Synthesis Strategy of Tetrapyrrolic Photosensitizers for Their Practical Application in Photodynamic Therapy

This review presents a wide range of tetrapyrrole photosensitizers used for photodynamic therapy (PDT), antimicrobial photodynamic therapy, photoinactivation of pathogens. Methods of synthesis and design of new photosensitizers with greater selectivity of accumulation in tumor tissue and increased photoinduced antitumor activity are considered. The issues of studying the properties of new photosensitizers, their photoactivity, the ability to generate singlet oxygen, and the possibility of using targeted photodynamic therapy in clinical practice are discussed. The review examines the work on PDT by national and foreign researchers.

Photodynamic inactivation of Rhizopus oryzae - in vitro study

During the COVID-19 pandemic, several complications arose in infected patients, one of them being mucormycosis, which is an extremely aggressive fungal disease with a high mortality rate, especially in patients with compromised immune systems. Most cases of mucormycosis are caused by the fungus Rhizopus oryzae, also known as black fungus, with 90% of cases affecting the rhinocerebral site. The treatment tools used are based on high doses of amphotericin B and posaconazole, associated with surgical resections when possible. However, even with aggressive antifungal treatment, the estimated attributable mortality rate is high [1]. In the absence of surgical debridement of the infected tissue, antifungal treatment alone is not curative. So there is a need for development of adjuvant treatments. Antimicrobial Photodynamic Therapy (aPDT) may constitute an auxiliary therapeutic option for mucormycosis [2]. Due to the lack of reports on the photodynamic inactivation of R. oryzae, we investigated different protocols Photodithazine (PDZ) as a photosensitizer. The response on the fungus growing rate under distinct treatment parameters as photosensitizer concentration, incubation time, and association with surfactant, will be presented for both white and black hyphal phases, and infective spore phase. Preliminary results show the potential use of photodynamic therapy for the inactivation and growth control of the R. oryzae.Copyright © 2023

Nasal photodisinfection in an industrial workplace for COVID-19 suppression

Antimicrobial photodynamic therapy (aPDT) [1] has been deployed in tens of thousands of patients in Canada for preoperative intranasal bacterial suppression to reduce the prevalence rate of surgical site infections [2]. This treatment has proven safe and effective, with infection rate reductions of 40-80% in tertiary care systems despite only requiring 4 minutes of therapy [2]. We previously demonstrated that aPDT eliminates the RNA signature of wild-type SARS-CoV-2 in vitro, with reduction of RT-qPCR threshold counts (DELTACt = 22) in a light-dose dependent manner (C = 320 muM, lambda = 664 nm, F = 36 J/cm2) [3]. Photodynamic targets were found to include the receptor binding domain, spike protein and nucleocapsid domain, consistent with a broad spectrum peroxidative effect on anionic moieties throughout the virion [3]. This work describes the benefits of using regular aPDT treatments in the industrial workplace for the purpose of employee COVID-19 prevention. From July 2020 to August 2021, aPDT was deployed at a large Canadian food processing plant. Meat processing facilities face distinctive challenges in control of infectious diseases, including SARS-CoV-2. Factors that increase processing workers' risk for exposure to SARS-CoV-2 include close contact for 8-12 hour shifts, shared transportation, and congregate housing [4,5]. The presence of a slaughtering plant in a community is associated with a 51 to 75% increase in COVID-19 cases per thousand over the baseline community rate, and a 37 to 50% increase in death rate over the baseline community rate [5]. Methylene blue-mediated aPDT (SteriwaveTM Nasal Photodisinfection System, Ondine Biomedical Inc., Vancouver, BC) was added to the standard infection control bundle at the plant, along with employee education. Treatments were administered free of charge to approximately 1,500 employees on a voluntary basis during paid work hours. Compliance levels of employees requesting aPDT were 85%. To determine intervention efficacy, the rate of qPCR-positive COVID-19 tests over the treatment time period was compared to the same rate in the surrounding province. Results demonstrated a reduction of COVID-19 rate of over 3 times (p<.0001, Fisher's Exact Test) in the treated population compared to the untreated population, with the largest adverse event being mild (self-limiting) rhinorrhea in < 1% of cases. The plant continued production and distribution of products without disruption. Important outcomes from this quality improvement initiative included (a) aPDT proved to be a rapid, lightweight intervention that could be deployed at high compliance levels in a commercial high-throughput food processing operation, (b) significant impact (>3X reduction) on the COVID-19 rates was observed and (c) COVID-19-related comorbidities including acute and long-term illness, disability, and death were proportionately avoided.Copyright © 2023

Molecular docking study of potential antimicrobial photodynamic therapy as a potent inhibitor of SARS-CoV-2 main protease: An in silico insight.

