Sonosensitizer For Sonodynamic Therapy Research Articles

Glutathione-triggered release of SO2 gas to augment oxidative stress for enhanced chemodynamic and sonodynamic therapy.

Recently, gas therapy has emerged as a promising alternative treatment for deep-seated tumors. However, some challenges regarding insufficient or uncontrolled gas generation as well as unclear therapeutic mechanisms restrict its further clinical application. Herein, a well-designed nanoreactor based on intracellular glutathione (GSH)-triggered generation of sulfur dioxide (SO2) gas to augment oxidative stress has been developed for synergistic chemodynamic therapy (CDT)/sonodynamic therapy (SDT)/SO2 gas therapy. The nanoreactor (designed as CCM@FH-DNs) is constructed by employing iron-doped hollow mesoporous silica nanoparticles as carriers, the surface of which was modified with the SO2 prodrug 2,4-dinitrobenzenesulfonyl (DNs) and further coated with cancer cell membranes for homologous targeting. The CCM@FH-DNs can not only serve as a Fenton-like agent for CDT, but also as a sonosensitizer for SDT. Importantly, CCM@FH-DNs can release SO2 for SO2-mediated gas therapy. Both in vitro and in vivo evaluations demonstrate that the CCM@FH-DNs nanoreactor performs well in augmenting oxidative stress for SO2 gas therapy-enhanced CDT/SDT via GSH depletion and glutathione peroxidase-4 enzyme deactivation as well as superoxide dismutase inhibition. Moreover, the doped iron ions ensure that the CCM@FH-DNs nanoreactors enable magnetic resonance imaging-guided therapy. Such a GSH-triggered SO2 gas therapy-enhanced CDT/SDT strategy provides an intelligent paradigm for developing efficient tumor microenvironment-responsive treatments.

Nano-Sonosensitized Sonodynamic Nanomedicine Augments Tumor-Selective Catalytic Tumor Eradication

Inspired by the distinct metabolic pathway of tumor cells, here a new anti-cancer therapy (i.e., Cu-TCPP(Fe) metal-organic frameworks (MOFs) with sonosensitizer for sonodynamic therapy (SDT) and tumor microenvironment (TME)-specific release of copper/iron for chemical catalysis) is introduced and verified. Upon exposure to ultrasound, the porphyrin structure in the MOFs yields reactive oxygen species (ROS), and the copper/iron induces the Fenton reaction in the TME existing H2O2 and acid. Thus, highly toxic ROS are generated through these TME-specific reactions to trigger the apoptosis and death of tumor cells. The current work paves a new avenue to design SDT with catalytic nanomedicine for the selective and effective treatment of tumors.

An Urchin-Shaped Copper-Based Metalloporphyrin Nanosystem as a Sonosensitizer for Sonodynamic Therapy.

Sonodynamic therapy (SDT), as a novel cancer therapy strategy, might be a promising approach due to the depth-penetration property in tissue. Sonosensitizers are the key element for efficient SDT. However, the development of sonosensitizers with strong sonosensitization efficacy is still a significant challenge. Herein, an urchin-shaped copper-based metalloporphyrin liposome nanosystem (FA–L–CuPP) is constructed and identified as an excellent sonosensitizer. Under ultrasound (US) irradiation, FA–L–CuPP can be highly excited to generate several reactive oxygen species (ROS), such as singlet oxygen (1O2) and free radicals (⋅OH). The molecular orbital distribution calculations reveal that a strong intramolecular charge transfer might occur in the CuPP complex under US irradiation, which could afford enough energy to the surrounding O2 and H2O to concert 1O2, O2− and ⋅OH. Working as “ammunitions”, the largely produced ROS can kill 4T1 tumor cells, effectively inhibiting tumor growth. This work provides an urchin-shaped nanosonosensitizer based on a copper complex, which might provide an idea to design a novel sonosensitizer for noninvasive and precise SDT antitumor applications.

Phycocyanin Nanoparticle as a Novel Sonosensitizer for Tumor Sonodynamic Therapy of Michigan Cancer Foundation-7 Cells In Vitro.

