Preclinical investigation of folate receptor-targeted nanoparticles for photodynamic therapy of malignant pleural mesothelioma

Our plain-English summary of Preclinical investigation of folate receptor-targeted nanoparticles for photodynamic therapy of malignant pleural mesothelioma, by T. Kato, C.S. Jin, D. Lee, et al (International Journal of Oncology, 2018).

The study

• Authors: T. Kato, C.S. Jin, D. Lee, H. Ujiie, K. Fujino, H.P. Hu, H. Wada, L. Wu, J. Chen, R.A. Weersink, H. Kanno, Y. Hatanaka, K.C. Hatanaka, K. Kaga, Y. Matsui, Y. Matsuno, M. De Perrot, B.C. Wilson, G. Zheng, K. Yasufuku
• Journal: International Journal of Oncology
• Published: 2018;53(5):2034-2046
• Cited by: 16 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Photodynamic therapy (PDT) following lung-sparing extended pleurectomy for malignant pleural mesothelioma (MPM) has been investigated as a potential means to kill residual microscopic cells. High expression levels of folate receptor 1 (FOLR1) have been reported in MPM; therefore, targeting FOLR1 has been considered a novel potential strategy. The present study developed FOLR1‑targeting porphyrin-lipid nanoparticles (folate-porphysomes, FP) for the treatment of PDT. Furthermore, inhibition of activated epidermal growth factor (EGFR)-associated survival pathways enhance PDT efficacy. In the present study, these approaches were combined; FP-based PDT was used together with an EGFR-tyrosine kinase inhibitor (EGFR-TKI). The frequency of FOLR1 and EGFR expression in MPM was analyzed using tissue microarrays. Confocal microscopy and a cell viability assay were performed to confirm the specificity of FOLR1‑targeting cellular uptake and photocytotoxicity in vitro. In vivo fluorescence activation and therapeutic efficacy were subsequently examined. The effects of EGFR-TKI were also assessed in vitro. The in vivo combined antitumor effect of EGFR-TKI and FP-PDT was then evaluated. The results revealed that FOLR1 and EGFR were expressed in 79 and 89% of MPM samples, respectively. In addition, intracellular uptake of FP corresponded well with FOLR1 expression. When MPM cells were incubated with FP and then irradiated at 671 nm, there was significant in vitro cell death, which was inhibited in the presence of free folic acid, thus suggesting the specificity of FPs. FOLR1 targeting resulted in disassembly of the porphysomes and subsequent fluorescence activation in intrathoracic disseminated MPM tumors, as demonstrated by ex vivo tissue imaging. FP-PDT resulted in significant cellular damage and apoptosis in vivo. Furthermore, the combination of pretreatment with EGFR-TKI and FP-PDT induced a marked improvement of treatment responses. In conclusion, FP-based PDT induced selective destruction of MPM cells based on FOLR1 targeting, and pretreatment with EGFR-TKI further enhanced the therapeutic response.

In plain English

This laboratory and animal study tested an experimental light-activated treatment (photodynamic therapy) for malignant pleural mesothelioma. It did not study asbestos exposure. The authors first stained tumor tissue from 52 patients operated on in Sapporo, Japan, between 1990 and 2012. A folate receptor (FOLR1) was found in 41 of 52 cases (79%), EGFR in 89%, and both in 71%. The authors then made nanoparticles carrying folic acid (folate-porphysomes) designed to be taken up by cells with FOLR1. In cell experiments, these particles plus red laser light reduced mesothelioma cell survival, and adding free folic acid blocked the effect. In mice, tumor uptake of targeted and untargeted particles did not differ significantly. In mice with tumors under the skin, treatment slowed growth, but tumors regrew and all treated mice reached the endpoint by day 21. In mice, giving the drug erlotinib before treatment increased tumor cell death on tissue examination. The authors concluded the approach worked in preclinical models. They noted that in mice the combined treatment's effect was measured only by tissue examination, done 24 hours after treatment.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Preclinical study: tissue microarray staining of human mesothelioma samples, cell-line experiments, and mouse tumor experiments
• Who was studied: Tumor tissue from 52 patients with malignant pleural mesothelioma who had surgery at Hokkaido University Hospital and affiliated hospitals (Sapporo, Japan) between February 1990 and April 2012. Of these, 33 tumors were epithelioid, 13 biphasic, 5 sarcomatoid and 1 desmoplastic, and 92.3% of patients were men. The study also used mouse and human mesothelioma cell lines and nude mice implanted with AE17-sOVA mesothelioma cells.
• Exposure: Not an asbestos exposure study. The interventions were folate-receptor-targeted porphyrin nanoparticles (folate-porphysomes) activated by 671 nm laser light, with or without pretreatment with the EGFR inhibitor erlotinib.
• Main results:
  • FOLR1 was found in 41 of 52 patient mesothelioma cases (79%).
  • EGFR was found in 89% of the 52 patient cases.
  • 71% of the 52 patient cases expressed both FOLR1 and EGFR.
  • In cell experiments, folate-porphysomes plus light at 5 and 10 J/cm2 reduced cell viability to 57.9 and 48.1% in H2052 cells, and to 37.7 and 28.9% in AE17-sOVA cells.
  • In cell experiments, the cell-killing effect was completely blocked by adding free folic acid.
  • In mice with tumors in the chest cavity, tumor uptake of targeted versus untargeted particles was 1.22 versus 0.82 percent of injected dose per gram of tissue. The difference was not statistically significant (P=0.11).
  • In the same mice, uptake of targeted particles was significantly higher in the liver (4.6 versus 0.63 percent of injected dose per gram).
  • In the 6 mice with tumors under the skin that received the treatment, tumors regrew. One mouse reached the endpoint at day 14 and the other five at day 21, compared with untreated tumors, which reached the endpoint after 5 days.
  • In cell experiments, erlotinib pretreatment lowered AE17-sOVA cell viability after folate-porphysome photodynamic therapy at 5 and 10 J/cm2 from 55.2 and 31.2% to 36.1 and 21.7%.
  • In mice, with tumors examined 24 hours after treatment, adding erlotinib pretreatment to folate-porphysome photodynamic therapy lowered the tumor proliferation marker Ki-67 to 23.2% (compared with 42.9% with photodynamic therapy alone). It raised the cell-death marker cleaved caspase-3 to 99.5% (compared with 48.9% with photodynamic therapy alone).
• The authors' conclusion: The authors concluded that folate-porphysome photodynamic therapy was effective against FOLR1-positive mesothelioma in preclinical cell and mouse models, and that erlotinib pretreatment added to the effect. They stated that, if clinically translatable, the approach could improve the efficacy and safety of intrapleural photodynamic therapy.
• Limitations the authors state:
  • The treatment did not eliminate tumors in mice. Tumors recurred in all treated mice, and the authors described the doses used as sub-optimized.
  • In mice, the enhanced response with erlotinib was measured only by histological (tissue) analysis.
  • Because particle fluorescence was only partially unquenched, imaging gave only relative uptake between targeted and untargeted particles.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, EGFR, Tyrosine Kinase Inhibitor, Intrathoracic, Apoptosis.

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