First autopsy analysis of the efficacy of intra-operative additional photodynamic therapy for patients with glioblastoma

Akimoto, Jiro; Fukami, Shinjiro; Suda, Tomohiro; Ichikawa, Makiko; Haraoka, Rei; Kohno, Michihiro; Shishido‐Hara, Yukiko; Nagao, Toshitaka; Kuroda, Masahiko

doi:10.1007/s10014-019-00351-0

Cited by 17 publications

(10 citation statements)

References 11 publications

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“…In preclinical studies, post-PDT inflammatory changes influence the antitumor adaptive immune response [ 51 , 52 , 53 ]. We also confirmed an acute inflammatory response post-PDT, labeling CD-68 macrophages; the invasion of myeloid cells by tumors was already reported in other preclinical and clinical studies [ 54 , 55 ]. Moreover, Vidyarthi et al demonstrated (using Kaplan–Meir survival plots) that patients with low M2 marker expression exhibited better survival rates, indicating that M2 targeting is an effective and promising strategy [ 56 ].…”

Section: Discussionsupporting

confidence: 89%

Targeting Glioblastoma-Associated Macrophages for Photodynamic Therapy Using AGuIX®-Design Nanoparticles

et al. 2023

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Glioblastoma (GBM) is the most difficult brain cancer to treat, and photodynamic therapy (PDT) is emerging as a complementary approach to improve tumor eradication. Neuropilin-1 (NRP-1) protein expression plays a critical role in GBM progression and immune response. Moreover, various clinical databases highlight a relationship between NRP-1 and M2 macrophage infiltration. In order to induce a photodynamic effect, multifunctional AGuIX®-design nanoparticles were used in combination with a magnetic resonance imaging (MRI) contrast agent, as well as a porphyrin as the photosensitizer molecule and KDKPPR peptide ligand for targeting the NRP-1 receptor. The main objective of this study was to characterize the impact of macrophage NRP-1 protein expression on the uptake of functionalized AGuIX®-design nanoparticles in vitro and to describe the influence of GBM cell secretome post-PDT on the polarization of macrophages into M1 or M2 phenotypes. By using THP-1 human monocytes, successful polarization into the macrophage phenotypes was argued via specific morphological traits, discriminant nucleocytoplasmic ratio values, and different adhesion abilities based on real-time cell impedance measurements. In addition, macrophage polarization was confirmed via the transcript-level expression of TNFα, CXCL10, CD-80, CD-163, CD-206, and CCL22 markers. In relation to NRP-1 protein over-expression, we demonstrated a three-fold increase in functionalized nanoparticle uptake for the M2 macrophages compared to the M1 phenotype. The secretome of the post-PDT GBM cells led to nearly a three-fold increase in the over-expression of TNFα transcripts, confirming the polarization to the M1 phenotype. The in vivo relationship between post-PDT efficiency and the inflammatory effects points to the extensive involvement of macrophages in the tumor zone.

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Section: Discussionsupporting

confidence: 89%

Targeting Glioblastoma-Associated Macrophages for Photodynamic Therapy Using AGuIX®-Design Nanoparticles

et al. 2023

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“…Moreover, RT may increase the antitumor response by promoting antigen presentation and T-cell activation [45]. 5-ALA PDT can activate an otherwise quiescent local immune response under certain circumstances [46][47][48][49]. PDT may induce vascular shutdown by destroying endothelial cells and the vascular basement membrane, resulting in oxygen deprivation.…”

Section: Discussionmentioning

confidence: 99%

DNA Strand Break Properties of Protoporphyrin IX by X-ray Irradiation against Melanoma

Hasegawa

Takahashi

Nagasawa

et al. 2020

IJMS

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Recent reports have suggested that 5-aminolevulinic acid (5-ALA), which is a precursor to protoporphyrin IX (PpIX), leads to selective accumulation of PpIX in tumor cells and acts as a radiation sensitizer in vitro and in vivo in mouse models of melanoma, glioma, and colon cancer. In this study, we investigated the effect of PpIX under X-ray irradiation through ROS generation and DNA damage. ROS generation by the interaction between PpIX and X-ray was evaluated by two kinds of probes, 3′-(p-aminophenyl) fluorescein (APF) for hydroxyl radical (•OH) detection and dihydroethidium (DHE) for superoxide (O2•-). •OH showed an increase, regardless of the dissolved oxygen. Meanwhile, the increase in O2•- was proportional to the dissolved oxygen. Strand breaks (SBs) of DNA molecule were evaluated by gel electrophoresis, and the enhancement of SBs was observed by PpIX treatment. We also studied the effect of PpIX for DNA damage in cells by X-ray irradiation using a B16 melanoma culture. X-ray irradiation induced γH2AX, DNA double-strand breaks (DSBs) in the context of chromatin, and affected cell survival. Since PpIX can enhance ROS generation even in a hypoxic state and induce DNA damage, combined radiotherapy treatment with 5-ALA is expected to improve therapeutic efficacy for radioresistant tumors.

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“…Additionally, given that 5-ALA PDT can activate an otherwise quiescent local immune response under certain circumstances [51][52][53][54], 5aai has the potential to further our efforts to "harness synergistic biology between radiation and immunotherapy" [55].…”

Section: Discussionmentioning

confidence: 99%

A New Treatment Opportunity for DIPG and Diffuse Midline Gliomas: 5-ALA Augmented Irradiation, the 5aai Regimen

Kast¹,

Michael

Sardi

et al. 2020

Brain Sciences

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Prognosis for diffuse intrinsic pontine glioma (DIPG) and generally for diffuse midline gliomas (DMG) has only marginally improved over the last ~40 years despite dozens of chemotherapy and other therapeutic trials. The prognosis remains invariably fatal. We present here the rationale for a planned study of adding 5-aminolevulinic acid (5-ALA) to the current irradiation of DIPG or DMG: the 5aai regimen. In a series of recent papers, oral 5-ALA was shown to enhance standard therapeutic ionizing irradiation. 5-ALA is currently used in glioblastoma surgery to enable demarcation of overt tumor margins by virtue of selective uptake of 5-ALA by neoplastic cells and selective conversion to protoporphyrin IX (PpIX), which fluoresces after excitation by 410 nm (blue) light. 5-ALA is also useful in treating glioblastomas by virtue of PpIX’s transfer of energy to O2 molecules, producing a singlet oxygen that in turn oxidizes intracellular DNA, lipids, and proteins, resulting in selective malignant cell cytotoxicity. This is called photodynamic treatment (PDT). Shallow penetration of light required for PpIX excitation and resultant energy transfer to O2 and cytotoxicity results in the inaccessibility of central structures like the pons or thalamus to sufficient light. The recent demonstration that keV and MeV photons can also excite PpIX and generate singlet O2 allows for reconsideration of 5-ALA PDT for treating DMG and DIPG. 5-ALA has an eminently benign side effect profile in adults and children. A pilot study in DIPG/DMG of slow uptitration of 5-ALA prior to each standard irradiation session—the 5aai regimen—is warranted.

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First autopsy analysis of the efficacy of intra-operative additional photodynamic therapy for patients with glioblastoma

Cited by 17 publications

References 11 publications

Targeting Glioblastoma-Associated Macrophages for Photodynamic Therapy Using AGuIX®-Design Nanoparticles

Targeting Glioblastoma-Associated Macrophages for Photodynamic Therapy Using AGuIX®-Design Nanoparticles

DNA Strand Break Properties of Protoporphyrin IX by X-ray Irradiation against Melanoma

A New Treatment Opportunity for DIPG and Diffuse Midline Gliomas: 5-ALA Augmented Irradiation, the 5aai Regimen

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