The development of novel sonosensitizers with safety and efficiency is a key problem in anti-tumor sonodynamic therapy. Phycocyanin (PC) has been proved to have the singlet oxygen radicals (ROS) generation ability, and the potential of PC as a novel sonosensitizer has been investigated. To overcome the disadvantages of PC in vivo, such as poor stability and low half-life, PC nanoparticles (PCNP) were prepared by the cross-linking method. According to the results, PCNP has been found with good morphology, good particle size distribution and good stability. Human breast cancer cell line MCF-7 was used to investigate PCNP cell uptake ability. ROS generation and cytotoxicity under ultrasonic irradiation (sonotoxicity) were also studied on this cell. Under the condition of 0.75 w/cm² ultrasound, PCNP has a good ROS productivity and is equivalent to the sonotoxicity of the known sonosensitizer hematoporphyrin monomethyl Ether (HMME). In conclusion, PCNP is expected to be developed as an effective sonosensitizer for the sonodynamic therapy of tumors.

Preparation, characterization, and sonodynamic antitumor effect of the folate receptor targeted FA-EN-β-CD containing hematoporphyrin in vitro.

To improve water solubility, reduce phototoxicity and increase the tumor-targeting ability of hematoporphyrin (Hp) as a sonosensitizer for sonodynamic therapy under ultrasonic conditions, a novel folate receptor (FR)-targeted, folate-conjugated ethylenediamine-β-cyclodextrin (FA-EN-β-CD) containing Hp (FA-EN-β-CD-Hp) was constructed. β-Cyclodextrin containing Hp (β-CD-Hp) was also established as a nontargeted control. The inclusion efficiencies of Hp in FA-EN-β-CD-Hp and β-CD-Hp were determined to be 90.4 ± 2.7% (wt/wt) and 92.5 ± 3.4% (wt/wt), respectively. Growth inhibition rates in HepG-2 cells in vitro were assessed upon ultrasound exposure. The results indicated that the growth inhibition rates of FA-EN-β-CD-Hp, β-CD-Hp, and F-Hp (Hp: 150 μg/ml) reached 96.4 ± 3.6%, 53.4 ± 3.4%, and 48.2 ± 2.8%, respectively. These results indicated that FA-EN-β-CD-Hp is a promising drug delivery system in the field of sonodynamic cancer therapy.

Ultrasound triggered drug delivery for mitochondria targeted sonodynamic therapy

Mitochondria, which play an essential effect in cell apoptosis, are targets for cancer treatment. Here, mitochondria targeted liposomes loaded with sonosensitizer for sonodynamic therapy (SDT) of caner were studied. The (3-Carboxypropyl) triphenylphosphonium bromide (TPP), was grafted onto the liposomes using cholesterol (Chol) as anchor for mitochondria targeting. The hematoporphyrin monomethyl ether (HMME), a hydrophobic sonosensitizer, was loaded in the liposomes. The release of HMME from liposomes could be triggered by the irradiation of an extra ultrasound due to the oxidation of the lipid in liposomes. After incubation with cancer cells, the TPP modified liposomes (Lipo-TPP) could accumulate in the mitochondria and assist the HMME to achieve greater cancer cell inhibition effect in SDT. This work gives insights into the design of mitochondria-targeted carrier for SDT of cancer.

Preparation and Sonodynamic Antitumor Effect of Protohemin-Conjugated Multiwalled Carbon Nanotubes Functionalized with Carboxylic Group.

Preclinical Research Sonodynamic therapy (SDT) is a cutting edge approach to treating cancer that involves necrosis and/or apoptosis. Multiwalled carbon nanotubes functionalized with carboxylic groups (MWCNTs-COOH) due their physicochemical structure represent a novel drug delivery system in the field of nanomedicine. The purpose of the research reported in this paper was to increase the antitumor potency and reduce the potential side effects of protohemin (Ph), a sonosensitizer for SDT, which was noncovalently encapsulated into MWCNTs-COOH (MWCNTs-Ph). The Ph loading efficiency in MWCNTs-COOH carrier was determined as approximately 68.8% (w/w). The growth inhibition rate of MWCNTs-Ph (Ph: 180 μg/mL) was approximately 95 ± 8.5%, whereas Ph-F (Ph: 180 μg/mL) inhibited 58 ± 4.5% of tumor cell. Ph (Ph: 180 μg/mL) alone had no antitumor effect in HepG-2 cells using ultrasound treatment at 1.0 MHz and 0.5 W/cm(2) for 100 s. Assessment of the antitumor effects of MWCNTs-Ph and Ph-F at day 11 after SDT showed that he tumor inhibition ratio for MWCNTs-Ph (6.18 × 10(-2) g·kg(-1) ·d(-1) ) was 82.8%, twice that of Ph-F (6.18 × 10(-2) g·kg(-1) ·d(-1) ) ay 41.8%. In conclusion, MWCNTs-Ph had increased antitumor efficiency and also decreased potential side effects. Drug Dev Res 77 : 152-158, 2016. © 2016 Wiley Periodicals, Inc.

