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Photodynamic Therapy as Important Tool for Biological Breakthroughs

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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 (30 April 2023) | Viewed by 16583

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Special Issue Editors

Dr. João P. C. Tomé

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Centro de Química Estrutural, Institute of Molecular Science and Departamento de Engenharia Química, Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal
Interests: (photo)active (hybrid)materials; porphyrins; phthalocyanines; photomedicine; photoinduced energy; electron-transfer materials; optical (chemo)sensors; (photo)catalysis
Special Issues, Collections and Topics in MDPI journals

Dr. Augusto C. Tomé

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LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
Interests: synthesis and functionalization of porphyrins, phthalocyanines and porphyrin-type compounds; photodynamic therapy; photoinactivation of microorganisms; chemical sensing; solar cells
Special Issues, Collections and Topics in MDPI journals

Dr. Leandro M. O. Lourenço

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Guest Editor

LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
Interests: photochemistry; chromophores; light-activated systems; donor–acceptor structures; covalent and noncovalent chemistry
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Photodynamic therapy (PDT) is an effective and valuable clinical procedure for the treatment of cancer or microorganisms. This clinical method combines a photosensitizer (PS), molecular oxygen, and visible or near-infrared light irradiation for the production of cytotoxic reactive oxygen species (ROS), leading to the destruction of cancer cells or microorganisms. Comparing this method with conventional therapies, PDT has several returns because it is a relatively non-invasive procedure. Because irradiation is restricted to the biological target, and the PS accumulates mainly in a specific site, it provides a lower systemic toxicity and a selective destruction. The PDT methodology also has a great tolerability profile, the absence of particular resistance mechanisms, a great cosmetic outcome, and the capability to promote the immune approach. Nevertheless, the PDT has certain limitations, and therefore, there is a substantial possibility for development, particularly in the area of new efficient PS drugs. Promising PS should be logically designed to match the features of an ideal PS drug.

The purpose of this Special Issue centered on Photodynamic Therapy (PDT) is to present the latest information in this topic, especially new PS drugs, their photochemical and photobiological properties, and cancer/microorganism therapies. Special importance is dedicated to the design and synthesis of the PS and to their photophysical properties. Moreover, the biological evaluation of each formulation will be emphasized, expecting that the collected knowledge will encourage the development of other effective photoactive drugs. We invite original research manuscripts and comprehensive reviews covering recent findings related to the abovementioned topics.

Prof. Dr. João Paulo C. Tomé
Dr. Augusto C. Tomé
Dr. Leandro M. O. Lourenço
Guest Editors

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.

Keywords

photodynamic theraphy (aPDT)
photochemistry
dyes
photosensitizers
porphyrins, phthalocyanines, and other derivatives
reactive oxygen species (ROS)
singlet oxygen
cancer

Published Papers (10 papers)

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Editorial

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9 pages, 3645 KiB

Open AccessEditorial

Editorial: Photodynamic Therapy as an Important Tool for Biological Breakthroughs—Photoactive Photosensitizers Applied from Cancer to Microbial Targets

by Leandro M. O. Lourenço, Augusto C. Tomé and João P. C. Tomé

Int. J. Mol. Sci. 2024, 25(1), 330; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25010330 - 26 Dec 2023

Viewed by 536

Abstract

Photodynamic therapy (PDT) stands as an approved clinical treatment for both oncologic and nononcologic disorders [...] Full article

(This article belongs to the Special Issue Photodynamic Therapy as Important Tool for Biological Breakthroughs)

Research

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21 pages, 3748 KiB

Open AccessArticle

Perfluorocarbon Nanoemulsions with Fluorous Chlorin-Type Photosensitizers for Antitumor Photodynamic Therapy in Hypoxia

by Minh Tuan Nguyen, Elizaveta V. Guseva, Aida N. Ataeva, Andrey L. Sigan, Anna V. Shibaeva, Maria V. Dmitrieva, Ivan D. Burtsev, Yulia L. Volodina, Alexandra S. Radchenko, Anton E. Egorov, Alexey A. Kostyukov, Pavel V. Melnikov, Nikolai D. Chkanikov, Vladimir A. Kuzmin, Alexander A. Shtil and Alina A. Markova

Int. J. Mol. Sci. 2023, 24(9), 7995; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24097995 - 28 Apr 2023

