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Molecular Advances in Oncologic Photodynamic Therapy

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (20 April 2025) | Viewed by 14621

Special Issue Editor


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Guest Editor
1. Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands
2. Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing 314041, China
Interests: molecular oncology; photodynamic therapy; chemotherapy; photosensitization; surgery; gastroenterology; liver diseases; nanotechnology; medicinal chemistry; biochemistry; immunology
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Special Issue Information

Dear Colleagues,

Oncological photodynamic therapy is an expanding field that has produced clinical treatment modalities for cancer, especially in cases of superficially located tumors. For non-superficial tumors, PDT still suffers from several challenges that have hampered the widespread implementation of PDT in patients with deeper rooted malignancies. In this Special Issue, we would like to focus on studies that address the following challenges so as to ultimately bring PDT of non-superficial tumors closer to clinical application. First, intravenous injection of free photosensitizer molecules leads to their systemic clearance and accumulation in the skin, which reduces the extent of tumor photosensitization and results in skin phototoxicity. To this end, photonanomedicines have been developed that comprise photosensitizers packaged into targeted photosensitizer delivery systems. Studies are, therefore, welcome that describe novel photosensitizers and nanoparticulate photosensitizer delivery systems and demonstrate their rudimentary in vitro proof-of-concepts (intracellular delivery and localization, dark toxicity; PDT efficacy) and in vivo utility (toxicology, pharmacokinetics, disposition and biodistribution, and pharmacodynamics). Models and methodological approaches used to assess these outcome parameters are also eligible on the condition that these are novel, state-of-the-art, or provide unprecedented insights. Second, therapeutic efficacy relies on the degree that post-PDT survival signaling is suppressed and cell death is induced. Molecular biology studies on these phenomena and pharmacological strategies or interventions to inhibit survival pathways or induce tumor cell death will also be published. Third, the post-PDT immune response is critical in long-term tumor control and abscopal effects. Papers that shed new light on anti-tumor immune mechanisms and studies that deal with post-PDT immunomodulation to favor therapeutic outcomes (e.g., checkpoint inhibitors; vaccines) will be considered. Finally, molecular biology and bioinformatics have evidenced that PDT modifies certain pathways that are associated with a poor clinical prognosis, such as phenotypic features related to tumor cell stemness (e.g., PDT-mediated downregulation of certain CD antigens, such as CD44 and CD133). Manuscripts that address any topic in this niche will also be added to the Special Issue.

Prof. Dr. Michal Heger
Guest Editor

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Keywords

  • oncology
  • photodynamic therapy
  • photosensitizer
  • targeted drug delivery system
  • photonanomedicines
  • phototoxicity
  • photo cytotoxicity
  • dark toxicity
  • superficial tumors
  • intracellular delivery and localization
  • anti-tumor immunity
  • bioinformatics analysis
  • therapy-induced tumor cell death
  • stemness of cancer cells

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Published Papers (6 papers)

