-
Bioengineering (Basel, Switzerland) Feb 2022The effectiveness of photodynamic therapy (PDT) is based on the triad effects of photosensitizer (PS), molecular oxygen and visible light on malignant tumors. Such... (Review)
Review
The effectiveness of photodynamic therapy (PDT) is based on the triad effects of photosensitizer (PS), molecular oxygen and visible light on malignant tumors. Such complex induces a multifactorial manner including reactive-oxygen-species-mediated damage and the killing of cells, vasculature damage of the tumor, and activation of the organism immunity. The effectiveness of PDT depends on the properties of photosensitizing drugs, their selectivity, enhanced photoproduction of reactive particles, absorption in the near infrared spectrum, and drug delivery strategies. Photosensitizers of the tetrapyrrole structure (porphyrins) are widely used in PDT because of their unique diagnostic and therapeutic functions. Nevertheless, the clinical use of the first-generation PS (sodium porfimer and hematoporphyrins) revealed difficulties, such as long-term skin photosensitivity, insufficient penetration into deep-seated tumors and incorrect localization to it. The second generation is based on different approaches of the synthesis and conjugation of porphyrin PS with biomolecules, which made it possible to approach the targeted PDT of tumors. Despite the fact that the development of the second-generation PS started about 30 years ago, these technologies are still in demand and are in intensive development, especially in the direction of improving the process of optimization split linkers responsive to input. Bioconjugation and encapsulation by targeting molecules are among the main strategies for developing of the PS synthesis. A targeted drug delivery system with the effect of increased permeability and retention by tumor cells is one of the ultimate goals of the synthesis of second-generation PS. This review presents porphyrin PS of various generations, discusses factors affecting cellular biodistribution and uptake, and indicates their role as diagnostic and therapeutic (theranostic) agents. New complexes based on porphyrin PS for photoimmunotherapy are presented, where specific antibodies are used that are chemically bound to PS, absorbing light from the near infrared part of the spectrum. Additionally, a two-photon photodynamic approach using third-generation photosensitizers for the treatment of tumors is discussed, which indicates the prospects for the further development of a promising method antitumor PDT.
PubMed: 35200435
DOI: 10.3390/bioengineering9020082 -
Frontiers in Oncology 2021Blood vessels in the brain tissue form a compact vessel structure and play an essential role in maintaining the homeostasis of the neurovascular system. The low dosage...
Blood vessels in the brain tissue form a compact vessel structure and play an essential role in maintaining the homeostasis of the neurovascular system. The low dosage of photodynamic intervention (PDT) significantly affects the expression of cellular biomarkers. To understand the impact of photodynamic interventions on cerebrovascular endothelial cells, we evaluated the dosage-dependent impact of porfimer sodium-mediated PDT on B.END3 cells using flow cytometer, comet assay, RNA sequencing, and bioinformatics analysis. To examine whether PDT can induce disorder of intracellular organelles, we did not observe any significance damage of DNA and cellular skeleton. Moreover, expression levels of cellular transporters-related genes were significantly altered, implying the drawbacks of PDT on cerebrovascular functions. To address the potential molecular mechanisms of these phenotypes, RNA sequencing and bioinformatics analysis were employed to identify critical genes and pathways among these processes. The gene ontology (GO) analysis and protein-protein interaction (PPI) identified 15 hub genes, highly associated with cellular mitosis process (, , , , , , , , , ) and DNA replication (, , , ). Gene set enrichment analysis (GSEA) reveals that and pathways may play a critical role in regulating expression levels of transporter-related genes. To further perform qRT-PCR assays, we find that and pathways were substantially up-regulated, consistent with GSEA analysis. The current findings suggested that a low dosage of PDT intervention may be detrimental to the homeostasis of blood-brain barrier (BBB) by inducing the inflammatory response and affecting the expression of surface biomarkers.
PubMed: 34881175
DOI: 10.3389/fonc.2021.731414 -
Esophagus : Official Journal of the... Oct 2021Talaporfin sodium photodynamic therapy (tPDT) is an effective salvage treatment for local failure after chemoradiotherapy for esophageal cancer. Repeated tPDT could also...
BACKGROUND
Talaporfin sodium photodynamic therapy (tPDT) is an effective salvage treatment for local failure after chemoradiotherapy for esophageal cancer. Repeated tPDT could also be indicated for local recurrence or residue after the first salvage tPDT. However, the safety and efficacy of repeated tPDT have not been elucidated.
METHODS
We reviewed 52 patients with esophageal cancer who were treated with the first tPDT at Kyoto University Hospital between October 2015 and April 2020.
RESULTS
Among 52 patients, repeated tPDT after the first tPDT was indicated for 13 patients (25%), of which six had residual tumor, four had local recurrence after complete response (CR) after the first tPDT at the primary site, and six had metachronous lesion. The total session of repeated tPDT was 25; 16 were for primary sites and nine were for metachronous sites. Among them, six patients (46.2%) achieved local (L)-CR and nine lesions (56.3%) achieved lesion L-CR. By session, 10 sessions (40%) achieved L-CR. There were no severe adverse events except for one patient; this patient showed grade 3 esophageal stenosis and perforation after the third tPDT on the same lesion that was previously treated with porfimer sodium photodynamic therapy four times.
