sinoporphyrin-sodium and Breast-Neoplasms

Sonodynamic therapy (SDT), wherein focused ultrasound is used to guide the site-specific delivery of nano-sonosensitizers and trigger profound sono-damage, has great potential in cancer theranostics. The development of nanosensitizers with high sono-activatable efficiency and good biosafety is however challenging.

Topics: Animals; Biocompatible Materials; Breast Neoplasms; Cell Death; Cell Line; Cell Proliferation; Drug Liberation; Endocytosis; Exosomes; Female; Humans; Hydrogen-Ion Concentration; Lung Neoplasms; Mice, Inbred BALB C; Nanoparticles; Neoplasms; Porphyrins; Singlet Oxygen; Tissue Distribution; Ultrasonic Therapy

Anti-microtubule therapy represents one of the most strategic cancer therapeutics. Tublin inhibitor such as paclitaxel (PTX) is well known to disturb the dynamic nature of microtubules, being considered as the first-line drug for various malignancies. However, PTX does not show favorable clinical outcomes due to serious systemic toxicities and low selectivity. The development of PTX delivery systems and combinational therapies has been conducted to enhance PTX efficacy with poorly defined mechanisms. Herein, we introduced a reactive oxygen species producible composite liposome based on a new photosensitizer sinoporphyrin sodium (DVDMS) to enhance the therapeutic effect of PTX through photochemical stimulation, and more importantly, the pivotal molecular regulation mechanisms were specifically explored. Compared with DVDMS-liposome (DL) or PTX-liposome (PL), the composite liposome DVDMS-PTX-liposome (PDL) exhibited a superior anti-tumor advantage following laser irradiation against MCF-7 breast cancer. The localized PTX release after PDL administration greatly decreased the drug dosage and laser power required, leading to much higher safety and lower costs. In vitro, the combined treatment significantly suppressed cell viability and potentiated cell apoptosis. The apoptotic central regulator Mcl-1 as a favorable target, was evaluated in association with photochemically enhanced sensitivity to anti-tubulin chemotherapeutics. Phosphorylation of Mcl-1 led to its direct degradation with the proteasome system, making it relatively unstable and potentiating cell death resulting from photochemical synergy via PDL plus laser irradiation. Further, a decrease in ATP production and glycolysis after PDL plus laser would prevent the possible energy-switch and apoptosis-escape by PTX alone treatment, thereby resulted in increased cell death in combinational therapy. Systemic administration of PDL followed by in vivo photochemotherapy achieved significantly improved therapeutic effects compared to either alone. And, the intrinsic fluorescence of DVDMS facilitated real-time imaging of PDL in tumors. Therefore, the present strategy with details at the molecular regulation could be a promising platform for antitublin chemotherapeutics.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Breast Neoplasms; Energy Metabolism; Female; Humans; Liposomes; MCF-7 Cells; Mice, Inbred BALB C; Mice, Nude; Mitochondria; Paclitaxel; Photosensitizing Agents; Porphyrins

We previously demonstrated that the photosensitizer sinoporphyrin sodium (DVDMS) mediated photodynamic therapy (PDT) had potential advantages in inhibiting tumor growth and metastasis. However, details regarding the mechanism of cell migration inhibition remain unclear. Therefore, in this study, we aimed to investigate the effects of DVDMS-PDT on F-actin filaments, cell migration, apoptotic response and the possible interactions between them in human breast cancer MDA-MB-231 cells.. The cell viability was evaluated by MTT and Guava ViaCount assays. The subcellular localization of DVDMS and reactive oxygen species (ROS) generation were analyzed by fluorescence microscope and flow cytometry. FITC-phalloidin was used to evaluate the changes of F-actin filaments. Cell migration was analyzed by scratch assay and Transwell assay. Cell apoptosis was determined by nuclear TUNEL staining and Annexin V-PE/7-AAD assay. Jasplakinolide, an F-actin stabilizer, was applied to dissect the influences of F-actin filaments disruption on cell migration and apoptosis.. DVDMS-PDT significantly suppressed cell proliferation, promoted early apoptotic response, triggered collapse of F-actin filaments and inhibited cell migration in MDA-MB-231 cells. Cell migration significantly increased when cells were pretreated with F-actin stabilizer jasplakinolide after PDT, while cell apoptosis was not obviously affected. Moreover, ROS was a key factor in causing collapse of F-actin filaments.. We demonstrated that DVDMS-PDT triggered cell apoptosis and collapse of F-actin filaments through the induction of ROS in MDA-MB-231 cells. F-actin filaments contributed to cell migration but produced no obvious effect on cell apoptosis.

