Photodynamic therapy of disseminated non-small cell lung carcinoma in a murine model

Abstract

Background and Objective Photodynamic therapy (PDT) of thoracic malignancies involving the pleural surfaces is an active area of clinical investigation. The present report aims to characterize a model for PDT of disseminated non-small cell lung carcinoma grown orthotopically in nude mice, and to evaluate PDT effect on tumor and normal tissues. Study Design H460 human non-small cell lung carcinoma (NSCLC) cells were injected percutaneously into the thoracic cavity of nude mice. HPPH-PDT (1 mg/kg, 24 h) was performed via the interstitial delivery (150 mW/cm) of 661 nm light to the thoracic cavity at fluences of 25-200 J/cm. Results H460 tumors exhibited exponential growth within the thoracic cavity consisting of diffuse, gross nodular disease within 9 days after intrathoracic injection. Tumor volume, measured by magnetic resonance imaging (MRI), was highly correlated with the aggregate tumor mass extracted from the corresponding animal. Intrathoracic PDT at fluences of ≥ 50 J/cm produced significant decreases in tumor burden as compared to untreated controls, however mortality increased with rising fluence. Accordingly, 50 J/cm was selected for MRI studies to measure intra-animal PDT effects. Tumor distribution favored the ventral (vs. dorsal), caudal (vs. cranial), and right (vs. left) sides of the thoracic cavity by MRI; PDT did not change this spatial pattern despite an overall effect on tumor burden. Histopathology revealed edema and fibrin deposition within the pulmonary interstitium and alveoli of the PDT-treated thoracic cavity, as well as occasional evidence of vascular disruption. Prominent neutrophil infiltration with a concomitant decline in the lymphocyte compartment was also noted in the lung parenchyma within 24 hours after PDT. Conclusion HPPH-PDT of an orthotopic model of disseminated NSCLC is both feasible and effective using intracavitary light delivery. We establish this animal model, together with the treatment and monitoring approaches, as novel and valuable methods for the pre-clinical investigation of intrathoracic PDT of disseminated pleural malignancies.

Fluence Rate Differences in Photodynamic Therapy Efficacy and Activation of Epidermal Growth Factor Receptor after Treatment of the Tumor-Involved Murine Thoracic Cavity

“…Fluence rate effects of intrathoracic PDT were investigated in our previously described murine model [ 24 ]. Disease was propagated by the percutaneous injection of H460 cells in the thoracic cavity and developed as disseminated bilateral intrathoracic masses that visibly ranged from pinpoint to mm-sized nodules.…”

“…In the studies reported here, we evaluated fluence rate effect on EGFR activation in tumor nodules of the PDT-treated murine thoracic cavity. Human tumor xenografts of non-small cell lung carcinoma (NSCLC) were grown as disseminated disease in the murine thoracic cavity [ 24 ]. In contrast to a single nodule of disease at either a subcutaneous or orthotopic site, our intrathoracic model recapitulates the multinodular and diffuse spread of pleural malignancies that are treated in clinical trials of pleural PDT.…”

Utility and Applications of Orthotopic Models of Human Non‐Small Cell Lung Cancer (NSCLC) for the Evaluation of Novel and Emerging Cancer Therapeutics

“…This problem is circumvented by using bioluminescence imaging, computed tomography (CT), and magnetic resonance imaging (MRI) (Grossman et al, 2011; Mordant et al, 2011; Justilien et al, 2012; Liu et al, 2012; Madero-Visbal et al, 2012;). Lung orthotopic tumors formed by cancer cells transduced to express the firefly luciferase gene can be monitored for progression, invasion, and metastasis in vivo using the IVIS Spectrum imaging device and associated protocols.…”

Devices based on light emitting fabrics dedicated to PDT preclinical studies

“…As visible light depth penetration within biological tissues is limited to few millimeters [16], external illumination are mostly dedicated to superficial lesions or in vitro studies. External illuminations can be performed in intracavitary locations with optical fiber devices (panels, balloons or cylindrical diffuser) [12,[17][18][19][20][21] and in topical locations with frontal end optical fibers, LASER beams or LED panels [22][23][24][25][26].…”