Apoptosis of THP-1 Macrophages Induced by Pseudohypericin-Mediated Sonodynamic Therapy Through the Mitochondria-Caspase Pathway

Background/Aims: Pseudohypericin (P-HY) and its congener hypericin are the major hydroxylated phenanthroperylenediones present in Hypericum species. Our previous study indicated that hypericin was able to function as a sonosensitizer. The potential use of P-HY as a sonosensitizer for sonodynamic therapy (SDT) requires further exploration. Thus, this study aimed to investigate the effects of P-HY-SDT on THP-1 macrophages. Methods: THP-1 macrophages were incubated with P-HY, and cell viability was measured using a CCK-8 assay. Fluorescence microscopy assessed the intracellular reactive oxygen species (ROS), mitochondrial membrane potential (∆Ψm) and mitochondrial permeability transition pore (mPTP) opening. Apoptotic and necrotic cell levels were measured by the flow cytometry analysis. Western blots were employed to assay BAX, Cytochrome C expression and apoptosis-related proteins. Results: P-HY-SDT induced THP-1 macrophage apoptosis. The levels of ROS were significantly increased in the SDT group, resulting in both mPTP opening and ∆Ψm loss, which led to apoptosis. In addition, the translocation of BAX, release of Cytochrome C and the upregulated expression of apoptosis-related proteins after P-HY-SDT were observed, all of which were reversed by N-acetyl cysteine (NAC). Conclusion: P-HY-SDT induced THP-1 macrophage apoptosis through the mitochondria-caspase pathway via ROS generation, the translocation of BAX and the release of Cytochrome C to regulate the mPTP opening.

Core–shell structured Fe3O4@TiO2-doxorubicin nanoparticles for targeted chemo-sonodynamic therapy of cancer

To facilitate targeting drug delivery and combined therapy, we develop titanium dioxide-encapsulated Fe3O4 nanoparticles (Fe3O4@TiO2 NPs). Titanium dioxide (TiO2), which is employed as a sonosensitizer for sonodynamic therapy (SDT), can also be used for the loading of doxorubicin (DOX). The fabricated Fe3O4@TiO2 NPs exhibit pH-dependent loading and release of doxorubicin (DOX) in vitro. After incubation with cancer cells, reactive oxygen species (ROS) are generated efficiently upon the irradiation of ultrasound. In the biodistribution experiments, extremely high in vivo tumor accumulation of Fe3O4@TiO2 NPs and long-time retention effect are observed. Compared with chemotherapy or sonodynamic treatment alone, the combined therapy demonstrated a synergistic effect, resulting in stronger cytotoxicity and higher therapeutic efficacy. Thus, the constructed NPs are endowed with multifunctions which allow them to selectively deliver combinatorial therapeutic payload to tumor with enhanced therapeutic effectiveness and minimal side effects.

Potential sonodynamic anticancer activities of artemether and liposome-encapsulated artemether.

The potential application of artemether as a novel sonosensitizer for sonodynamic therapy (SDT) was explored and illustrated for the first time. In addition, liposome-encapsulated artemether exhibited significantly enhanced sonodynamic anticancer activity. Our findings indicated that artemisinin derivatives may serve as a new kind of sonosensitizer for SDT.

Apoptosis of THP-1 Derived Macrophages Induced by Sonodynamic Therapy Using a New Sonosensitizer Hydroxyl Acetylated Curcumin