CONCLUSION
Repeated tPDT could be an effective and safe treatment for local failure even after salvage tPDT for esophageal cancer.
Topics: Carcinoma, Squamous Cell; Esophageal Neoplasms; Humans; Neoplasm Recurrence, Local; Photochemotherapy; Porphyrins
PubMed: 34106353
DOI: 10.1007/s10388-021-00853-x -
Clinical Endoscopy Jul 2021Photodynamic therapy, a curative local treatment for esophageal squamous cell carcinoma, involves a photosensitizing drug (photosensitizer) with affinity for tumors and... (Review)
Review
Photodynamic therapy, a curative local treatment for esophageal squamous cell carcinoma, involves a photosensitizing drug (photosensitizer) with affinity for tumors and a photodynamic reaction triggered by laser light. Previously, photodynamic therapy was used to treat superficial esophageal squamous cell carcinoma judged to be difficult to undergo endoscopic resection. Recently, photodynamic therapy has mainly been performed for local failure after chemoradiotherapy. Although surgery is the most promising treatment for local failure after chemoradiotherapy, its morbidity and mortality rates are high. Endoscopic resection is feasible for local failure after chemoradiotherapy but requires advanced skills, and its indication is limited to within the submucosal layer by depth. Photodynamic therapy is less invasive than surgery and has a wider indication than endoscopic resection. Porfimer sodium (a first-generation photosensitizer) causes a high frequency of side effects related to photosensitivity and requires the long-term sun-shade period. Talaporfin (a second-generation photosensitizer) requires a much shorter sun-shade period than porfimer sodium. Photodynamic therapy will profoundly change treatment strategies for local failure after chemoradiotherapy.
PubMed: 32422695
DOI: 10.5946/ce.2020.073 -
Photochemistry and Photobiology Mar 2020The objective of the present study was to develop a predictive model for Photofrin -mediated interstitial photodynamic therapy (I-PDT) of locally advanced tumors. Our...
Irradiance, Photofrin Dose and Initial Tumor Volume are Key Predictors of Response to Interstitial Photodynamic Therapy of Locally Advanced Cancers in Translational Models.
The objective of the present study was to develop a predictive model for Photofrin -mediated interstitial photodynamic therapy (I-PDT) of locally advanced tumors. Our finite element method was used to simulate 630-nm intratumoral irradiance and fluence for C3H mice and New Zealand White rabbits bearing large squamous cell carcinomas. Animals were treated with light only or I-PDT using the same light settings. I-PDT was administered with Photofrin at 5.0 or 6.6 mg kg , 24 h drug-light interval. The simulated threshold fluence was fixed at 45 J cm while the simulated threshold irradiance varied, intratumorally. No cures were obtained in the mice treated with a threshold irradiance of 5.4 mW cm . However, 20-90% of the mice were cured when the threshold irradiances were ≥8.6 mW cm . In the rabbits treated with I-PDT, 13 of the 14 VX2 tumors showed either local control or were cured when threshold irradiances were ≥15.3 mW cm and fluence was 45 J cm . No tumor growth delay was observed in VX2 treated with light only (n = 3). In the mouse studies, there was a high probability (92.7%) of predicting cure when the initial tumor volume was below the median (493.9 mm ) and I-PDT was administered with a threshold intratumoral irradiance ≥8.6 mW cm .
Topics: Animals; Dihematoporphyrin Ether; Dose-Response Relationship, Radiation; Mice; Mice, Inbred C3H; Neoplasms; Photosensitizing Agents; Rabbits
PubMed: 31887227
DOI: 10.1111/php.13207 -
O determined from the measured PDT dose and O predicts long-term response to Photofrin-mediated PDT.Physics in Medicine and Biology Jan 2020Photodynamic therapy (PDT) that employs the photochemical interaction of light, photosensitizer and oxygen is an established modality for the treatment of cancer....
Photodynamic therapy (PDT) that employs the photochemical interaction of light, photosensitizer and oxygen is an established modality for the treatment of cancer. However, dosimetry for PDT is becoming increasingly complex due to the heterogeneous photosensitizer uptake by the tumor, and complicated relationship between the tissue oxygenation ([O]), interstitial light distribution, photosensitizer photobleaching and PDT effect. As a result, experts argue that the failure to realize PDT's true potential is, at least partly due to the complexity of the dosimetry problem. In this study, we examine the efficacy of singlet oxygen explicit dosimetry (SOED) based on the measurements of the interstitial light fluence rate distribution, changes of [O] and photosensitizer concentration during Photofrin-mediated PDT to predict long-term control rates of radiation-induced fibrosarcoma tumors. We further show how variation in tissue [O] between animals induces variation in the treatment response for the same PDT protocol. PDT was performed with 5 mg kg Photofrin (a drug-light interval of 24 h), in-air fluence rates (ϕ ) of 50 and 75 mW cm and in-air fluences from 225 to 540 J cm. The tumor regrowth was tracked for 90 d after the treatment and Kaplan-Meier analyses for local control rate were performed based on a tumor volume ⩽100 mm for the two dosimetry quantities of PDT dose and SOED. Based on the results, SOED allowed for reduced subject variation and improved treatment evaluation as compared to the PDT dose.