BACKGROUND: Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) is rapidly spreading. Recently, antimicrobial photodynamic therapy (aPDT) using safe and cost-effective photosensitizers is introduced as a valuable therapy for the eradication of microbial infections. OBJECTIVE: This in silico study aimed to investigate the potential of aPDT against of SARS-CoV-2 main protease (MPro). METHODS: In this study to evaluate possible inhibitors of SARS-CoV-2 during aPDT, a computational model of the SARS-CoV-2 MPro was constructed in complex with emodin, resveratrol, pterin, and hypericin as the natural photosensitizers. RESULTS: According to the molecular docking analysis of protein-ligand complexes, emodin and resveratrol with a high affinity for SARS-CoV-2 MPro showed binding affinity -7.65 and -6.81 kcal/mol, respectively. All natural photosensitizers with ligand efficiency less than 0.3 fulfilled all the criteria of Lipinski's, Veber's, and Pfizer's rules, except hypericin. Also, the results of molecular dynamic simulation confirmed the stability of the SARS-CoV-2 MPro and inhibitor complexes. CONCLUSION: As the results showed, emodin, resveratrol, and pterin could efficiently interact with MPro of SARS CoV-2. It can be concluded that aPDT using these natural photosensitizers may be considered as a potential SARS-CoV-2 MPro inhibitor to control COVID-19.

Phototherapies for COVID-19-associated opportunistic oral infections.

Opportunistic infections are widely described in patients with novel coronavirus disease 2019 (COVID-19); however, very few studies have addressed those affecting the oral cavity. Given the lack of information on the clinical presentations and the available treatment options, the present study aimed to show a case in which a combination of antimicrobial photodynamic therapy (aPDT) and photobiomodulation therapy (PBMT) was used for the management of two concomitant COVID-19-associated opportunistic oral infections (oral pseudomembranous candidiasis and recurrent herpes labialis). Within 7 days and without any systemic drug administration, all the lesions resolved completely, and the patient no longer reported oral pain or discomfort. According to the current case report and taking into consideration the significant gaps in the knowledge and understanding of COVID-19, this combination of phototherapy modalities seems to be a promising tool for managing viral and fungal opportunistic oral infections.

How can biophotonics help dentistry to avoid or minimize cross infection by SARS-CoV-2?

Biophotonics is defined as the combination of biology and photonics (the physical science of the light). It is a general term for all techniques that deal with the interaction between biological tissues/cells and photons (light). Biophotonics offers a great variety of techniques that can facilitate the early detection of diseases and promote innovative theragnostic approaches. As the COVID-19 infection can be transmitted due to the face-to-face communication, droplets and aerosol inhalation and the exposure to saliva, blood, and other body fluids, as well as the handling of sharp instruments, dental practices are at increased risk of infection. In this paper, a literature review was performed to explore the application of Biophotonics approaches in Dentistry focusing on the COVID-19 pandemic and how they can contribute to avoid or minimize the risks of infection in a dental setting. For this, search-related papers were retrieved from PubMED, Scielo, Google Schoolar, and American Dental Association and Centers for Disease Control and Prevention databases. The body of evidence currently available showed that Biophotonics approaches can reduce microorganism load, decontaminate surfaces, air, tissues, and minimize the generation of aerosol and virus spreading by minimally invasive, time-saving, and alternative techniques in general. However, each clinical situation must be individually evaluated regarding the benefits and drawbacks of these approaches, but always pursuing less-invasive and less aerosol-generating procedures, especially during the COVID-19 pandemic.

