Fluorescence image-guided brain tumour resection with adjuvant metronomic photodynamic therapy: pre-clinical model and technology development

Abstract

Fluorescence-guided resection (FGR) and photodynamic therapy (PDT) have previously been investigated separately with the objectives, respectively, of increasing the extent of brain tumour resection and of selectively destroying residual tumour post-resection. Both techniques have demonstrated trends towards improved survival, pre-clinically and clinically. We hypothesize that combining these techniques will further delay tumour re-growth. In order to demonstrate technical feasibility, we here evaluate fluorescence imaging and PDT treatment techniques in a specific intracranial tumour model. The model was the VX2 carcinoma grown by injection of tumour cells into the normal rabbit brain. An operating microscope was used for white light imaging and a custom-built fluorescence imaging system with co-axial excitation and detection was used for FGR. PDT treatment light was applied by intracranially-implanted light emitting diodes (LED). The fluorescent photosensitizer used for both FGR and PDT was ALA-induced PpIX. For PDT, ALA (100 mg kg(-1)) and low light doses (15 and 30 J) were administered over extended periods, which we refer to as metronomic PDT (mPDT). Eighteen tumour bearing rabbits were divided equally into three groups: controls (no resection); FGR; and FGR followed by mPDT. Histological whole brain sections (H&E stain) showed primary and recurrent tumours. No bacteriological infections were found by Gram staining. Selective tumour cell death through mPDT-induced apoptosis was demonstrated by TUNEL stain. These results demonstrate that the combined treatment is technically feasible and this model is a candidate to evaluate it. Further optimization of mPDT treatment parameters (drug/light dose rates) is required to improve survival.

A Telemetric light delivery system for metronomic photodynamic therapy (mPDT) in rats

“…However, the extended residence of fibers in the brain is expected to cause serious complications arising from the use of percutaneous ports. Previous mPDT studies performed on small animals used compact, battery powered devices with fiber optics or implanted light sources for intracranial light delivery [19,20,24]. Although these devices have shown to be capable to administer mPDT for some days, battery powered devices still have limitations in size and light fluence.…”

“…It therefore has been suggested that PDT with a light dose below the necrotic threshold of brain tissue [18] administered during an extended time period can lead to selective apoptosis of tumor cells that have remained in the brain after surgical resection. This approach has been called mPDT and is under investigation by a number of centers [19][20][21][22].…”

Selective Photodetection and Photodynamic Therapy for Prostate Cancer through Targeting of Proteolytic Activity

“…This concept of repetitive PDT has been already studied in spheroids models, in vivo and in the clinic mostly for the treatment of brain cancer (35)(36)(37)(38)(39). According to these studies, the use of multiple sessions enhanced elimination of deep tumor cells infiltrating the surrounding brain.…”

The role of photodynamic therapy (PDT) physics

“…Studies have shown some efficacy in the treatment of a variety of malignant and premalignant conditions including head and neck cancer, 2,3 lung cancer, [4][5][6] mesothelioma, 7 Barrett's esophagus, 8,9 prostate, 10-12 and brain tumors. 9,[13][14][15] Unlike radiation therapy, PDT uses nonionizing radiation and can be administered repeatedly without cumulative long-term complications since it does not appear to target DNA.…”