Curcumin is extracted from the rhizomes of the traditional Chinese herb Curcuma longa. Our previous study indicated curcumin was able to function as a sonosensitizer. Hydroxyl acylated curcumin was synthesized from curcumin to eliminate the unstable hydroxy perssad in our group. The potential use of Hydroxyl acylated curcumin as a sonosensitizer for sonodynamic therapy (SDT) requires further exploration. This study investigated the sonodynamic effect of Hydroxyl acylated curcumin on THP-1 macrophage. THP-1 macrophages were cultured with Hydroxyl acylated curcumin at a concentration of 5.0 μg/mL for 4 hours and then exposed to pulse ultrasound irradiation (0.5 W/cm2 with 1.0 MHz ) for 5 min, 10 min and 15 min. Six hours later, cell viability decreased significantly by CCK-8 assay. After ultrasound irradiation, the ratio of apoptosis and necrosis in SDT group was higher than that in control, Hydroxyl acylated curcumin alone and ultrasound alone. Moreover, the apoptotic rate was higher than necrotic rate with the flow cytometry analysis. Furthermore, Hydroxyl acylated curcumin-SDT induced reactive oxygen species (ROS) generation in THP-1 macrophages immediately after the ultrasound treatment while ROS generation was reduced significantly with the scavenger of singlet oxygen Sodium azide (NaN3). Hydroxyl acylated curcumin-SDT led to a conspicuous loss of mitochondrial membrane potential (MMP) compared with other groups, while MMP was increased significantly with the scavenger of singlet oxygen Sodium azide (NaN3), ROS inhibitor N-acetyl cysteine (NAC) and Mitochondrial Permeability Transition Pore (MPTP) inhibitor Cyclosporin A (CsA). The cytochrome C, cleaved-Caspase-9, cleaved-Caspase-3 and cleaved-PARP upregulated after SDT through Western blotting. These findings suggested that Hydroxyl acylated curcumin under low-intensity ultrasound had sonodynamic effect on THP-1 macrophages via generation of intracellular singlet oxygen and mitochondria-caspase signaling pathway, indicating that Hydroxyl acylated curcumin could be used as a novel sonosensitizer in SDT for atherosclerosis.

The Sonodynamic Effect of Curcumin on THP-1 Cell-Derived Macrophages

Curcumin is extracted from the rhizomes of the traditional Chinese herb Curcuma longa and has been proposed to function as a photosensitizer. The potential use of curcumin as a sonosensitizer for sonodynamic therapy (SDT) requires further exploration. This study investigated the sonodynamic effect of curcumin on macrophages, the pivotal inflammatory cells in atherosclerotic plaque. THP-1-derived macrophages were incubated with curcumin at a concentration of 40.7 μmol/L for 2 h and then exposed to pulse ultrasound irradiation (2 W/cm2 with 0.86 MHz) for 5–15 min. Six hours later, cell viability was decreased in cells that had been treated with ultrasound for 10 and 15 min. After ultrasound irradiation for 15 min, the ratio of apoptotic and necrotic cells in SDT group was higher than that in ultrasound group, and the ratio of apoptotic cells was higher than that of necrotic cells. Both loss of mitochondrial membrane potential and morphological changes of cytoskeleton were apparent 2 h after treatment with curcumin SDT. These findings support that curcumin had sonodynamic effect on THP-1-derived macrophages and that curcumin SDT could be a promising treatment for atherosclerosis.

SONODYNAMIC EFFECT OF BERBERINE ON MACROPHAGES

ObjectivesAtherosclerosis (AS) is the major contributing factor that results in acute cardiovascular events, which leading to the high mortality of cardiovascular diseases, which. The pathophysiological mechanism of atherosclerosis remains unknown....

Detection of sonoluminescence signals in a gel phantom in the presence of Protoporphyrin IX conjugated to gold nanoparticles

The particles in a liquid decrease the ultrasonic intensity threshold required for cavitation onset. In this study, a new nanoconjugate composed of Protoporphyrin IX and gold nanoparticles (Au–PpIX) was used as a nucleation site for cavitation. The nonradiative relaxation time of Protoporphyrin IX in the presence of gold nanoparticles is longer than the similar time without gold nanoparticles. The acoustic cavitation activity was investigated via recording of the integrated sonoluminescence signal in the wavelength range of 220–700nm in a gel phantom by a cooled charge coupled device (CCD) at different intensities of 1MHz ultrasound. In order to confirm these results, a chemical dosimetric method was utilized, too. The recorded sonoluminescence signal in the gel phantom containing Au–PpIX was higher than the other phantoms. These records have been confirmed by the chemical dosimetric data. Therefore, we anticipate that a new nanoconjugate composed of Protoporphyrin IX and gold nanoparticles can act as an efficient sonoluminescence agent and could be introduced as a novel sonosensitizer for sonodynamic therapy.