Evaluation of methylene blue based photodynamic inactivation (PDI) against intracellular B-CoV and SARS-CoV2 viruses under different light sources in vitro as a basis for new local treatment strategies in the early phase of a Covid19 infection.

The local antiviral photodynamic inactivation (PDI) may prove to be a helpful tool reducing the viral load in the nose and throat area in the early phase of a Covid19 infection. Both the infectivity and the prognosis of SARS-CoV-2 infections in the early phase can depend on the viral load in this area. The aim of our study was to find a simplified PDI therapy option against corona viruses in this region with low dose methylene blue (MB) as photosensitizer and use of LED light instead of laser. As a substitute for SARS-CoV2 viruses we started with BCoV infected U373 cells first. We used an 810nm diode laser with 300mW/cm2 and 100J/cm2 light dose as well as a 590 nm LED and a broadband LED with irradiation intensity of 10,000 lx each (irradiation time 2.5 and 10 min) and concentrations of the sensitizer of 0.001% and 0.0001%. The 0.001% MB sensitizer experiments showed similar results with all exposures. The logarithmic reduction factor varied between ≥ 5.29 and ≥ 5.31, (0.001% MB sensitizer) and ≥ 4.6 and ≥ 5.31 (0.0001% MB) respectively. Extending the LED irradiation time from 2 to 5 and 10 minutes did not change these results. In contrast approaches of BCoV-infected cells in the dark, treated with 0.001% and 0.0001% MB sensitizer alone, a lot of residual viruses could be detected after 10 minutes of incubation (RF 0.9 and RF 1.23 for 0.001% MB and 0.0001% MB respectively) In our SARS-CoV-2 experiments with VERO E6 infected cells the irradiation time was reduced to 1, 2 and 3 minutes for both concentrations with increasing broadband LED radiation intensity from 20 to 50 and 100.000 lx. (RF 4.67 for 0.001% and 0.0001% respectively). This showed a minimum concentration of 0.0001%MB and a minimum radiation intensity of 20,000 lx leads to a 99.99% reduction of intracellular and extracellular viruses after one minute exposure.

Methylene Blue-Based Nano and Microparticles: Fabrication and Applications in Photodynamic Therapy.

Methylene blue (MB) has been used in the textile industry since it was first extracted by the German chemist Heinrich Caro. Its pharmacological properties have also been applied toward the treatment of certain diseases such as methemoglobinemia, ifosfamide-induced encephalopathy, and thyroid conditions requiring surgery. Recently, the utilization of MB as a safe photosensitizer in photodynamic therapy (PDT) has received attention. Recent findings demonstrate that photoactivated MB exhibits not only anticancer activity but also antibacterial activity both in vitro and in vivo. However, due to the hydrophilic nature of MB, it is difficult to create MB-embedded nano- or microparticles capable of increasing the clinical efficacy of the PDT. This review aims to summarize fabrication techniques for MB-embedded nano and microparticles and to provide both in vitro and in vivo examples of MB-mediated PDT, thereby offering a future perspective on improving this promising clinical treatment modality. We also address examples of MB-mediated PDT in both cancer and infection treatments. Both in-vitro and in-vivo studies are summarized here to document recent trends in utilizing MB as an effective photosensitizer in PDT. Lastly, we discuss how developing efficient MB-carrying nano- and microparticle platforms would be able to increase the benefits of PDT.

Photobiomodulation therapy and antimicrobial photodynamic therapy for orofacial lesions in patients with COVID-19: A case series.

Oral lesions related to the novel Coronavirus Disease 2019 (COVID-19) have been increasingly described; however, clinical and epidemiological information is still scant. Although a diversity of therapeutic strategies for the management of these lesions are present in the literature, one can note a lack of standardization and doubtful effectiveness. Thus, the present study aimed to report a series of cases in which a combination of antimicrobial photodynamic therapy (aPDT) and photobiomodulation therapy (PBMT) was used for orofacial lesions in patients suffering from COVID-19. It was noted, in all cases, a marked improvement in tissue repair and pain relief within a few days; moreover, the patients recovered their orofacial functions satisfactorily. Based on the present series of cases and having in mind the conspicuous lack of information on the different aspects of COVID-19, the protocol which combined aPDT with PMBT seemed to be effective in the management of COVID-19-related orofacial lesions.

