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Pharmaceutics
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Natural Products in Photodynamic Therapy
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Natural Products in Photodynamic Therapy

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: closed (20 March 2025) | Viewed by 9023

Special Issue Editors

Prof. Dr. Renato Sonchini Gonçalves

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Guest Editor
Department of Chemistry, Laboratory of Chemistry of Natural Products, Federal University of Maranhão, São Luís 65080-805, Brazil
Interests: combination therapy; nanotechnology; nanomedicine; photodynamic therapy; natural products
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Gustavo Braga

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Guest Editor
Department of Chemistry, Federal University of Maranhão, São Luís 65080-805, Brazil
Interests: nanoformulation; nanotechnology; nanomedicine; physical-chemistry; photodynamic therapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

More than a century ago, scientists discovered that when light is combined with specific chemicals, it can cause the death of cells. Acridine, eosin, and haematoporphyrin were the first natural products of the timeline employed as photosensitizers (PS) in photodynamic therapy (PDT). PS, light, and oxygen are the three main elements of PDT, and are required to selectively generate reactive oxygen species in therapeutic targets, leading the cell to die with less invasiveness, low toxicity, and side effects. From 1999 onwards, first- and second-generation PS, like porphyrin, chlorin, and cyanine, and other dyes, such as methylene blue, toluidine blue, rose bengal, and hypericin, were used in the design of drugs for use in PDT, with some of these being approved by the FDA. Despite increasing amounts of research in the last decade focusing on PDT, its effects and applications, to date, less attention has been paid to plant extracts or molecules of natural origin and the study of their phototoxic activity. In this Special Issue, we aim to receive original research articles and review articles regarding the use of natural products as PS and/or as bioactive compounds in association with photodynamic therapy for application as combination therapy.

Prof. Dr. Renato Sonchini Gonçalves
Prof. Dr. Gustavo Braga
Guest Editors

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Keywords

  • photodynamic therapy
  • photosensitizer
  • natural product
  • bioactive compounds
  • combination therapy

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Published Papers (8 papers)