Cited by 3 | Viewed by 2476

Abstract

The efficacy of photodynamic therapy (PDT) strictly depends on the availability of molecular oxygen to trigger the light-induced generation of reactive species. Fluorocarbons have an increased ability to dissolve oxygen and are attractive tools for gas delivery. We synthesized three fluorous derivatives of chlorin with peripheral polyfluoroalkyl substituents. These compounds were used as precursors for preparing nanoemulsions with perfluorodecalin as an oxygen depot. Therefore, our formulations contained hydrophobic photosensitizers capable of absorbing monochromatic light in the long wavelength region and the oxygen carrier. These modifications did not alter the photosensitizing characteristics of chlorin such as the generation of singlet oxygen, the major cytocidal species in PDT. Emulsions readily entered HCT116 colon carcinoma cells and accumulated largely in mitochondria. Illumination of cells loaded with emulsions rapidly caused peroxidation of lipids and the loss of the plasma membrane integrity (photonecrosis). Most importantly, in PDT settings, emulsions potently sensitized cells cultured under prolonged (8 weeks) hypoxia as well as cells after oxygen depletion with sodium sulfite (acute hypoxia). The photodamaging potency of emulsions in hypoxia was significantly more pronounced compared to emulsion-free counterparts. Considering a negligible dark cytotoxicity, our materials emerge as efficient and biocompatible instruments for PDT-assisted eradication of hypoxic cells. Full article

(This article belongs to the Special Issue Photodynamic Therapy as Important Tool for Biological Breakthroughs)

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25 pages, 3236 KiB

Open AccessArticle

Cytotoxic Effects of Combinative ZnPcS₄ Photosensitizer Photodynamic Therapy (PDT) and Cannabidiol (CBD) on a Cervical Cancer Cell Line

by Radmila Razlog, Cherie Ann Kruger and Heidi Abrahamse

Int. J. Mol. Sci. 2023, 24(7), 6151; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24076151 - 24 Mar 2023

Cited by 4 | Viewed by 1793

Abstract

The most prevalent type of gynecological malignancy globally is cervical cancer (CC). Complicated by tumor resistance and metastasis, it remains the leading cause of cancer deaths in women in South Africa. Early CC is managed by hysterectomy, chemotherapy, radiation, and more recently, immunotherapy. Although these treatments provide clinical benefits, many patients experience adverse effects and secondary CC spread. To minimize this, novel and innovative treatment methods need to be investigated. Photodynamic therapy (PDT) is an advantageous treatment modality that is non-invasive, with limited side effects. The Cannabis sativa L. plant isolate, cannabidiol (CBD), has anti-cancer effects, which inhibit tumor growth and spread. This study investigated the cytotoxic combinative effect of PDT and CBD on CC HeLa cells. The effects were assessed by exposing in vitro HeLa CC-cultured cells to varying doses of ZnPcS₄ photosensitizer (PS) PDT and CBD, with a fluency of 10 J/cm² and 673 nm irradiation. HeLa CC cells, which received the predetermined lowest dose concentrations (ICD₅₀) of 0.125 µM ZnPcS₄ PS plus 0.5 µM CBD to yield 50% cytotoxicity post-laser irradiation, reported highly significant and advantageous forms of cell death. Flow cytometry cell death pathway quantitative analysis showed that only 13% of HeLa cells were found to be viable, 7% were in early apoptosis and 64% were in late favorable forms of apoptotic cell death, with a minor 16% of necrosis post-PDT. Findings suggest that this combined treatment approach can possibly induce primary cellular destruction, as well as limit CC metastatic spread, and so warrants further investigation. Full article

(This article belongs to the Special Issue Photodynamic Therapy as Important Tool for Biological Breakthroughs)

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10 pages, 1071 KiB

Open AccessArticle

In Vitro Photoinactivation of Fusarium oxysporum Conidia with Light-Activated Ammonium Phthalocyanines

by Sara R. D. Gamelas, Isabel N. Sierra-Garcia, Augusto C. Tomé, Ângela Cunha and Leandro M. O. Lourenço

Int. J. Mol. Sci. 2023, 24(4), 3922; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24043922 - 15 Feb 2023

