title: 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.
authors.affiliation: Division of Biophysics and Bioimaging, Ontario Cancer Institute, University Health Network and University of Toronto, Toronto, Ontario, M5G 2M9, Canada.
authors.forename: Arjen
authors.initials: A
authors.lastname: Bogaards
authors.forename: Abhay
authors.initials: A
authors.lastname: Varma
authors.forename: Kai
authors.initials: K
authors.lastname: Zhang
authors.forename: David
authors.initials: D
authors.lastname: Zach
authors.forename: Stuart K
authors.initials: SK
authors.lastname: Bisland
authors.forename: Eduardo H
authors.initials: EH
authors.lastname: Moriyama
authors.forename: Lothar
authors.initials: L
authors.lastname: Lilge
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Muller
authors.forename: Brian C
authors.initials: BC
authors.lastname: Wilson
mesh_terms: D000622:Aminolevulinic Acid / Q000737:chemistry; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001932:Brain Neoplasms / Q000473:pathology / Q000601:surgery / Q000628:therapy*; D002277:Carcinoma / Q000473:pathology / Q000601:surgery / Q000628:therapy*; D003952:Diagnostic Imaging; D004195:Disease Models, Animal; D005240:Feasibility Studies; D007091:Image Processing, Computer-Assisted; D008027:Light; D008297:Male; D008856:Microscopy, Fluorescence / Q000379:methods; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents / Q000627:therapeutic use; D011817:Rabbits; D011829:Radiation Dosage
chemical_list: D017319:Photosensitizing Agents; D000622:Aminolevulinic Acid