Chavarria Víctor, Ortiz-Islas Emma, Salazar Alelí, Pérez-de la Cruz Verónica, Espinosa-Bonilla Alejandra, Figueroa Rubén, Ortíz-Plata Alma, Sotelo Julio, Sánchez-García Francisco Javier, Pineda Benjamín
Neuroimmunology and Neuro-Oncology Unit, Instituto Nacional de Neurología y Neurocirugía (INNN), Mexico City 14269, Mexico.
Laboratorio de Inmunorregulación, Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City 11340, Mexico.
Pharmaceutics. 2022 Jan 29;14(2):327. doi: 10.3390/pharmaceutics14020327.
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 ( = 0.005) when administered in situ. These findings indicate that lactate-loaded silica nanoparticles are cytotoxic on glioma cells in vitro and in vivo.
胶质母细胞瘤是一种侵袭性恶性胶质来源肿瘤，尽管采用了多模式治疗方法，其预后仍然很差。乳酸在肿瘤微环境中起主要作用，具有免疫调节作用，同时也是肿瘤生长的碳源。乳酸稳态取决于细胞内乳酸调节系统的正常功能，如参与其合成和降解的转运蛋白和酶，有证据表明细胞内乳酸过载会给肿瘤细胞带来代谢压力并导致肿瘤细胞死亡。我们提出，载有乳酸的纳米颗粒所携带的乳酸过载，若能使乳酸在细胞内释放，将会损害肿瘤细胞的存活。我们合成并表征了负载乳酸的二氧化硅和二氧化钛纳米颗粒，以评估其在常氧和化学性低氧条件下对C6细胞的细胞摄取、代谢活性、pH调节和细胞毒性，最后确定原位给药后原位恶性胶质瘤模型的存活率。在常氧条件下发现处理过的细胞代谢活性呈剂量依赖性降低，但在低氧条件下未发现，且与葡萄糖浓度无关。负载乳酸的二氧化硅纳米颗粒具有高度细胞毒性（58.1%的死亡细胞）并导致上清液显著酸化。在体内，原位给药时，负载乳酸的二氧化硅纳米颗粒显著延长了荷恶性胶质瘤大鼠的中位生存时间（P = 0.005）。这些发现表明，负载乳酸的二氧化硅纳米颗粒在体外和体内对胶质瘤细胞均具有细胞毒性。