Cited by 2 | Viewed by 1121

Abstract

Antimicrobial photodynamic therapy (aPDT) has been explored as an innovative therapeutic approach because it can be used to inactivate a variety of microbial forms (vegetative forms and spores) without causing significant damage to host tissues, and without the development of resistance to the photosensitization process. This study assesses the photodynamic antifungal/sporicidal activity of tetra- and octasubstituted phthalocyanine (Pc) dyes with ammonium groups. Tetra- and octasubstituted zinc(II) phthalocyanines (1 and 2) were prepared and tested as photosensitizers (PSs) on Fusarium oxysporum conidia. Photoinactivation (PDI) tests were conducted with photosensitizer (PS) concentrations of 20, 40, and 60 µM under white-light exposure at an irradiance of 135 mW·cm^–2, applied during 30 and 60 min (light doses of 243 and 486 J·cm⁻²). High PDI efficiency corresponding to the inactivation process until the detection limit was observed for both PSs. The tetrasubstituted PS was the most effective, requiring the lowest concentration and the shortest irradiation time for the complete inactivation of conidia (40 µM, 30 min, 243 J·cm⁻²). Complete inactivation was also achieved with PS 2, but a longer irradiation time and a higher concentration (60 µM, 60 min, 486 J·cm⁻²) were necessary. Because of the low concentrations and moderate energy doses required to inactivate resistant biological forms such as fungal conidia, these phthalocyanines can be considered potent antifungal photodynamic drugs. Full article

(This article belongs to the Special Issue Photodynamic Therapy as Important Tool for Biological Breakthroughs)

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25 pages, 8055 KiB

Open AccessArticle

Photodynamic Therapy of Aluminum Phthalocyanine Tetra Sodium 2-Mercaptoacetate Linked to PEGylated Copper–Gold Bimetallic Nanoparticles on Colon Cancer Cells

by Nokuphila Winifred Nompumelelo Simelane, Gauta Gold Matlou and Heidi Abrahamse

Int. J. Mol. Sci. 2023, 24(3), 1902; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24031902 - 18 Jan 2023

Cited by 6 | Viewed by 1542

Abstract

This work reports for the first time on the synthesis, characterization, and photodynamic therapy efficacy of the novel aluminium (III) chloride 2(3), 9(10), 16(17), 23(24)-tetrakis-(sodium 2-mercaptoacetate) phthalocyanine (AlClPcTS41) when alone and when conjugated to PEGylated copper–gold bimetallic nanoparticles (PEG-CuAuNPs) as photosensitizers on colon cancer cells (Caco-2). The novel AlClPcTS41 was covalently linked to the PEG-CuAuNPs via an amide bond to form AlClPcTS41-PEG-CuAuNPs. The amide bond was successfully confirmed using FTIR while the crystal structures were studied using XRD. The morphological and size variations of the PEG-CuAuNPs and AlClPcTS41-PEG-CuAuNPs were studied using TEM, while the hydrodynamic sizes and polydispersity of the particles were confirmed using DLS. The ground state electron absorption spectra were also studied and confirmed the typical absorption of metallated phthalocyanines and their nanoparticle conjugates. Subsequently, the subcellular uptake, cellular proliferation, and PDT anti-tumor effect of AlClPcTS41, PEG-CuAuNPs, and AlClPcTS41-PEG-CuAuNPs were investigated within in vitro Caco-2 cells. The designed AlClPcTS41 and AlClPcTS41-PEG-CuAuNPs demonstrated significant ROS generation abilities that led to the PDT effect with a significantly decreased viable cell population after PDT treatment. These results demonstrate that the novel AlClPcTS41 and AlClPcTS41-PEG-CuAuNPs had remarkable PDT effects against Caco-2 cells and may trigger apoptosis cell death pathway, indicating the potential of the AlClPcTS41 and AlClPcTS41-PEG-CuAuNPs in enhancing the cytotoxic effect of PDT treatment. Full article

(This article belongs to the Special Issue Photodynamic Therapy as Important Tool for Biological Breakthroughs)

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12 pages, 5587 KiB

Open AccessArticle

Cell-Level Analysis Visualizing Photodynamic Therapy with Porphylipoprotein and Talaporphyrin Sodium

by Mayuka Kamiyanagi, Atsushi Taninaka, Shunta Ugajin, Yu Nagoshi, Hiromi Kurokawa, Takahiro Ochiai, Yusuke Arashida, Osamu Takeuchi, Hirofumi Matsui and Hidemi Shigekawa

