5-aminolevulinic acid photodynamic therapy for the treatment of high-grade gliomas

Abstract

Photodynamic therapy (PDT) is a two-step treatment involving the local administration of a photosensitive agent followed by its activation at a specific light wavelength. PDT has been approved by the United States Food and Drug Administration (FDA) for the treatment of premalignant and malignant diseases, such as actinic keratoses, Barrett's esophagus, esophageal cancers, and endobronchial non-small cell lung cancers, as well as for the treatment of choroidal neovascularization. In oncology, clinical trials are currently underway to demonstrate PDT efficacy against a number of malignancies that include glioblastoma (GBM) and other brain tumors. Both photosensitizers and photosensitizing precursors have been used for PDT. Photofrin and Visudyne are photosensitizers with FDA approval for PDT of high-grade dysplasia in Barrett's esophagus and subfoveal choroidal neovascularization, respectively. 5-aminolevulinic acid (5-ALA), an intermediate in the heme synthesis pathway, is a photosensitizing precursor with FDA approval for PDT of actinic keratosis and fluorescence-guided visualization of malignant tissue during glioma surgery. In this review, the history and current use of 5-ALA PDT for the treatment of high-grade gliomas (HGGs) will be discussed.

Photodynamic Therapy for the Treatment of Glioblastoma

“…triggering necrosis, apoptosis, local ischemia (due to occlusion of neoplastic vessels) as well as subsequent immunological reactions (14). Singlet oxygen diffuses over short distances (i.e., ∼0.02-1.00 µm) and has a limited lifespan (i.e., ∼0.04-4.0 µs) contributing to local tumor ablation while minimizing risk of damage to adjacent normal tissue (15). The type of photosensitizer and photo-activation determines the specific intracellular components affected as well as the degree and type of damage incurred by those components.…”

“…Photo-irradiation with longer wavelength light is preferred because it penetrates more deeply and delivers sufficiently energetic photons to activate the photosensitizer. Given the excitation peaks of clinically available photosensitizers and the limitations of photon propagation through biological tissues, PDT generally utilizes wavelengths between ∼400 and 900 nm, with an optimal window of 600-800 nm (15). PDT stimulation may be applied in a continuous or pulsed fashion (14), with consideration that pulsed delivery may facilitate tumor reoxygenation between pulses.…”

“…They are usually activated by wavelengths >600 nm and are more potent in generating singlet oxygen. Chlorins (talaporfin sodium and temoporfin) and 5-Aminolevulinic acid (5-ALA) are examples of second-generation photosensitizers (15).…”

Clinical Trials and Basic Research in Photodynamic Diagnostics and Therapies from the Center for Laser Diagnostics and Therapy in Poland

“…5‐ALA was approved by the FDA for intraoperative fluorescence imaging in 2017, and the combination of 5‐ALA fluorescence‐guided imaging of gliomas with surgery has improved patient outcome (7,15). Furthermore, 5‐ALA is in clinical trial for PDT on inoperable high‐grade gliomas and intraoperative resection cavities (16). There are also currently molecular and clinical studies of metronomic PDT for glioma treatment, analogous to metronomic chemotherapy (17,18).…”

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

“…5-ALA also functions in photodynamic therapy (PDT) in that light activation at~410 or 635 nm of the selectively accreted PpIX generates reactive oxygen (singlet oxygen molecules, 1 O 2 and others) that in turn causes cytotoxicity to glioma cells or any other cell that has preferentially taken up 5-ALA [15,16]. In PDT, photon energy is low, non-tissue self-destructs.…”