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Research

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17 pages, 3991 KiB  
Article
A Synergistic Strategy Combining Chemotherapy and Photodynamic Therapy to Eradicate Prostate Cancer
by Aditi A. Shirke, Ethan Walker, Sriprada Chavali, Gopalakrishnan Ramamurthy, Lifang Zhang, Abhiram Panigrahi, James P. Basilion and Xinning Wang
Int. J. Mol. Sci. 2024, 25(13), 7086; https://doi.org/10.3390/ijms25137086 - 28 Jun 2024
Cited by 2 | Viewed by 2306
Abstract
Prostate cancer is the most prevalent cancer among men in the United States and is a leading cause of cancer-related death. Prostate specific membrane antigen (PSMA) has been established as a biomarker for prostate cancer diagnosis and treatment. This study aimed to develop [...] Read more.
Prostate cancer is the most prevalent cancer among men in the United States and is a leading cause of cancer-related death. Prostate specific membrane antigen (PSMA) has been established as a biomarker for prostate cancer diagnosis and treatment. This study aimed to develop a novel theranostic agent, PSMA-1-MMAE-Pc413, which integrates a PSMA-targeting ligand, the photosensitizer Pc413, and the microtubular inhibitor monomethyl auristatin E (MMAE) for synergistic therapeutic efficacy. In vitro uptake studies revealed that PSMA-1-MMAE-Pc413 demonstrated selective and specific uptake in PSMA-positive PC3pip cells but not in PSMA-negative PC3flu cells, with the uptake in PC3pip cells being approximately three times higher. In vitro cytotoxicity assays showed that, when exposed to light, PSMA-1-MMAE-Pc413 had a synergistic effect, leading to significantly greater cytotoxicity in PSMA-positive cells (IC50 = 2.2 nM) compared to PSMA-1-Pc413 with light irradiation (IC50 = 164.9 nM) or PSMA-1-MMAE-Pc413 without light irradiation (IC50 = 12.6 nM). In vivo imaging studies further demonstrated the selective uptake of PSMA-1-MMAE-Pc413 in PC3pip tumors. In in vivo studies, PSMA-1-MMAE-Pc413 dramatically improves the therapeutic outcome for prostate cancer by providing a synergistic effect that surpasses the efficacy of each treatment modality alone in PC3pip tumors. These findings suggest that PSMA-1-MMAE-Pc413 has strong potential for clinical application in improving prostate cancer treatment. Full article
(This article belongs to the Special Issue Molecular Advances in Oncologic Photodynamic Therapy)
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24 pages, 7433 KiB  
Article
Cellular Imaging and Time-Domain FLIM Studies of Meso-Tetraphenylporphine Disulfonate as a Photosensitising Agent in 2D and 3D Models
by Andrea Balukova, Kalliopi Bokea, Paul R. Barber, Simon M. Ameer-Beg, Alexander J. MacRobert and Elnaz Yaghini
Int. J. Mol. Sci. 2024, 25(8), 4222; https://doi.org/10.3390/ijms25084222 - 11 Apr 2024
Cited by 1 | Viewed by 4516
Abstract
Fluorescence lifetime imaging (FLIM) and confocal fluorescence studies of a porphyrin-based photosensitiser (meso-tetraphenylporphine disulfonate: TPPS2a) were evaluated in 2D monolayer cultures and 3D compressed collagen constructs of a human ovarian cancer cell line (HEY). TPPS2a is known to be an [...] Read more.
Fluorescence lifetime imaging (FLIM) and confocal fluorescence studies of a porphyrin-based photosensitiser (meso-tetraphenylporphine disulfonate: TPPS2a) were evaluated in 2D monolayer cultures and 3D compressed collagen constructs of a human ovarian cancer cell line (HEY). TPPS2a is known to be an effective model photosensitiser for both Photodynamic Therapy (PDT) and Photochemical Internalisation (PCI). This microspectrofluorimetric study aimed firstly to investigate the uptake and subcellular localisation of TPPS2a, and evaluate the photo-oxidative mechanism using reactive oxygen species (ROS) and lipid peroxidation probes combined with appropriate ROS scavengers. Light-induced intracellular redistribution of TPPS2a was observed, consistent with rupture of endolysosomes where the porphyrin localises. Using the same range of light doses, time-lapse confocal imaging permitted observation of PDT-induced generation of ROS in both 2D and 3D cancer models using fluorescence-based ROS together with specific ROS inhibitors. In addition, the use of red light excitation of the photosensitiser to minimise auto-oxidation of the probes was investigated. In the second part of the study, the photophysical properties of TPPS2a in cells were studied using a time-domain FLIM system with time-correlated single photon counting detection. Owing to the high sensitivity and spatial resolution of this system, we acquired FLIM images that enabled the fluorescence lifetime determination of the porphyrin within the endolysosomal vesicles. Changes in the lifetime dynamics upon prolonged illumination were revealed as the vesicles degraded within the cells. Full article
(This article belongs to the Special Issue Molecular Advances in Oncologic Photodynamic Therapy)
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Review

