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

Abstract

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.

Photohyperthermal therapy using liposomally formulated indocyanine green for feline nasal lymphoma: A case report

“…It is proposed that continuous treatment is required for long-term remission. It was recently reported that the antitumour effect of the PHT/ICG-Lipo combination therapy was associated with an immunological mechanism (20). According to a report into using immunotherapy with programmed death (PD)-ligand 1 to treat a tumour, the tumour size temporarily increased and subsequently decreased (21).…”

Photodynamic Therapy for the Treatment of Glioblastoma

“…Activated CD8 + T cells actively surveil the body for neoplastic cells and induce apoptosis whenever tumor cells are encountered, thereby providing longterm tumor control. Therefore, ICD induced by PDT has the potential to stimulate immune activation and surveillance, contributing to long term tumor control is observed in preclinical models (63,(66)(67)(68)(69).…”

Hyperthermia treatment advances for brain tumors

“…Photodynamic therapy (PDT) is a therapeutic approach involving the administration of a photosensitizer which upon the application of light, produces cytotoxic levels of ROS and triggers antitumor immune responses [148,231]. Most of the photosensitizers such as protoporphyrin IX (PpIX), 5,10,15,20tetrakis(3-hydroxyphenyl) chlorin (mTHPC) and photofrin are excited with visible spectrum light which lacks the penetrating properties of NIR light [148,232,233].…”

“…UCNP have been utilized for PTT and PDT of GBM after NIR irradiation exhibiting pronounced antitumor effects in vitro and in vivo [206,235]. Moreover, some researchers have utilized indocyanine (ICG) conjugated liposomal and silk fibroin nanoparticles that do not possess any light emitting properties coupled with NIR spectrum light and have reported substantial PDT/PTT effects in rodent GBM models without the use of UCNP or visible light application [221,231].…”