Int. J. Mol. Sci. 2022, 23(21), 13140; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232113140 - 28 Oct 2022

Cited by 2 | Viewed by 1370

Abstract

We revealed the difference in the mechanism of photodynamic therapy (PDT) between two photosensitizers: porphylipoprotein (PLP), which has recently attracted attention for its potential to be highly effective in treating cancer, and talaporphyrin sodium (NPe6). (1) NPe6 accumulates in lysosomes, whereas PLP is incorporated into phagosomes formed by PLP injection. (2) PDT causes NPe6 to generate reactive oxygen species, thereby producing actin filaments and stress fibers. In the case of PLP, however, reactive oxygen species generated by PDT remain in the phagosomes until the phagosomal membrane is destroyed, which delays the initiation of RhoA activation and RhoA*/ROCK generation. (4) After the disruption of the phagosomal membrane, however, the outflow of various reactive oxygen species accelerates the production of actin filaments and stress fibers, and blebbing occurs earlier than in the case of NPe6. (5) PLP increases the elastic modulus of cells without RhoA activity in the early stage. This is because phagosomes are involved in polymerizing actin filaments and pseudopodia formation. Considering the high selectivity and uptake of PLP into cancer cells, a larger effect with PDT can be expected by skillfully combining the newly discovered characteristics, such as the appearance of a strong effect at an early stage. Full article

(This article belongs to the Special Issue Photodynamic Therapy as Important Tool for Biological Breakthroughs)

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18 pages, 3162 KiB

Open AccessArticle

A Novel PSMA-Targeted Probe for NIRF-Guided Surgery and Photodynamic Therapy: Synthesis and Preclinical Validation

by Martina Capozza, Rachele Stefania, Valentina Dinatale, Valeria Bitonto, Laura Conti, Cristina Grange, Renata Skovronova and Enzo Terreno

Int. J. Mol. Sci. 2022, 23(21), 12878; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232112878 - 25 Oct 2022

Cited by 5 | Viewed by 2121

Abstract

A total of 20% to 50% of prostate cancer (PCa) patients leave the surgery room with positive tumour margins. The intraoperative combination of fluorescence guided surgery (FGS) and photodynamic therapy (PDT) may be very helpful for improving tumour margin delineation and cancer therapy. PSMA is a transmembrane protein overexpressed in 90–100% of PCa cells. The goal of this work is the development of a PSMA-targeted Near InfraRed Fluorescent probe to offer the surgeon a valuable intraoperative tool for allowing a complete tumour removal, implemented with the possibility of using PDT to kill the eventual not resected cancer cells. PSMA-617 binding motif was conjugated to IRDye700DX-NHS and the conjugation did not affect the photophysical characteristics of the fluorophore. The affinity of IRDye700DX-PSMA-617 towards PCa cells followed the order of their PSMA expression, i.e., PC3-PIP > LNCaP > PC3, PC3-FLU. NIRF imaging showed a significant PC3-PIP tumour uptake after the injection of 1 or 5 nmol with a maximum tumour-to-muscle ratio (ca. 60) observed for both doses 24 h post-injection. Importantly, urine, healthy prostate, and the bladder were not fluorescent at 24 h post-injection. Flow cytometry and confocal images highlighted a co-localization of PSMA+ cells with IRDye700DX-PSMA uptake. Very interestingly, ex vivo analysis on a tumour specimen highlighted a significant PSMA expression by tumour-associated macrophages, likely attributable to extracellular vesicles secreted by the PSMA(+) tumour cells. FGS proved that IRDye700DX-PSMA was able to easily delineate tumour margins. PDT experiments showed a concentration-dependent decrease in cell viability (from 75% at 10 nM to 12% at 500 nM), whereas controls did not show any cytotoxicity. PC3-PIP tumour-bearing mice subjected to photodynamic therapy showed a delayed tumour growth. In conclusion, a novel PSMA-targeted NIRF dye with dual imaging-PDT capabilities was synthesized and displayed superior specificity compared to other small PSMA targeted molecules. Full article

(This article belongs to the Special Issue Photodynamic Therapy as Important Tool for Biological Breakthroughs)

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16 pages, 2783 KiB

Open AccessArticle

Anti-Viral Photodynamic Inactivation of T4-like Bacteriophage as a Mammalian Virus Model in Blood

by Patrícia Santos, Ana T. P. C. Gomes, Leandro M. O. Lourenço, Maria A. F. Faustino, Maria G. P. M. S. Neves and Adelaide Almeida