Topics: Actin Cytoskeleton; Actins; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Humans; Photochemotherapy; Photosensitizing Agents; Porphyrins; Reactive Oxygen Species; Treatment Outcome

Sono-photodynamic therapy (SPDT) is a promising anti-cancer strategy. Briefly, SPDT combines ultrasound and light to activate sensitizers that produce mechanical, sonochemical and photochemical activities. Sinoporphyrin sodium (DVDMS) is a newly identified sensitizer that shows great potential in both sonodynamic therapy (SDT) and photodynamic therapy (PDT). In this study, we primarily evaluated the combined effects of SDT and PDT by using DVDMS on breast cancer both in vitro and in vivo. In vitro, DVDMS-SPDT elicits much serious cytotoxicity compared with either SDT or PDT alone by MTT and colony formation assays. 2',7'-Dichlorodihydrofluo-rescein-diacetate (DCFH-DA) and dihydroethidium (DHE) staining revealed that intracellular reactive oxygen species (ROS) were significantly increased in groups given combined therapy. Terephthalic acid (TA) method and FD500-uptake assay reflected that cavitational effects and cell membrane permeability changes after ultrasound irradiation were also involved in the enhancement of combination therapy. In vivo, DVDMS-SPDT markedly inhibits the tumor volume and tumor weight growth. Hematoxylin-eosin staining and immunohistochemistry analysis show DVDMS-SPDT greatly suppressed tumor proliferation. Further, DVDMS-SPDT significantly inhibits tumor lung metastasis in the highly metastatic 4T1 mouse xenograft model, which is consistent well with the in vitro findings evaluated by transwell assay. Moreover, DVDMS-SPDT did not produces obvious effect on body weight and major organs in 4T1 xenograft model. The results suggest that by combination SDT and PDT, the sensitizer DVDMS would produce much better therapeutic effects, and DVDMS-SPDT may be a potential strategy against highly metastatic breast cancer.

Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Female; Humans; In Vitro Techniques; Mice; Mice, Inbred BALB C; Photochemotherapy; Porphyrins

Sinoporphyrin sodium (DVDMS) is a newly identified photosensitizer that was isolated from Photofrin. Experimental and clinical results have demonstrated that repeated application of PDT greatly improved the therapeutic efficacy. Here, we comparatively studied two kinds of photodynamic therapy (PDT) strategies by using DVDMS (2mg/kg) in murine breast cancer 4T1 xenograft model to provide evidence which strategy exerts a better antitumor effect. Regimen (1): DVDMS was injected one time into tumor-bearing mice, which were then repeatedly exposed to 50J/cm(2) light 24h, 30h and 36h later. Regimen (2): DVDMS was injected 3 times and mice exposed to 50J/cm(2) light 24h after each injection, with 5days intervals between each DVDMS injection. On day 21 after the tumor cell injection, in regimen (1) the tumor volume inhibition ratio was reached to 85.75±7.60%. While at the same day the inhibition ratio was 65.74±8.64% of regimen (2). Additionally, regimen (1) appeared to more effectively initiate tumor tissue destruction and cancer cell apoptosis, inhibit lung metastasis, suppress cancer cell proliferation and angiogenesis. Moreover, no obvious effect on body weight and other side effects were observed in the treated mice. These results suggest that regimen (1) might be a potentially efficient strategy against breast cancer.

Topics: Animals; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Female; Immunohistochemistry; Light; Lung Neoplasms; Mice; Mice, Inbred BALB C; Microscopy, Fluorescence; Neovascularization, Pathologic; Photochemotherapy; Photosensitizing Agents; Porphyrins; Transplantation, Homologous

Photodynamic therapy (PDT) is an emerging theranostic modality for various cancers and diseases. Photosensitizers are critical components for PDT. Sinoporphyrin sodium, referred to as DVDMS, is a newly identified photosensitizer that was isolated from Photofrin. Here, we evaluated the effects of DVDMS-mediated PDT (DVDMS-PDT) on tumor cell proliferation and metastasis in the highly metastatic 4T1 cell line and a mouse xenograft model. DVDMS-PDT elicited a potent phototoxic effect in vitro, which was abolished using the reactive oxygen species (ROS) scavenger N-acetylcysteine. In addition, DVDMS-PDT effectively inhibited the migration of 4T1 cells in scratch wound-healing and transwell assays. Using an in vivo mouse model, DVDMS-PDT greatly prolonged the survival time of tumor-bearing mice and inhibited tumor growth and lung metastasis, consistent with in vitro findings. PDT with DVDMS had a greater anti-tumor efficacy than clinically used Photofrin. Moreover, preliminary toxicological results indicate that DVDMS is relatively safe. These results suggest that DVDMS is a promising sensitizer that warrants further development for use in cancer treatment with PDT or other sensitizing agent-based therapies.

Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Female; Mice; Mice, Inbred BALB C; Photochemotherapy; Photosensitizing Agents; Porphyrins