounds, known as sonosensitizers, to generate reactive oxygen species that destroy cancer cells in the immediate vicinity, while avoiding systemic side effects. The strategy is similar to light-based photodynamic therapy, but ultrasound can penetrate deeper into tissue than light, so the strategy, in principle, could treat more inaccessible tumors. Although the technology has been tested in a handful of patients, the field is still in its infancy. Huiyu Liu at the Beijing University of Chemical Technology and colleagues have now designed a sonosensitizer based

Metal-Organic-Framework-Derived Carbon Nanostructure Augmented Sonodynamic Cancer Therapy.

Sonodynamic therapy (SDT) can overcome the critical issue of depth-penetration barrier of photo-triggered therapeutic modalities. However, the discovery of sonosensitizers with high sonosensitization efficacy and good stability is still a significant challenge. In this study, the great potential of a metal-organic-framework (MOF)-derived carbon nanostructure that contains porphyrin-like metal centers (PMCS) to act as an excellent sonosensitizer is identified. Excitingly, the superior sonosensitization effect of PMCS is believed to be closely linked to the porphyrin-like macrocycle in MOF-derived nanostructure in comparison to amorphous carbon nanospheres, due to their large highest occupied molecular orbital (HOMO)-lowest unoccupied molecular orbital (LUMO) gap for high reactive oxygen species (ROS) production. The nanoparticle-assisted cavitation process, including the visualized formation of the cavitation bubbles and microjets, is also first captured by high-speed camera. High ROS production in PMCS under ultrasound is validated by electron spin resonance and dye measurement, followed by cellular destruction and high tumor inhibition efficiency (85%). This knowledge is important from the perspective of understanding the structure-dependent SDT enhancement of a MOF-derived carbon nanostructure.

Two dimensional semiconductors for ultrasound-mediated cancer therapy: the case of black phosphorus nanosheets.

With black phosphorus (BP) as an example, the first two-dimensional (2D) semiconductor based sonosensitizer (Au@BP nanohybrids) was fabricated. Under ultrasound irradiation, Au@BP nanohybrids can generate 1O2 in deep tissues and eradicate tumors with high efficacy. This platform paves the way for the application of 2D semiconductors in sonodynamic cancer therapy.

Magnetically responsive microbubbles as delivery vehicles for targeted sonodynamic and antimetabolite therapy of pancreatic cancer

Magnetically responsive microbubbles (MagMBs), consisting of an oxygen gas core and a phospholipid coating functionalised with Rose Bengal (RB) and/or 5-fluorouracil (5-FU), were assessed as a delivery vehicle for the targeted treatment of pancreatic cancer using combined antimetabolite and sonodynamic therapy (SDT). MagMBs delivering the combined 5-FU/SDT treatment produced a reduction in cell viability of over 50% when tested against a panel of four pancreatic cancer cell lines in vitro. Intravenous administration of the MagMBs to mice bearing orthotopic human xenograft BxPC-3 tumours yielded a 48.3% reduction in tumour volume relative to an untreated control group (p<0.05) when the tumour was exposed to both external magnetic and ultrasound fields during administration of the MagMBs. In contrast, application of an external ultrasound field alone resulted in a 27% reduction in tumour volume. In addition, activated caspase and BAX protein levels were both observed to be significantly elevated in tumours harvested from animals treated with the MagMBs in the presence of magnetic and ultrasonic fields when compared to expression of those proteins in tumours from either the control or ultrasound field only groups (p<0.05). These results suggest MagMBs have considerable potential as a platform to enable the targeted delivery of combined sonodynamic/antimetabolite therapy in pancreatic cancer.

Metalloporphyrin-Encapsulated Biodegradable Nanosystems for Highly Efficient Magnetic Resonance Imaging-Guided Sonodynamic Cancer Therapy.

Traditional photodynamic therapy (PDT) suffers from the critical issues of low tissue-penetrating depth of light and potential phototoxicity, which are expected to be solved by developing new dynamic therapy-based therapeutic modalities such as sonodynamic therapy (SDT). In this work, we report on the design/fabrication of a high-performance multifunctional nanoparticulate sonosensitizer for efficient in vivo magnetic resonance imaging (MRI)-guided SDT against cancer. The developed approach takes the structural and compositional features of mesoporous organosilica-based nanosystems for the fabrication of sonosensitizers with intriguing theranostic performance. The well-defined mesoporosity facilitates the high loading of organic sonosensitizers (protoporphyrin, PpIX) and further chelating of paramagnetic transitional metal Mn ions based on metalloporphyrin chemistry (MnPpIX). The mesoporous structure of large surface area also maximizes the accessibility of water molecules to the encapsulated paramagnetic Mn ions, endowing the composite sonosensitizers with markedly high MRI performance (r1 = 9.43 mM-1 s-2) for SDT guidance and monitoring. Importantly, the developed multifunctional sonosensitizers (HMONs-MnPpIX-PEG) with controllable biodegradation behavior and high biocompatibility show distinctively high SDT efficiency for inducing the cancer-cell death in vitro and suppressing the tumor growth in vivo. This report provides a paradigm that nanotechnology-enhanced SDT based on elaborately designed high-performance multifunctional sonosensitizers will pave a new way for efficient cancer treatment by fully taking the advantages (noninvasiveness, convenience, cost-effectiveness, etc.) of ultrasound therapy and quickly developing nanomedicine.