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14 pages, 1851 KiB  
Article
The Natural Anthraquinone Parietin Inactivates Candida tropicalis Biofilm by Photodynamic Mechanisms
by Juliana Marioni, Bianca C. Romero, Ma. Laura Mugas, Florencia Martinez, Tomas I. Gómez, Jesús M. N. Morales, Brenda S. Konigheim, Claudio D. Borsarelli and Susana C. Nuñez-Montoya
Pharmaceutics 2025, 17(5), 548; https://doi.org/10.3390/pharmaceutics17050548 - 23 Apr 2025
Viewed by 247
Abstract
Background/Objectives: Parietin (PTN), a blue-light absorbing pigment from Teloschistes spp. lichens, exhibit photosensitizing properties via Type I (superoxide anion, O2•−) and Type II (singlet oxygen, 1O2) mechanisms, inactivating bacteria in vitro after photoexcitation. We evaluate the [...] Read more.
Background/Objectives: Parietin (PTN), a blue-light absorbing pigment from Teloschistes spp. lichens, exhibit photosensitizing properties via Type I (superoxide anion, O2•−) and Type II (singlet oxygen, 1O2) mechanisms, inactivating bacteria in vitro after photoexcitation. We evaluate the in vitro antifungal activity of PTN against Candida tropicalis biofilms under actinic irradiation, its role in O2•− and 1O2 production, and the cellular stress response. Methods: Minimum inhibitory concentration (MIC) of PTN was determined in C. tropicalis NCPF 3111 under dark and actinic light conditions. Biofilm susceptibility was assessed at MIC/2, MIC, MICx2, MICx4, and MICx6 in the same conditions, and viability was measured by colony-forming units. Photodynamic mechanisms were examined using Tiron (O2•− scavenger) or sodium azide (1O2 quencher). O2•− production was measured by the nitro-blue tetrazolium (NBT) reduction and nitric oxide (NO) generation by Griess assay. Total antioxidant capacity was studied by FRAP (Ferrous Reduction Antioxidant Potency) assay and superoxide dismutase (SOD) activity by NBT assay. Results: Photoexcitation of PTN reduced C. tropicalis biofilm viability by four logs at MICx2. Sodium azide partially reversed the effect, whereas Tiron fully inhibited it, indicating the critical role of O2•−. PTN also increased O2•− and NO levels, enhancing SOD activity and FRAP. However, this antioxidant response was insufficient to prevent biofilm photoinactivation. Conclusions: Photoinactivation of C. tropicalis biofilms by PTN is primarily mediated by O2•−, with a minor contribution from 1O2 and an imbalance in NO levels. These findings suggest PTN is a promising photosensitizer for antifungal photodynamic therapy. Full article
(This article belongs to the Special Issue Natural Products in Photodynamic Therapy)
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22 pages, 57415 KiB  
Article
Enhanced Nanogel Formulation Combining the Natural Photosensitizer Curcumin and Pectis brevipedunculata (Asteraceae) Essential Oil for Synergistic Daylight Photodynamic Therapy in Leishmaniasis Treatment
by Lara Maria Oliveira Campos, Estela Mesquita Marques, Daniele Stéfanie Sara Lopes Lera-Nonose, Maria Julia Schiavon Gonçalves, Maria Valdrinez Campana Lonardoni, Glécilla Colombelli de Souza Nunes, Gustavo Braga and Renato Sonchini Gonçalves
Pharmaceutics 2025, 17(3), 286; https://doi.org/10.3390/pharmaceutics17030286 - 21 Feb 2025
Viewed by 474
Abstract
Background/Objectives: Neglected tropical diseases (NTDs), such as leishmaniasis, remain a global health challenge due to limited therapeutic options and rising drug resistance. In this study, we developed an advanced nanogel formulation incorporating curcumin (CUR) and Pectis brevipedunculata essential oil (EOPb) [...] Read more.
Background/Objectives: Neglected tropical diseases (NTDs), such as leishmaniasis, remain a global health challenge due to limited therapeutic options and rising drug resistance. In this study, we developed an advanced nanogel formulation incorporating curcumin (CUR) and Pectis brevipedunculata essential oil (EOPb) within an F127/Carbopol 974P matrix to enhance bioavailability and therapeutic efficacy against Leishmania (Leishmania) amazonensis (LLa) promastigotes. Methods: The chemical profile of EOPb was determined through GC-MS and NMR analyses, confirming the presence of key bioactive monoterpenes such as neral, geranial, α-pinene, and limonene. The nanogel formulation (nGPC) was optimized to ensure thermosensitivity, and stability, exhibiting a sol–gel transition at physiological