Int. J. Mol. Sci. 2022, 23(19), 11548; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911548 - 30 Sep 2022

Cited by 4 | Viewed by 1493

Abstract

The laboratorial available methods applied in plasma disinfection can induce damage in other blood components. Antimicrobial photodynamic therapy (aPDT) represents a promising approach and is approved for plasma and platelet disinfection using non-porphyrinic photosensitizers (PSs), such as methylene blue (MB). In this study, the photodynamic action of three cationic porphyrins (Tri-Py(+)-Me, Tetra-Py(+)-Me and Tetra-S-Py(+)-Me) towards viruses was evaluated under white light irradiation at an irradiance of 25 and 150 mW·cm^−2, and the results were compared with the efficacy of the approved MB. None of the PSs caused hemolysis at the isotonic conditions, using a T4-like phage as a model of mammalian viruses. All porphyrins were more effective than MB in the photoinactivation of the T4-like phage in plasma. Moreover, the most efficient PS promoted a moderate inactivation rate of the T4-like phage in whole blood. Nevertheless, these porphyrins, such as MB, can be considered promising and safe PSs to photoinactivate viruses in blood plasma. Full article

(This article belongs to the Special Issue Photodynamic Therapy as Important Tool for Biological Breakthroughs)

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13 pages, 1839 KiB

Open AccessArticle

New Route to Glycosylated Porphyrins via Aromatic Nucleophilic Substitution (S_NAr)—Synthesis and Cellular Uptake Studies

by Mariusz Rosa, Natalia Jędryka, Sandra Skorupska, Ilona Grabowska-Jadach and Maciej Malinowski

Int. J. Mol. Sci. 2022, 23(19), 11321; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911321 - 26 Sep 2022

Cited by 4 | Viewed by 1647

Abstract

Glycoporphyrins are group of compounds of high value for the purpose of photodynamic therapy and other biomedical applications. Despite great progress in the field, new diversity-oriented syntheses of carbohydrate-porphyrin hybrids are increasingly desired. Herein, we present efficient, mild, and metal-free conditions for synthesis of glycoporphyrins. The versatile nature of the S_NAr procedure is presented in 16 examples. Preliminary biological studies have been conducted on the cytotoxicity and cellular uptake of the final molecules. Full article

(This article belongs to the Special Issue Photodynamic Therapy as Important Tool for Biological Breakthroughs)

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13 pages, 3713 KiB

Open AccessArticle

Precision Killing of Sinoporphyrin Sodium-Mediated Photodynamic Therapy against Malignant Tumor Cells

by Guixiang Lv, Zhihui Dong, Yunhan Zhao, Ning Ma, Xiaochen Jiang, Jia Li, Jinyue Wang, Jiaxin Wang, Wenxiu Zhang, Xin Lin and Zheng Hu

Int. J. Mol. Sci. 2022, 23(18), 10561; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231810561 - 12 Sep 2022

Cited by 1 | Viewed by 1255

Abstract

Photodynamic therapy (PDT) has significant advantages in the treatment of malignant tumors, such as high efficiency, minimal invasion and less side effects, and it can preserve the integrity and quality of the organs. The power density, irradiation time and photosensitizer (PS) concentration are three main parameters that play important roles in killing tumor cells. However, until now, the underlying relationships among them for PDT outcomes have been unclear. In this study, human malignant glioblastoma U-118MG and melanoma A375 cells were selected, and the product of the power density, irradiation time and PS concentration was defined as the total photodynamic parameter (TPP), in order to investigate the mechanisms of PS sinoporphyrin sodium (DVDMS)-mediated PDT (DVDMS-PDT). The results showed that the survival rates of the U-118MG and A375 cells were negatively correlated with the TPP value in the curve, and the correlation exactly filed an e-exponential function. Moreover, according to the formula, we realized controllable killing effects of the tumor cells by randomly adjusting the three parameters, and we finally verified the accuracy and repeatability of the formula. In conclusion, the establishment and implementation of a newly functional relationship among the PDT parameters are essential for predicting PDT outcomes and providing personalized precise treatment, and they are contributive to the development of PDT dosimetry. Full article

(This article belongs to the Special Issue Photodynamic Therapy as Important Tool for Biological Breakthroughs)

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