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54 pages, 3159 KiB  
Review
Biomimetic Tumour Model Systems for Pancreatic Ductal Adenocarcinoma in Relation to Photodynamic Therapy
by Olivia M. Smith, Nicole Lintern, Jiahao Tian, Bárbara M. Mesquita, Sabrina Oliveira, Veronika Vymetalkova, Jai Prakash, Andrew M. Smith, David G. Jayne, Michal Heger and Yazan S. Khaled
Int. J. Mol. Sci. 2025, 26(13), 6388; https://doi.org/10.3390/ijms26136388 - 2 Jul 2025
Viewed by 969
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and is associated with poor prognosis. Despite years of research and improvements in chemotherapy regimens, the 5-year survival rate of PDAC remains dismal. Therapies for PDAC often face resistance owing in [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and is associated with poor prognosis. Despite years of research and improvements in chemotherapy regimens, the 5-year survival rate of PDAC remains dismal. Therapies for PDAC often face resistance owing in large part to an extensive desmoplastic stromal matrix. Modelling PDAC ex vivo to investigate novel therapeutics is challenging due to the complex tumour microenvironment and its heterogeneity in native tumours. Development of novel therapies is needed to improve PDAC survival rates, for which disease models that recapitulate the tumour biology are expected to bear utility. This review focuses on the existing preclinical models for human PDAC and discusses advancements in tissue remodelling to guide translational PDAC research. Further emphasis is placed on photodynamic therapy (PDT) due to the ability of this treatment modality to not only directly kill cancer cells by minimally invasive means, but also to perturb the tumour microenvironment and elicit a post-therapeutic anti-tumour immune response. Accordingly, more complex preclinical models that feature multiple biologically relevant PDAC components are needed to develop translatable PDT regimens in a preclinical setting. Full article
(This article belongs to the Special Issue Molecular Advances in Oncologic Photodynamic Therapy)
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21 pages, 3260 KiB  
Review
Laser-Free Photosensitive Systems in Cancer Therapy: A Comprehensive Review
by Ruixue Jia, Shuyun Zhang, Jicheng Zhang and Yi Li
Int. J. Mol. Sci. 2025, 26(4), 1437; https://doi.org/10.3390/ijms26041437 - 8 Feb 2025
Viewed by 1406
Abstract
Photodynamic therapy (PDT) involves the use of photosensitizers (PSs) that, upon activation by specific wavelengths of light, generate reactive oxygen species (ROS), including singlet oxygen (1O2) and hydroxyl radicals (·OH), within the targeted tissue, typically tumor cells. The generated [...] Read more.
Photodynamic therapy (PDT) involves the use of photosensitizers (PSs) that, upon activation by specific wavelengths of light, generate reactive oxygen species (ROS), including singlet oxygen (1O2) and hydroxyl radicals (·OH), within the targeted tissue, typically tumor cells. The generated ROS induces cellular damage, disrupts cellular processes, and ultimately leads to apoptosis or necrosis of the tumor cells. However, the clinical application of PDT is significantly hindered by the limited tissue penetration ability of light. To address this limitation, laser-free self-luminescent photosensitive systems have emerged as potential solutions for achieving deep-tissue PDT and imaging. This review provides a comprehensive analysis of various laser-independent photosensitive systems, with a particular emphasis on those based on resonance energy transfer (RET), chemically induced electron exchange luminescence (CIEEL), and Cherenkov radiation energy transfer (CRET). The aim is to offer a theoretical framework for the development of novel photodynamic systems and to reassess the application potential of certain previously overlooked photosensitizers (PSs). Full article
(This article belongs to the Special Issue Molecular Advances in Oncologic Photodynamic Therapy)
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15 pages, 2042 KiB  
Review
Shedding Light on Chemoresistance: The Perspective of Photodynamic Therapy in Cancer Management
by Fernanda Viana Cabral, Jose Quilez Alburquerque, Harrison James Roberts and Tayyaba Hasan
Int. J. Mol. Sci. 2024, 25(7), 3811; https://doi.org/10.3390/ijms25073811 - 29 Mar 2024
Cited by 10 | Viewed by 2428
Abstract
The persistent failure of standard chemotherapy underscores the urgent need for innovative and targeted approaches in cancer treatment. Photodynamic therapy (PDT) has emerged as a promising photochemistry-based approach to address chemoresistance in cancer regimens. PDT not only induces cell death but also primes [...] Read more.
The persistent failure of standard chemotherapy underscores the urgent need for innovative and targeted approaches in cancer treatment. Photodynamic therapy (PDT) has emerged as a promising photochemistry-based approach to address chemoresistance in cancer regimens. PDT not only induces cell death but also primes surviving cells, enhancing their susceptibility to subsequent therapies. This review explores the principles of PDT and discusses the concept of photodynamic priming (PDP), which augments the effectiveness of treatments like chemotherapy. Furthermore, the integration of nanotechnology for precise drug delivery at the right time and location and PDT optimization are examined. Ultimately, this study highlights the potential and limitations of PDT and PDP in cancer treatment paradigms, offering insights into future clinical applications. Full article
(This article belongs to the Special Issue Molecular Advances in Oncologic Photodynamic Therapy)
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14 pages, 1711 KiB  
Review
PDT-Induced Activation Enhanced by Hormone Response to Treatment
by Wojciech Domka, Dorota Bartusik-Aebisher, Maria Przygoda, Klaudia Dynarowicz, Jerzy Tomik and David Aebisher
Int. J. Mol. Sci. 2023, 24(18), 13917; https://doi.org/10.3390/ijms241813917 - 10 Sep 2023
Cited by 3 | Viewed by 1888
Abstract
Photodynamic therapy (PDT) is a medical treatment with the use of a photosensitizing agent (PS), which, when activated by light, results in selective tissue damage with a cytotoxic effect on tumor cells. PDT leads to the induction of an acute-phase response, which results [...] Read more.
Photodynamic therapy (PDT) is a medical treatment with the use of a photosensitizing agent (PS), which, when activated by light, results in selective tissue damage with a cytotoxic effect on tumor cells. PDT leads to the induction of an acute-phase response, which results in the involvement of adrenal glucocorticoid (GC) hormones. PDT, by activating the hormonal response, affects the treatment of cancer. GC release is observed due to adrenal activity, which is driven by changes in the hypothalamic pituitary–adrenal axis triggered by stress signals emanating from the PDT treated tumor. The hormones released in this process in the context of the PDT-induced acute-phase response perform many important functions during anticancer therapy. They lead, among other things, to the systemic mobilization of neutrophils and the production of acute-phase reagents, and also control the production of immunoregulatory proteins and proteins that modulate inflammation. GCs can radically affect the activity of various inflammatory and immune cells, including the apoptosis of cancer cells. A better understanding of the modulation of GC activity could improve the outcomes of cancer patients treated with PDT. Full article
(This article belongs to the Special Issue Molecular Advances in Oncologic Photodynamic Therapy)
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