Radiotherapy vs. photodynamic therapy: a comparison of antitumor effects and pulmonary toxicity in preclinical models

Interstitial lung disease (ILD) and lung cancer are often associated, and ILD-associated lung cancer is a difficult condition to treat. Radiotherapy (RTx) is one of a standard therapeutic modalities for lung cancer, but pre-existing ILD is known to be a significant risk factor for developing severe radiation pneumonitis (RP) after treatment. In this context, there is a demand for alternative treatment modalities for ILD-associated localized lung cancer. Photodynamic therapy (PDT) is a minimally invasive treatment modality for lung cancer that can be performed endoscopically. In this study, we investigated proof-of-concept animal studies comparing RTx vs. PDT for (I) anti-tumor effects in a mouse xenograft model; and (II) pulmonary toxicity in a rat ILD model.

For the mouse tumor study, NCr-Foxn1nu athymic mice were subcutaneously inoculated with A549 or H460 human lung cancer cells to unilateral thigh and followed for growth until 8-12 mm sized. Ultrasmall nanostructured nanoparticle porphylipoprotein (PLP) was used in this study. The mice were divided into three intervention groups; control, RTx, and PDT. RTx group received a single 20 Gy local irradiation, while PDT group received an intravenous PLP (4 mg/kg) 24 hours before treatment, followed by laser ablation (671 nm) at 100 J/cm². For the rat ILD study, Sprague-Dawley immunocompetent rats were given an intratracheal single dose of bleomycin (BLM; 2 mg/kg) or vehicle control, and were followed up for 3 weeks to develop ILD. RTx group received a single 20 Gy irradiation, while PDT group had PLP administration (4 mg/kg), laser fiber delivered to the left lung base under computed tomography (CT) guidance with mechanical ventilation support and PDT performed at 100 J/cm². Chest CT was evaluated monthly and an autopsy was done after 1- or 3-month follow-up.

In the mouse xenograft model, PLP biodistribution showed the best tumor-to-contralateral background muscle ratio at 24 hours post-injection. In day 7, both RTx and PDT showed a significant tumor volume difference in A549 and H460 xenografts over control, while PDT showed a significant tumor volume difference in A549 xenograft compared to RTx. In rat ILD model, chest CT showed that BLM + RTx exhibited increased lung infiltrates at week 15 compared to BLM + PDT. Leukocyte cell fractionation of bronchoalveolar lavage at 15 weeks showed that BLM + RTx had significantly higher cell counts than BLM + PDT or control in total leukocyte, neutrophil, and macrophage. In Ashcroft's lung fibrosis pathology score, BLM + RTx showed more significant score increases over control, BLM, or BLM + PDT.

Despite the differences in dose delivery between RTx and PDT, PDT demonstrated comparable antitumor efficacy to RTx in mouse xenograft model and a safer pulmonary toxicity profile than RTx in rat ILD model. PDT is possibly a promising treatment modality for lung cancer associated with ILD.