temperatures. Rheological analysis revealed that nGPC exhibited Newtonian behavior at 5 °C, transitioning to shear-thinning and thixotropic characteristics at 25 and 32 °C, respectively. This behavior facilitates its application and controlled drug release, making it ideal for topical formulations. Dynamic light scattering (DLS) analysis demonstrated that nGPC maintained a stable nanoscale structure with hydrodynamic radius below 300 nm, while Fourier-transform infrared spectroscopy (FTIR) confirmed strong molecular interactions between EOPb, CUR, and the polymer matrix. Biological assays demonstrated that nGPC significantly enhanced anti-promastigote activity compared to free CUR and OEPb. Results: At the highest tested concentration (50 μg/mL EOPb and 17.5 μg/mL CUR) nGPC induced over 88% mortality in LLa promastigotes across 24, 48, and 72 h, indicating sustained efficacy. Even at lower concentrations, nGPC retained dose-dependent activity, suggesting a synergistic effect between CUR and EOPb. These findings highlight the potential of nGPC as an innovative nanocarrier for daylight photodynamic therapy (dPDT) in the treatment of leishmaniasis. Future studies will investigate the underlying mechanisms of this synergism and explore the potential application of photodynamic therapy (PDT) to further enhance therapeutic outcomes. Full article
(This article belongs to the Special Issue Natural Products in Photodynamic Therapy)
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17 pages, 13618 KiB  
Article
Cytotoxic and Immunomodulatory Effects of Hypericin as a Photosensitizer in Photodynamic Therapy Used on Skin Cell Cultures
by Magdalena Krupka-Olek, Andrzej Bożek, Zenon P. Czuba, Małgorzata Kłósek, Grzegorz Cieślar and Aleksandra Kawczyk-Krupka
Pharmaceutics 2024, 16(6), 696; https://doi.org/10.3390/pharmaceutics16060696 - 23 May 2024
Cited by 1 | Viewed by 1752
Abstract
Determination of the hypericin–photodynamic (HY–PDT) effect on the secretion of cytokines secreted by the skin cells, may be the basis for using the immunomodulatory effect of photodynamic action in the treatment of inflammatory skin diseases. The study aimed to evaluate the cytotoxic and [...] Read more.
Determination of the hypericin–photodynamic (HY–PDT) effect on the secretion of cytokines secreted by the skin cells, may be the basis for using the immunomodulatory effect of photodynamic action in the treatment of inflammatory skin diseases. The study aimed to evaluate the cytotoxic and immunomodulatory effects of hypericin (HY) in photodynamic therapy (PDT) performed in vitro on cultures of selected skin cell lines. The study used two human cell lines, primary dermal fibroblast (HDFa) and primary epidermal keratinocytes (HEKa). The MTT test was used to define the metabolic activity of treated cells. Cell supernatants subjected to sublethal PDT were assessed to determine the interleukins: IL-2, IL-8, IL-10, IL-11, IL-19, IL-22, and metalloproteinase 1 (MMP-1). The results confirm the destructive effect of HY–PDT and the immunomodulatory effects of sublethal doses on the selected skin cells, depending on the concentration of HY and the light doses. No statistically significant differences were noted in IL-2 and IL-10 concentration after HY–PDT for HEKa and HDFa lines. After using HY–PDT, the concentration of IL-8, MMP-1, IL-22, and IL-11 significantly decreased in the HEKa line. Moreover, the concentration of IL-19 and MMP-1 significantly decreased in the HDFa line. The concentration of IL-11 in the HDFa line after using only the HY, without the light, increased but decreased after HY–PDT. Our experiment confirmed that HY–PDT has not only a cytotoxic effect but, used in sublethal doses, also presents immunomodulatory properties. These may be an advantage of HY–PDT when used in the treatment of persistent skin inflammation, connected with the release of pro-inflammatory cytokines resistant to conventional treatment methods. Full article
(This article belongs to the Special Issue Natural Products in Photodynamic Therapy)
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12 pages, 2649 KiB  
Article
Natural Phytochemical and Visible Light at Different Wavelengths Show Synergistic Antibacterial Activity against Staphylococcus aureus
by Jae-Young Jeong and You-Jin Hwang
Pharmaceutics 2024, 16(5), 612; https://doi.org/10.3390/pharmaceutics16050612 - 1 May 2024
