Photo-immune therapy with liposomally formulated phospholipid-conjugated indocyanine green induces specific antitumor responses with heat shock protein-70 expression in a glioblastoma model

摘要

Glioblastoma (GBM) is the most common malignant brain tumor, and infiltrates into the surrounding normal brain tissue. Induction of a tumor-specific immune response is one of the best methods to obtain tumor-specific cytotoxicity. Photodynamic therapy (PDT) is known to effectively induce an antitumor immune response. We have developed a clinically translatable nanoparticle, liposomally formulated phospholipid-conjugated indocyanine green (LP-iDOPE), applicable for PDT. This nanoparticle accumulates in tumor tissues by the enhanced permeability and retention effect, and releases heat and singlet oxygen to injure cancer cells when activated by near infrared (NIR) light. We assessed the effectiveness of the LP-iDOPE system in brain using the rat 9L glioblastoma model. Treatment with LP-iDOPE and NIR irradiation resulted in significant tumor growth suppression and prolongation of survival. Histopathological examination showed induction of both apoptosis and necrosis and accumulation of CD8+ T-cells and macrophages/microglia accompanied by marked expressions of heat shock protein-70 (HSP70), which was not induced by mild hyperthermia alone at 45° C or an interleukin-2-mediated immune reaction. Notably, the efficacy was lost in immunocompromised nude rats. These results collectively show that the novel nanoparticle LP-iDOPE in combination with NIR irradiation can efficiently induce a tumor-specific immune reaction for malignant gliomas possibly by inducing HSP70 expression which is known to activate antigen-presenting cells through toll-like receptor signaling.