sinoporphyrin-sodium and Glioma

The aim of the present study was to explore the antitumor effects of sinoporphyrin sodium (DVDMS)‑mediated photodynamic therapy (PDT) and sonodynamic therapy (SDT) in glioma, and to reveal the underlying mechanisms. The uptake of DVDMS by U‑118 MG cells was detected by flow cytometry (FCM). A 630‑nm semiconductor laser and 1‑MHz ultrasound were used to perform PDT and SDT, respectively. Cell proliferation and apoptosis were evaluated using the Cell Counting Kit‑8 assay, FCM and Hoechst 33258 staining, respectively. Western blot analysis was used to detect protein expression and phosphorylation levels. BALB/c nude mice were used to establish a xenograft model of U‑118 MG cells. DVDMS was injected intravenously and PDT and SDT were performed 24 h later. An in vivo imaging system was used to evaluate the fluorescence of DVDMS, to measure tumor sizes, and to evaluate the therapeutic effects. The uptake of DVDMS by U‑118 MG cells was optimal after 4 h. PDT and SDT following DVDMS injection significantly inhibited the proliferation and increased apoptosis of glioma cells in vitro (P<0.05, P<0.01) respectively. In vivo, the fluorescence intensity of DVDMS was lower in the PDT and SDT groups compared with the DVDMS group, while tumor cell proliferation and weight were lower in the PDT and SDT groups than in the control group (P<0.05, P<0.01). However, there was no significant difference when laser, ultrasound or DVDMS were applied individually, compared with the control group. Hematoxylin and eosin staining suggested that both PDT and SDT induced significant apoptosis and vascular obstruction in cancer tissues. DVDMS‑mediated PDT and SDT inhibited the expression levels of proliferating cell nuclear antigen (PCNA) and Bcl‑xL, increased cleaved ‑caspase 3 levels, and decreased the protein phosphorylation of the PI3K/AKT/mTOR signaling pathway. Changes in the expression of PCNA, and Bcl‑xL and in the levels of cleaved‑caspase 3 were partly reversed by N‑acetyl‑L‑cysteine, a reactive oxygen species (ROS) scavenger. Similar results were obtained with FCM. DVDMS‑mediated PDT and SDT inhibited glioma cell proliferation and induced cell apoptosis in vitro and in vivo, potentially by increasing the generation of ROS and affecting protein expression and phosphorylation levels.

Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Combined Modality Therapy; Flow Cytometry; Glioma; Humans; Lasers, Semiconductor; Mice; Photochemotherapy; Porphyrins; Reactive Oxygen Species; Ultrasonic Therapy; Xenograft Model Antitumor Assays

Malignant glioma is one of the most common and severe brain diseases, which is extremely hard to treat due to the presence of the blood-brain barrier (BBB). Ultrasound (US) triggered sonodynamic therapy (SDT) is rapidly emerging as a noninvasive cancer treatment which benefits from the deep penetration of ultrasound waves. It has been reported that US can reversibly open the BBB for the enhancement of drug delivery. Therefore, a few researchers have paid attention to sonodynamic therapy for the in situ treatment of gliomas. Herein, we report the augmentation of SDT efficacy with the use of a combination of ultrasound-targeted microbubble destruction (UTMD) and iRGD modified DVDMS liposome (iRGD-Lipo-DVDMS), in which the sonoactivated sensitizer DVDMS (also called sinoporphyrin sodium) is loaded into the targeting liposomes and the sonodynamic effect is shown to boost the reactive oxygen species formation in response to focused US exposure. By using a strategy where the treatment was repeated twice with a five-day interval in between, where UTMD was first applied followed by iRGD-DVDMS injection and then focused US exposure, the orthotopically implanted C6 gliomas were greatly suppressed. Additionally, the median survival time increased to 40 days compared to 15 days in the control, 19 days in free DVDMS-SDT, and 24 days in general Lipo-DVDMS-SDT. Such targeted iRGD-Lipo-DVDMS mediated SDT also alleviated the body weight loss of tumor bearing mice because of the injury caused by orthotopic implantation, showing outstanding anti-glioma efficacy. After BBB opening with UTMD, the iRGD modified liposomes showed enhanced tumor targeting ability compared to the ones without iRGD modification, both in vivo and in vitro. The iRGD-Lipo-DVDMS exhibited significantly improved drug accumulation in monolayer cells, 3D tumor spheroids and transplanted C6 tumors, thus causing significant glioma cell apoptosis. Moreover, the developed targeting nanosonosensitizer (referred to as iRGD-Lipo-DVDMS) showed good in vivo biocompatibility and was promising in fluorescence image guided sonodynamic cancer therapy. Taken together, the established platform has considerable potential to enable the targeted delivery of sonodynamic treatment and would be an alternative strategy for glioma treatment.

Topics: Animals; Apoptosis; Biocompatible Materials; Blood-Brain Barrier; Cell Line, Tumor; Glioma; Liposomes; Mice; Microbubbles; NIH 3T3 Cells; Oligopeptides; Porphyrins; Reactive Oxygen Species; Sonication; Spheroids, Cellular; Tissue Distribution; Transplantation, Homologous; Ultrasonography

Glioma is the most frequent primary brain tumour of the central nervous system. Its high aggressiveness and deep-seated brain lesion make it a great challenge to develop a non-invasive, precise and effective treatment approach. Here, we report a multifunctional theranostic agent that can integrate imaging and therapy into a single nano-platform for imaging-guided sonodynamic therapy (SDT). The SDT agents were fabricated by encapsulation of sinoporphyrin sodium (DVDMS) chelating with manganese ions into nanoliposomes (DVDMS-Mn-LPs). DVDMS-Mn-LPs are physiologically stable and biologically compatible, and they can produce singlet oxygen upon ultrasound irradiation to kill cancer cells. Both cell and animal studies demonstrated that SDT with DVDMS-Mn-LPs can significantly improve the antitumour growth efficiency even in the presence of skull. In addition, DVDMS-Mn-LPs are good for MR and fluorescence imaging. Thus, DVDMS-Mn-LPs reported here may provide a promising strategy for imaging-guided modality for glioma treatment.

Topics: Animals; Apoptosis; Cell Line, Tumor; Contrast Media; Fluorescence; Glioma; Humans; Magnetic Resonance Imaging; Mice; Photochemotherapy; Porphyrins; Theranostic Nanomedicine; Ultrasonic Therapy