Molecular Advances in Oncologic Photodynamic Therapy

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

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

• 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

Title: Light spectroscopic quantitative analysis of liposomal tirapazamine in the nanomolar concentration range
Authors: Daniel J. de Klerk; Mans Broekgaarden; Azeem Ullah; Mingjuan Li; Jiahao Tian; Yingnan Ge; Ruud C. Cox; Maarten R. Egmond; Michal Hege
Affiliation: 1 Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, P.R. China 2 Laboratory of Experimental Oncology, Department of Pathology, Erasmus MC, Rotterdam, the Netherlands 3 Université Grenoble Alpes, Inserm U 1209, CNRS UMR 5309, Institute for Advanced Biosciences, 38000, Grenoble, France 4 Membrane Biochemistry and Biophysics, Institute of Biomembranes, University of Utrecht, Padualaan 8, 3584 CH Utrecht, the Netherlands 5 Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, University of Utrecht, Utrecht, the Netherlands

Title: Pharmacological Targeting of Nuclear Factor (Erythroid-Derived 2)- Like 2 (NRF2) To Improve the Efficacy of Photodynamic Therap
Authors: Daniel J. de Klerk; Mark J. de Keijzer; Leonardo P. Franchi; Jiahao Tian; Yingnan Ge; Bárbara Mesquita; Gideon E. Saelman; Lianne R. de Haan; Mingjuan Li; Lionel M. Dias; Tony G. Kleijn; Perry D. Moerland; Yunlei Li; Andrew P. Stubbs; Michal Heger
Affiliation: 1 Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, P.R. China 2 Laboratory of Experimental Oncology, Department of Pathology, Erasmus MC, Rotterdam, the Netherlands 3 Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands 4 Department of Biochemistry and Molecular Biology, Institute of Biological Sciences (ICB 2), Federal University of Goiás (UFG), Goiânia, Goiás, Brazil 5 Department of Epidemiology and Data Science, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands 6 Department of Pathology and Clinical Bioinformatics, Erasmus Medical Center, Rotterdam, the Netherlands 7 Membrane Biochemistry and Biophysics, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, the Netherlands
Abstract: The recalcitrance of tumors to photodynamic therapy (PDT) has been linked to PDT-induced activation of survival pathways in sublethally afflicted cancer cells that modulate cellular responses to oxidative stress and damage. Accordingly, PDT efficacy can be improved by intervening in these pathways using molecular inhibitors of key modulators of survival signaling. A promising target for pharmacological intervention is the nuclear factor (erythroid-derived 2)-like 2 (NRF2) pathway, which induces the antioxidant and xenobiotic stress response that helps cells cope with prolonged periods of oxidative stress after PDT. This review outlines our current understanding of this pathway, how it is activated, and how it confers cytoprotective effects and ensures cell survival. Studies are addressed in which the activation of the NRF2 pathway by PDT has been demonstrated. Lastly, an overview of NRF2 pathway inhibitors that could serve as potential adjuvants to PDT is presented to augment therapeutic efficacy in treatment-resistant cancers and cancers that are known to recur after PDT.