Lactate-Loaded Nanoparticles Induce Glioma Cytotoxicity and Increase the Survival of Rats Bearing Malignant Glioma Brain Tumor

Abstract

A glioblastoma is an aggressive form of a malignant glial-derived tumor with a poor prognosis despite multimodal therapy approaches. Lactate has a preponderant role in the tumor microenvironment, playing an immunoregulatory role as well as being a carbon source for tumor growth. Lactate homeostasis depends on the proper functioning of intracellular lactate regulation systems, such as transporters and enzymes involved in its synthesis and degradation, with evidence that an intracellular lactate overload generates metabolic stress on tumor cells and tumor cell death. We propose that the delivery of a lactate overload carried in nanoparticles, allowing the intracellular release of lactate, would compromise the survival of tumor cells. We synthesized and characterized silica and titania nanoparticles loaded with lactate to evaluate the cellular uptake, metabolic activity, pH modification, and cytotoxicity on C6 cells under normoxia and chemical hypoxia, and, finally, determined the survival of an orthotopic malignant glioma model after in situ administration. A dose-dependent reduction in metabolic activity of treated cells under normoxia was found, but not under hypoxia, independent of glucose concentration. Lactated-loaded silica nanoparticles were highly cytotoxic (58.1% of dead cells) and generated significant supernatant acidification. In vivo, lactate-loaded silica nanoparticles significantly increased the median survival time of malignant glioma-bearing rats (p = 0.005) when administered in situ. These findings indicate that lactate-loaded silica nanoparticles are cytotoxic on glioma cells in vitro and in vivo.

Melatonin in Combination with Albendazole or Albendazole Sulfoxide Produces a Synergistic Cytotoxicity against Malignant Glioma Cells through Autophagy and Apoptosis

“…Future perspectives include the evaluation in an in vivo model of orthotopic malignant glioma, which will allow us to evaluate the impact of the combined administration of these drugs on molecular markers, tumor eradication, and survival time, given that survival is a parameter of great importance to determine the therapeutic efficacy of a drug in the management of GB [ 64 ]. Potential in vivo studies could be based on the use of classical immunocompetent orthotopic malignant glioma models, as we have previously reported with C6 cells implanted in the brain parenchyma of Wistar rats [ 65 ], or as the model performed with GL621 mouse glioma cells in C57BL/6 mice [ 66 ].…”

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“…After that, the lactate content was determined by the colorimetric reaction of lactate with iron­(III) chloride hexahydrate, as reported by Borshchevskaya et al The incubation solution was allowed to stand; the supernatant (250 μL) was mixed with ferric chloride solution (0.2 w/v %, 2 mL); and then the characteristic UV absorption peak of the test solution was determined at 407 nm. Finally, the content of lactic acid was calculated. − …”

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“…Therefore, innovative biomarkers and more specific targeted treatments become increasingly important to improve the survival rate of patients with gliomas. Histologically, gliomas are glial-derived tumors [ 4 ], which share characteristics of normal glial or neural precursor and stem cells based on the molecular similarities [ 5 ]. Thus, molecules enriched in the brain are most likely to be specific targets for glioma treatments.…”