Cited by 2 | Viewed by 1612 | Correction
Abstract
As the risk of antibiotic-resistant bacteria increases, interest in non-antibiotic treatment is also increasing. Among the methods used in non-antibiotic therapy, natural antibiotics such as essential oils have disadvantages such as low efficiency. In the case of phototherapy, the light used for antibacterial [...] Read more.
As the risk of antibiotic-resistant bacteria increases, interest in non-antibiotic treatment is also increasing. Among the methods used in non-antibiotic therapy, natural antibiotics such as essential oils have disadvantages such as low efficiency. In the case of phototherapy, the light used for antibacterial activities has low penetration into the human body because of its short wavelength, making it of low medical utility. To solve this problem, this study aimed to determine conditions for enhancing the antibacterial activity of natural phytochemicals and visible light. Four natural phytochemical extracts that showed high antibacterial properties in previous studies were analyzed. Synergistic effects on antibacterial activity and cytotoxicity were determined when natural phytochemical extracts and visible light were simultaneously used. As a result, it was confirmed that the antibacterial activity increased by four times when Sanguisorba officinalis L. was irradiated with 465 nm for 10 min and 520 nm for 40 min, and Uncaria gambir Roxb. was irradiated with 465 nm for 10 min and 520 nm for 60 min compared to when Sanguisorba officinalis L. and Uncaria gambir Roxb. were used alone. The synergistic effect on antibacterial activity was independent of the absorption peak of the natural phytochemical extracts. In addition, in the case of natural phytochemical extracts with improved antibacterial activity, it was confirmed that the improvement of antibacterial activity was increased in inverse proportion to the light irradiation wavelength and in proportion to the light irradiation time. The antibacterial activity was enhanced regardless of antibiotic resistance. In the case of cytotoxicity, it was confirmed that there was no toxicity to A549 cells when treated with 465 nm, the shortest wavelength among the natural phytochemical extracts. These results show how to replace blue light, which has been underutilized due to its low transmittance and cytotoxicity. They also demonstrate the high medical potential of using natural phytochemical and visible light as a combination therapy. Full article
(This article belongs to the Special Issue Natural Products in Photodynamic Therapy)
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18 pages, 5480 KiB  
Article
Immunomodulatory Effect of Hypericin-Mediated Photodynamic Therapy on Oral Cancer Cells
by Marcin Olek, Agnieszka Machorowska-Pieniążek, Zenon P. Czuba, Grzegorz Cieślar and Aleksandra Kawczyk-Krupka
Pharmaceutics 2024, 16(1), 42; https://doi.org/10.3390/pharmaceutics16010042 - 27 Dec 2023
Cited by 5 | Viewed by 1722
Abstract
In 2020, there were 377,713 new oral and lip cancer diagnoses and 177,757 deaths. Oral cancer is a malignancy of the head and neck region, and 90% of cases are squamous cell carcinomas (OSCCs). One of the alternative methods of treating pre-cancerous lesions [...] Read more.
In 2020, there were 377,713 new oral and lip cancer diagnoses and 177,757 deaths. Oral cancer is a malignancy of the head and neck region, and 90% of cases are squamous cell carcinomas (OSCCs). One of the alternative methods of treating pre-cancerous lesions and oral cancer is photodynamic therapy (PDT). In addition to the cytotoxic effect, an important mechanism of PDT action is the immunomodulatory effect. This study used the OSCC (SCC-25) cell line and the healthy gingival fibroblast (HGF-1) line. A compound of natural origin—hypericin (HY)—was used as the photosensitizer (PS). The HY concentrations of 0–1 µM were used. After two hours of incubation with PS, the cells were irradiated with light doses of 0–20 J/cm2. The MTT test determined sublethal doses of PDT. Cell supernatants subjected to sublethal PDT were assessed for interleukin 6 (IL-6), soluble IL-6 receptor alpha (sIL-6Ralfa), sIL-6Rbeta, IL-8, IL-10, IL-11 IL-20, IL-32, and Pentraxin-3 using the Bio-Plex ProTM Assay. The phototoxic effect was observed starting with a light dose of 5 J/cm2 and amplified with increasing HY concentration and a light dose. HY-PDT affected the SCC-25 cell secretion of sIL-6Rbeta, IL-20, and Pentraxin-3. HY alone increased IL-8 secretion. In the case of HGF-1, the effect of HY-PDT on the secretion of IL-8 and IL-32 was found. Full article