Porous Silicon as a Sensitizer for Biomedical Applications

Abstract Porous silicon (PSi) can activate (sensitize) biochemical reactions and physical processes of the energy dissipation under excitation (stimulus) by light illumination, ultrasound (US), and electromagnetic radiofrequency (RF) irradiation. Photosensitized biochemical effects of PSi layers and nanoparticles (NPs)were explored in numerous physical studies and biomedical experiments in vitro. The photothermal sensitizing with mesoporous PSi NPs was demonstrated to be efficient for the hyperthermia of cancer cells and tumors in small animal models. The sonosensitizing properties of bare PSi NPs and dextran-coated ones were revealed by both the physical studies and biomedical experiments, which indicated a good prospect for their applications in sonodynamic therapy of cancer. RF-induced hyperthermia sensitized by PSi NPs has been successfully used to destroy cancer cells and tumors in vitro and in vivo, respectively. Here, we review the results on the preparation, physical properties, and applications of PSi NPs as sensitizers for mild therapy of cancer.

ROS-generating TiO2 nanoparticles for non-invasive sonodynamic therapy of cancer.

The non-invasive photodynamic therapy has been limited to treat superficial tumours, primarily ascribed to poor tissue penetration of light as the energy source. Herein, we designed a long-circulating hydrophilized titanium dioxide nanoparticle (HTiO2 NP) that can be activated by ultrasound to generate reactive oxygen species (ROS). When administered systemically to mice, HTiO2 NPs effectively suppressed the growth of superficial tumours after ultrasound treatments. In tumour tissue, the levels of proinflammatory cytokines were elevated several fold and intense vascular damage was observed. Notably, ultrasound treatments with HTiO2 NPs also suppressed the growth of deeply located liver tumours at least 15-fold, compared to animals without ultrasound treatments. This study provides the first demonstration of the feasibility of using HTiO2 NPs as sensitizers for sonodynamic therapy in vivo.

Porphyrin-loaded nanoparticles for cancer theranostics.

Porphyrins have been used as pioneering theranostic agents not only for the photodynamic therapy, sonodynamic therapy and radiotherapy of cancer, but also for diagnostic fluorescence imaging, magnetic resonance imaging and photoacoustic imaging. A variety of porphyrins have been developed but very few of them have actually been employed in clinical trials due to their poor selectivity to tumorous tissue and high accumulation rates in the skin. In addition, most porphyrin molecules are hydrophobic and form aggregates in aqueous media. Nevertheless, the use of nanoparticles as porphyrin carriers shows great promise to overcome these shortcomings. Encapsulating or attaching porphyrins to nanoparticles makes them more suitable for tissue delivery because we can create materials with a conveniently specific tissue lifetime, specific targeting, immune tolerance, and hydrophilicity as well as other characteristics through rational design. In addition, various functional components (e.g. for targeting, imaging or therapeutic functions) can be easily introduced into a single nanoparticle platform for cancer theranostics. This review presents the current state of knowledge on porphyrin-loaded nanoparticles for the interwined imaging and therapy of cancer. The future trends and limitations of prophyrin-loaded nanoparticles are also outlined.

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.

Sonodynamic therapy of cancer. A comprehensive experimental study

Sonodynamic therapy in combination with antitumor drugs and sonosensitizers (theraphthal and its derivatives) was studied in preclinical testing against malignant tumors. The use of this therapy scheme enhances the destructive effect of ultrasound on tumors, promotes no metastasis, and make therapeutic drugs more bioavailable. The scheme was recommended for clinical use. A solid-phase sonosensitization mechanism was proposed. A possible system of laboratory and in vitro testing for selection of efficient sonosensitizers was outlined.

