Defining the therapeutic window of vertebral photodynamic therapy in a murine pre-clinical model of breast cancer metastasis using the photosensitizer BPD-MA (Verteporfin)

Abstract

Breast cancer is known to cause metastatic lesions in the bone, which can lead to skeletal-related events. Currently, radiation therapy and surgery are the treatment of choice, but the success rate varies and additional adjuncts are desirable. Photodynamic therapy (PDT) has been applied successfully as a non-radiative treatment for numerous cancers. Earlier work has shown that the athymic rat model is suitable to investigate the effect of PDT on bone metastasis and benzoporphyrin-derivative monoacid ring A (BPD-MA; verteporfin) has been shown to be a selective photosensitizer. The aim of this study was to define the therapeutic window of photosensitizer with regard to drug and light dose. Human breast carcinoma cells (MT-1)-stable transfected with the luciferase gene-were injected intra-cardiacally into athymic rats. At 14 days, the largest vertebral lesion by bioluminescence imaging was targeted for single treatment PDT. A drug escalating-de-escalating scheme was used (starting drug dose and light energy of 0.2 mg/kg and 50 J, respectively). Outcomes included 48 h post-treatment bioluminescence of remaining viable tumour, histomorphometric assessment of tumour burden, and neurologic evaluation. The region of effect by bioluminescence and histology increased with increasing drug dose and light energy. A safe and effective drug-light dose combination in this model appears to be 0.5 mg/kg BPD-MA and applied light energy of less than 50 J for the thoracic spine and 1.0 mg/kg and 75 J for the lumbar spine. For translation to clinical use, it is an advantage that BPD-MA (verteporfin), a second-generation photosensitizer, is already approved to treat age-related macular degeneration. Overall, PDT represents an exciting potential new minimally-invasive local, safe and effective therapy in the management of patients with spinal metastases.

Photodynamic Therapy with Indocyanine Green Injection and Near-Infrared Light Irradiation Has Phototoxic Effects and Delays Paralysis in Spinal Metastasis

“…13,14 Although PDT for spinal metastasis has been studied experimentally, [15][16][17] it has not yet been clinically applied.…”

Photodynamic Therapy in Spinal Metastases: A Qualitative Analysis of Published Results

“…Three appeared to be potentially relevant but were excluded on closer examination because they were review articles. Four studies [21][22][23][24] that met the inclusion criteria were extracted for more detailed evaluation. All 4 included studies were conducted in mice models.…”

“…A study by Akens et al 22 examined varying light and drug doses, as well as the therapeutic window at which PDT would maximize treatment effect and minimize side effects in a rat model of metastatic breast cancer. It was determined that a benzoporphyrin derivative monoacid dose of 0.5 mg/kg and a light dose of 50 J for thoracic vertebrae and 75 J for lumbar vertebrae was most effective in ablating tumor tissue while minimizing damage to the spinal cord.…”

“…It was determined that a benzoporphyrin derivative monoacid dose of 0.5 mg/kg and a light dose of 50 J for thoracic vertebrae and 75 J for lumbar vertebrae was most effective in ablating tumor tissue while minimizing damage to the spinal cord. 22,26 Won et al 23 published a study demonstrating a bone-enhancing effect provided by PDT on healthy vertebrae. In this study, the effects of PDT on the structural integrity and strength of the spine was evaluated in healthy Wistar rats both 1 and 6 weeks after treatment.…”

Mesh Morphing and Response Surface Analysis: Quantifying Sensitivity of Vertebral Mechanical Behavior

“…First is that there is some degree of arbitrariness in the deformations used to parameterize the geometry, although our choices were informed by an understanding of the anatomy and biomechanics of the vertebra. 2,12,23,46 Ideally morphometric data in which the nature and magnitude of the physiologic variations in shape would guide the deformations, however, such information is not available for the rat caudal vertebra.…”