(This article belongs to the Special Issue Natural Products in Photodynamic Therapy)
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22 pages, 633 KiB  
Systematic Review
The Role of Photodynamic Therapy Mediated by Natural Photosensitisers in the Management of Peri-Implantitis: A Systematic Review
by Aleksandra Warakomska, Jakub Fiegler-Rudol, Magdalena Kubizna, Dariusz Skaba and Rafał Wiench
Pharmaceutics 2025, 17(4), 443; https://doi.org/10.3390/pharmaceutics17040443 - 30 Mar 2025
Cited by 1 | Viewed by 532
Abstract
Background: Peri-implantitis, an inflammatory condition leading to progressive bone loss around dental implants, represents a significant challenge in modern implant dentistry. Conventional mechanical debridement and adjunctive antibiotics or antiseptics often fail to fully eradicate complex biofilms and may promote antibiotic resistance. Photodynamic [...] Read more.
Background: Peri-implantitis, an inflammatory condition leading to progressive bone loss around dental implants, represents a significant challenge in modern implant dentistry. Conventional mechanical debridement and adjunctive antibiotics or antiseptics often fail to fully eradicate complex biofilms and may promote antibiotic resistance. Photodynamic therapy (PDT) mediated by natural photosensitizers (e.g., curcumin, riboflavin, and 5-aminolevulinic acid) has emerged as a potential adjunctive strategy for peri-implantitis management due to its targeted antimicrobial and anti-inflammatory effects. Objectives: This systematic review aimed to evaluate the antimicrobial efficacy, clinical outcomes, and safety of PDT mediated by natural photosensitizers in the treatment of peri-implantitis and to identify optimal protocols regarding photosensitizer concentrations, light source parameters, and application techniques. Methods: Following PRISMA 2020 guidelines, databases (PubMed/Medline, Embase, Scopus, and Cochrane Library) were searched from 1 January 2015 to 3 January 2025 for English-language publications. Studies assessing naturally based PDT interventions for peri-implantitis or in vitro biofilms from diseased implant surfaces were included. Quality assessment used the Revised Cochrane Risk of Bias tool (RoB 2) for randomized controlled trials and a tailored nine-item framework for in vitro studies. Eleven studies met the inclusion criteria. Results: Despite heterogeneity in methodologies, especially regarding light wavelengths, energy densities, and photosensitizer formulations, most studies reported notable reductions in bacterial viability, biofilm mass, and clinical indices (probing depth and bleeding on probing). Curcumin and riboflavin frequently demonstrated comparable antimicrobial efficacy to standard disinfectants, while 5-aminolevulinic acid (5-ALA)-based PDT also showed promising clinical and microbiological improvements. However, complete biofilm eradication was rarely achieved. Conclusions: Natural-photosensitizer-based PDT appears to be a valuable adjunct to mechanical debridement for peri-implantitis, enhancing microbial control and clinical outcomes. Standardization of PDT protocols and further well-designed clinical trials with extended follow-up periods are warranted to confirm long-term efficacy and inform evidence-based guidelines. Full article
(This article belongs to the Special Issue Natural Products in Photodynamic Therapy)
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19 pages, 1011 KiB  
Systematic Review
Riboflavin-Mediated Photodynamic Therapy in Periodontology: A Systematic Review of Applications and Outcomes
by Jakub Fiegler-Rudol, Maciej Łopaciński, Artur Los, Dariusz Skaba and Rafał Wiench
Pharmaceutics 2025, 17(2), 217; https://doi.org/10.3390/pharmaceutics17020217 - 7 Feb 2025
Cited by 4 | Viewed by 898
Abstract
Background: Riboflavin (vitamin B2) has emerged as a promising photosensitizer in photodynamic therapy (PDT) due to its strong absorption of blue light and favourable safety profile. This systematic review aims to evaluate the efficacy of riboflavin-mediated PDT in periodontology, specifically [...] Read more.