Sonodynamic antitumor effect of a novel sonosensitizer on S180 solid tumor

The purpose of this study was to evaluate the sonodynamically induced antitumor effect of a novel sonosensitizer (DVDMS) in mice bearing sarcoma 180 solid tumors. In order to determine the optimum timing of ultrasound exposure after administration of DVDMS, a three-dimensional optical imaging system (IVIS spectrum) was used to observe the biodistribution of DVDMS in S180 tumor. The antitumor effects were estimated by the tumor inhibition ratio (volume and weight) after sonodynamic therapy. The experiments suggested that DVDMS has a preferential localization in tumors, but a low accumulation in most normal tissues. A significant synergistic effect of ultrasound combined with DVDMS was obtained when the load power indicated 4 W and DVDMS dose was above 2 mg/kg. At day 14 after DVDMS-SDT, the tumor volume inhibition ratio was 56.27%. In addition, the tumor weight inhibition ratio after the synergistic treatment was 55.37%, which was obviously stronger than ultrasound treatment alone (23.85%) and DVDMS alone (23.15%). Moreover, no metastasis occurred to the tumors in the SDT-treated mice compared with the control group. DVDMS is a potential sensitizer for sonodynamic cancer therapy. The antitumor effect of ultrasound could be enhanced in the presence of DVDMS, which might be involved in a sonochemical mechanism.

Sonodynamic therapy (SDT): A novel treatment of cancer based on sonosensitizer liposome as a new drug carrier

Cancer is a major cause of morbidity and mortality. Chemotherapy is one of the main means of cancer treatment. Conventional chemotherapy agents kill rapidly proliferating cells, resulting in some of the most common side effects of chemotherapy. Liposome-encapsulated drugs offer the possibility to increase target efficacy as well as reducing toxic side effects of chemotherapeutic drugs. However, the target specificity of liposome is dissatisfied. We urgently need to develop new approaches to improving drug target efficacy. Recently, sonodynamic therapy (SDT) of cancer, which is based on preferential uptake and retention of a sonosensitizer in tumor tissues and subsequent activation of drug by ultrasound radiation, is a developing field. In this article, we propose the use of sonosensitizers in combination with liposome to target chemotherapy drugs directly to tumor cells. SDT with low-intensity ultrasound combined with a sonosensitizer may be a promising approach to cancer therapy.

Nanosonotechnology: the next challenge in cancer sonodynamic therapy

AbstractSonodynamic therapy (SDT) is a newly developed anticancer treatment where ultrasound is used to trigger the cytotoxic effect of chemical compounds, known as sonosensitizers. Although SDT is similar to photodynamic therapy (PDT), SDT activates the chemical compounds through energy transfer using ultrasound rather than light. Moreover, SDT can focus the ultrasound energy onto malignant sites situa­ted deeply within tissues, thus overcoming the main drawback linked to the use of PDT. Several physical and chemical mechanisms underlying ultrasound bioeffects and anticancer SDT take advantage of the non-thermal effect of acoustic cavitation generated by selected pulsed or continuous ultrasound. As the physical-chemical structure of the sonosentizer is essential for the success of SDT, we believe that the different aspects related to nanotechnology in medicine might well be able to improve the triggering effect ultrasound has on sonosensitizing agents. Therefore, the aim of this review is to focus on how nanotechnology might improve this innovative anticancer therapeutic approach.

Sonodynamic therapy of cancer using a novel porphyrin derivative, DCPH‐P‐Na(I), which is devoid of photosensitivity

To improve the efficacy of sonodynamic therapy of cancer using photosensitizers, we developed a novel porphyrin derivative designated DCPH-P-Na(I) and investigated its photochemical characteristics and sonotoxicity on tumor cells. DCPH-P-Na(I) exhibited a minimum fluorescent emission by excitation with light, compared with a strong emission from ATX-70, which is known to reveal both photo- and sonotoxicity. According to this observation, when human tumor cells were exposed to light in the presence of DCPH-P-Na(I) in vitro, the least phototoxicity was observed, in contrast to the strong phototoxicity of ATX-70. However, DCPH-P-Na(I) exhibited a potent sonotoxicity on tumor cells by irradiation with ultrasound in vitro. This sonotoxicity was reduced by the addition of L-histidine, but not D-mannitol, thus suggesting that singlet oxygen may be responsible for the sonotoxicity of DCPH-P-Na(I). DCPH-P-Na(I) demonstrated significant sonotoxicity against a variety of cancer cell lines derived from different tissues. In addition, in a mouse xenograft model, a potent growth inhibition of the tumor was observed using sonication after the administration of DCPH-P-Na(I) to the mouse. These results suggest that sonodynamic therapy with DCPH-P-Na(I) may therefore be a useful clinical treatment for cancers located deep in the human body without inducing skin sensitivity, which tends to be a major side-effect of photosensitizers.

Mechanism of Crystallization in Polymer Gels as Applied to Sonodynamic Cancer Therapy

Mechanism of Crystallization in Polymer Gels as Applied to Sonodynamic Cancer Therapy