A Combined Approach Employing Chlorotoxin-Nanovectors and Low Dose Radiation To Reach Infiltrating Tumor Niches in Glioblastoma

Tamborini, Matteo; Locatelli, Erica; Rasile, Marco; Monaco, Ilaria; Rodighiero, Simona; Corradini, Irene; Franchini, Mauro Comes; Passoni, Lorena; Matteoli, Michela

doi:10.1021/acsnano.5b07375

Cited by 69 publications

(37 citation statements)

References 42 publications

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“…Nanoparticles were also shown to increase paclitaxel efficacy in a malignant glioma model [41]. In addition, nanoparticles could be used in combination with physical techniques, such as ultrasound therapy, photodynamic therapy or irradiation [42]. Focus ultrasound exposure was recently used to enhance temozolomide delivery to glioma [43].…”

Section: Discussionmentioning

confidence: 99%

Targeting the Potassium Channel Kv1.3 Kills Glioblastoma Cells

et al. 2017

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Background/Aims: Glioblastoma (GBM) is one of the most aggressive cancers, counting for a high number of the newly diagnosed patients with central nervous system (CNS) cancers in the United States and Europe. Major features of GBM include aggressive and invasive growth as well as a high resistance to treatment. Kv1.3, a potassium channel of the shaker family, is expressed in the inner mitochondrial membrane of many cancer cells. Inhibition of mitochondrial Kv1.3 was shown to induce apoptosis in several tumor cells at doses that were not lethal for normal cells. Methods: We investigated the expression of Kv1.3 in different glioma cell lines by immunocytochemistry, western blotting and electron microscopy and analyzed the effect of newly synthesized, mitochondria-targeted, Kv1.3 inhibitors on the induction of cell death in these cells. Finally, we performed in vivo studies on glioma bearing mice. Results: Here, we report that Kv1.3 is expressed in mitochondria of human and murine GL261, A172 and LN308 glioma cells. Treatment with the novel Kv1.3 inhibitors PAPTP or PCARBTP as well as with clofazimine induced massive cell death in glioma cells, while Psora-4 and PAP-1 were almost without effect. However, in vivo experiments revealed that the drugs had no effect on orthotopic brain tumors in vivo. Conclusion: These data serve as proof of principle that Kv1.3 inhibitors kills GBM cells, but drugs that act in vivo against glioblastoma must be developed to translate these findings in vivo.

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Section: Discussionmentioning

confidence: 99%

Targeting the Potassium Channel Kv1.3 Kills Glioblastoma Cells

et al. 2017

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“…Briefly, mice received a stereotaxically guided injection of 40,000 GL261 cells (20,000 cells/1 μl Tris HCl solution) into the primary motor cortex [11, 29, 30] using a Hamilton syringe. The GL261 cell solution was slowly delivered at a depth of 0.8–0.9 mm from the pial surface.…”

Section: Methodsmentioning

confidence: 99%

Progression of motor deficits in glioma-bearing mice: impact of CNF1 therapy at symptomatic stages

et al. 2017

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Glioblastoma (GBM) is the most aggressive type of brain tumor. In this context, animal models represent excellent tools for the early detection and longitudinal mapping of neuronal dysfunction, that are critical in the preclinical validation of new therapeutic strategies. In a mouse glioma model, we developed sensitive behavioral readouts that allow early recognizing and following neurological symptoms. We injected GL261 cells into the primary motor cortex of syngenic mice and we used a battery of behavioral tests to longitudinally monitor the dysfunction induced by tumor growth. Grip strength test revealed an early onset of functional deficit associated to the glioma growth, with a significant forelimb weakness appearing 9 days after tumor inoculation. A later deficit was observed in the rotarod and in the grid walk tasks. Using this model, we found reduced tumor growth and maintenance of behavioral functions following treatment with Cytotoxic Necrotizing Factor 1 (CNF1) at a symptomatic stage. Our data provide a detailed and precise examination of how tumor growth reverberates on the behavioral functions of glioma-bearing mice, providing normative data for the study of therapeutic strategies for glioma treatment. The reduced tumor volume and robust functional sparing observed in CNF1-treated, glioma-bearing mice strengthen the notion that CNF1 delivery is a promising strategy for glioma therapy.

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“…In addition to surgery and chemotherapy, radiotherapy is an important treatment in cancer therapy that is suitable for breast, 1,2 cervical, 3 lung 4-6 and brain 7,8 cancers. Despite recent efforts, radiotherapy fails to fully eradicate tumors due to inevitable damage to surrounding healthy tissues and the radiation insensitivity of some tumors.…”

Section: Introductionmentioning

confidence: 99%

Decorated ultrathin bismuth selenide nanosheets as targeted theranostic agents for in vivo imaging guided cancer radiation therapy

et al. 2017

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An efficient radiotherapeutic agent is synthesized using ultrathin two-dimensional 30-nm-wide and 2-nm-thick Bi 2 Se 3 nanosheets (NSs) as a radiosensitizer. Chitosan (CS) and RGD peptide are employed to enhance the radiotherapy efficiency and biocompatibility. The Bi 2 Se 3 -CS-RGD NSs exhibit excellent targeting ability to αvβ3 integrin-overexpressing cancer cells and potent radiosensitization efficiency with high stability. Detailed in vitro experiments show that the Bi 2 Se 3 -CS-RGD NSs enhance the sensitivity of HeLa cells to X-ray-induced cell death by inhibiting TrxR activities and activating downstream reactive oxygen species-mediated signaling pathways. In vivo experiments using intravenous or intratumor injection demonstrate that the Bi 2 Se 3 -CS-RGD NSs are more efficient tumor growth inhibitors compared to bare Bi 2 Se 3 NSs. The multifunctionality of the NSs enables the use of photoacoustic imaging and magnetic resonance imaging to examine their targeting ability and therapeutic effects, respectively. In addition, the RGD-decorated Bi 2 Se 3 NSs show much better in vivo biocompatibility and can be efficiently expelled from the body after 48 h post injection. This study reveals an effective and safe theranostic agent for next-generation cancer radiotherapy.

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A Combined Approach Employing Chlorotoxin-Nanovectors and Low Dose Radiation To Reach Infiltrating Tumor Niches in Glioblastoma

Cited by 69 publications

References 42 publications

Targeting the Potassium Channel Kv1.3 Kills Glioblastoma Cells

Targeting the Potassium Channel Kv1.3 Kills Glioblastoma Cells

Progression of motor deficits in glioma-bearing mice: impact of CNF1 therapy at symptomatic stages

Decorated ultrathin bismuth selenide nanosheets as targeted theranostic agents for in vivo imaging guided cancer radiation therapy

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