Topics: Animals; Dihematoporphyrin Ether; Female; Fibrosarcoma; Mice; Mice, Inbred C3H; Neoplasms, Radiation-Induced; Oxygen; Photobleaching; Photochemotherapy; Photosensitizing Agents; Radiometry; Singlet Oxygen
PubMed: 31751964
DOI: 10.1088/1361-6560/ab59f1 -
Journal of Biomedical Optics Nov 2019The goal of our study was to determine the susceptibility of different pancreatic cell lines to clinically applicable photodynamic therapy (PDT). The efficacy of PDT of...
The goal of our study was to determine the susceptibility of different pancreatic cell lines to clinically applicable photodynamic therapy (PDT). The efficacy of PDT of two different commercially available photosensitizers, verteporfin and sodium porfimer, was compared using a panel of four different pancreatic cancer cell lines, PANC-1, BxPC-3, CAPAN-2, and MIA PaCa-2, and an immortalized non-neoplastic pancreatic ductal epithelium cell line, HPNE. The minimum effective concentrations and dose-dependent curves of verteporfin and sodium porfimer on PANC-1 were determined. Since pancreatic cancer is known to have significant stromal components, the effect of PDT on stromal cells was also assessed. To mimic tumor-stroma interaction, a co-culture of primary human fibroblasts or human pancreatic stellate cell (HPSCs) line with PANC-1 was used to test verteporfin-PDT-mediated cell death of PANC-1. Two cytokines (TNF-α and IL-1β) were used for stimulation of primary fibroblasts (derived from human esophageal biopsies) or HPSCs. The increased expression of smooth muscle actin (α-SMA) confirmed the activation of fibroblasts or HPSC upon treatment with TNF-α and IL-1β. Cell death assays showed that both sodium porfimer- and verteporfin-mediated PDT-induced cell death in a dose-dependent manner. However, verteporfin-PDT treatment had a greater efficiency with 60 × lower concentration than sodium porfimer-PDT in the PANC-1 incubated with stimulated fibroblasts or HPSC. Moreover, activation of stromal cells did not affect the treatment of the pancreatic cancer cell lines, suggesting that the effects of PDT are independent of the inflammatory microenvironment found in this two-dimensional culture model of cancers.
Topics: Biopsy; Cell Death; Cell Line, Tumor; Coculture Techniques; Dihematoporphyrin Ether; Drug Screening Assays, Antitumor; Fibroblasts; Humans; Microscopy, Fluorescence; Pancreas; Pancreatic Neoplasms; Photochemotherapy; Stromal Cells; Tumor Microenvironment; Verteporfin
PubMed: 31741351
DOI: 10.1117/1.JBO.24.11.118001 -
Photochemistry and Photobiology Mar 2020Explicit dosimetry of treatment light fluence and implicit dosimetry of photosensitizer photobleaching are commonly used methods to guide dose delivery during clinical...
Explicit dosimetry of treatment light fluence and implicit dosimetry of photosensitizer photobleaching are commonly used methods to guide dose delivery during clinical PDT. Tissue oxygen, however, is not routinely monitored intraoperatively even though it is one of the three major components of treatment. Quantitative information about in vivo tissue oxygenation during PDT is desirable, because it enables reactive oxygen species explicit dosimetry (ROSED) for prediction of treatment outcome based on PDT-induced changes in tumor oxygen level. Here, we demonstrate ROSED in a clinical setting, Photofrin-mediated pleural photodynamic therapy, by utilizing tumor blood flow information measured by diffuse correlation spectroscopy (DCS). A DCS contact probe was sutured to the pleural cavity wall after surgical resection of pleural mesothelioma tumor to monitor tissue blood flow (blood flow index) during intraoperative PDT treatment. Isotropic detectors were used to measure treatment light fluence and photosensitizer concentration. Blood-flow-derived tumor oxygen concentration, estimated by applying a preclinically determined conversion factor of 1.5 × 10 μMs cm to the blood flow index, was used in the ROSED model to calculate the total reacted reactive oxygen species [ROS]rx. Seven patients and 12 different pleural sites were assessed and large inter- and intrapatient heterogeneities in [ROS]rx were observed although an identical light dose of 60 J cm was prescribed to all patients.
Topics: Animals; Dihematoporphyrin Ether; Humans; Mice; Photochemotherapy; Photosensitizing Agents; Pleural Neoplasms; Reactive Oxygen Species; Xenograft Model Antitumor Assays
PubMed: 31729774
DOI: 10.1111/php.13176