Background: Riboflavin (vitamin B2) has emerged as a promising photosensitizer in photodynamic therapy (PDT) due to its strong absorption of blue light and favourable safety profile. This systematic review aims to evaluate the efficacy of riboflavin-mediated PDT in periodontology, specifically examining its antimicrobial effects and potential to improve clinical outcomes compared to conventional or other PDT-based treatments. Methods: A systematic review was conducted following PRISMA guidelines. A comprehensive literature search was performed in PubMed/Medline, Embase, Scopus, and the Cochrane Library. Studies published in English within the last 10 years were considered, where riboflavin served as the primary photosensitizer for dental treatments. Data extraction focused on study design, photosensitizer concentration, light source parameters, and clinical or microbiological outcomes. The risk of bias was assessed independently by two reviewers using a predefined scoring system. Results: Ten studies met the inclusion criteria, all demonstrating a low risk of bias. Riboflavin-mediated PDT consistently reduced microbial biofilms and pathogen viability in periodontitis, peri-implantitis, and endodontic models. Although some studies reported slightly lower efficacy compared to chlorhexidine or toluidine blue–based PDT, riboflavin-mediated PDT exhibited advantages such as minimal staining, low cytotoxicity, and enhanced collagen crosslinking. However, most studies were in vitro or small-scale clinical trials, limiting conclusions on long-term effectiveness. Conclusions: Riboflavin-mediated PDT shows promise as a safe adjunctive therapy for periodontal infections. Larger, well-designed clinical trials with standardized parameters and extended follow-up are needed to further evaluate its efficacy and optimize treatment protocols for routine clinical application. Full article
(This article belongs to the Special Issue Natural Products in Photodynamic Therapy)
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24 pages, 464 KiB  
Systematic Review
Riboflavin- and Hypericin-Mediated Antimicrobial Photodynamic Therapy as Alternative Treatments for Oral Candidiasis: A Systematic Review
by Maciej Łopaciński, Jakub Fiegler-Rudol, Wojciech Niemczyk, Dariusz Skaba and Rafał Wiench
Pharmaceutics 2025, 17(1), 33; https://doi.org/10.3390/pharmaceutics17010033 - 28 Dec 2024
Cited by 6 | Viewed by 947
Abstract
Background: Oral candidiasis, predominantly caused by Candida albicans, presents significant challenges in treatment due to increasing antifungal resistance and biofilm formation. Antimicrobial photodynamic therapy (aPDT) using natural photosensitizers like riboflavin and hypericin offers a potential alternative to conventional antifungal therapies. Material and [...] Read more.
Background: Oral candidiasis, predominantly caused by Candida albicans, presents significant challenges in treatment due to increasing antifungal resistance and biofilm formation. Antimicrobial photodynamic therapy (aPDT) using natural photosensitizers like riboflavin and hypericin offers a potential alternative to conventional antifungal therapies. Material and Methods: A systematic review was conducted to evaluate the efficacy of riboflavin- and hypericin-mediated aPDT in reducing Candida infections. The PRISMA framework guided the selection and analysis of 16 eligible studies published between 2014 and 2024. Data on light parameters, photosensitizer concentrations, and outcomes were extracted to assess antifungal effects. Results: Both riboflavin- and hypericin-mediated aPDT demonstrated significant antifungal activity, achieving substantial reductions in Candida biofilm and planktonic cell viability. Riboflavin activated by blue light and hypericin activated by yellow or orange light effectively targeted fluconazole-resistant Candida strains with minimal cytotoxicity to host tissues. However, complete biofilm eradication remained challenging, and variations in protocols highlighted the need for standardization. Conclusions: Riboflavin- and hypericin-mediated aPDT present promising, biocompatible alternatives for managing antifungal resistance in Candida infections. Further clinical trials and standardized protocols are essential to optimize outcomes and confirm efficacy in broader clinical settings. Full article
(This article belongs to the Special Issue Natural Products in Photodynamic Therapy)
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