Robust antimicrobial photodynamic therapy with curcumin-poly (lactic-co-glycolic acid) nanoparticles against COVID-19: A preliminary in vitro study in Vero cell line as a model.

BACKGROUND: In this study, the ability of antimicrobial photodynamic therapy (aPDT) as a treatment approach and adjuvant therapy using curcumin-poly (lactic-co-glycolic acid) nanoparticles (Cur@PLGA-NPs) to inactivate Coronavirus disease 2019 (COVID-19) in plasma was investigated. Furthermore, to verify whether the quality requirement of aPDT-treated plasma is acceptable, the differences of the levels of clotting factors, total plasma proteins, and anti-A and/or anti-B antibodies titrations in plasma of patient before and after aPDT treatment were investigated. MATERIALS AND METHODS: Cur@PLGA-NPs was synthesized using Electrospinning process and characterized by different analysis including Scanning Electron Microscope (SEM), Transmission Electron Microscope (TEM), and Fourier Transform Infrared (FTIR) spectroscopy assays. The presence of the SARS-CoV-2 in the plasma samples of patients suspected of having COVID-19 was confirmed by real-time reverse transcription-polymerase chain reaction (RT-PCR) assay. Then, the treated plasma samples with Cur@PLGA-NPs plus blue laser were exposed to Vero cells. Eventually, cell cytotoxicity and apoptotic effects of treated Vero cells were evaluated. Levels of clotting factors including prothrombin time (PT) and activated partial thromboplastin time (APTT), total plasma proteins, and anti-A and/or anti-B antibodies measurements were performed using the coagulometer, method of Bradford, and titration procedure, respectively. RESULTS: The presence of SARS-CoV-2 was positive in 84.3 % of samples. Different concentrations of Cur@PLGA-NPs (3, 5, 7, and 10 % wt.), the irradiation times of blue laser (1, 3, and 5 min), and aPDT with the maximum dosed of blue laser light (522.8 J/cm2) plus 10 % wt. Cur@PLGA-NPs had no cytotoxicity. Although there were significant cell degradation and apoptotic effects in treated Vero cells with treated plasma using 10 % wt. Cur@PLGA-NPs, and a blue laser at an energy density of 522.8 J/cm2, no visible changes in cells and apoptosis were observed following aPDT. Total plasma protein content, PT, APTT, and anti-A and/or anti-B antibodies titers showed no significant changes (P > 0.05 for all comparisons) in treated plasma as compared to untreated plasma. CONCLUSION: aPDT exhibited in vitro anti-COVID-19 activities in the treated plasma containing SARS-COV-2 without Vero cell apoptosis and any adverse effects on plasma quality in aPDT-exposed plasma.

Computational Biology Analysis of COVID-19 Receptor-Binding Domains: A Target Site for Indocyanine Green Through Antimicrobial Photodynamic Therapy.

Introduction: The receptor-binding domain (RBD) in SARS-CoV-2 binds strongly to angiotensin-converting enzyme 2 (ACE2) receptors and causes coronavirus disease 2019 (COVID-19). Antimicrobial photodynamic therapy (aPDT) is a well-established treatment option for the treatment of several viral infections. This in silico study was conducted to target the RBD of SARS-CoV-2 as a target site for aPDT. Methods: SARS-CoV-2-RBD was selected as a novel target for indocyanine green (ICG) as a photosensitizer during aPDT to exploit its molecular modeling, hierarchical nature of protein structure, and physico-chemical properties using several bioinformatic tools. The binding mode of the RBD to ICG was assessed via protein-ligand docking. Results: The results of a computational biology analysis revealed that SARS-CoV-2-RBD has 223 amino acids with a molecular weight of 25098.40 Da. RBD is most similar to 6W41 with an E-value of 4e-167, identity of 100%, and query cover of 100%. The aliphatic index of the RBD protein sequences was 71.61, suggesting that the protein is stable in a broad spectrum of temperatures. The predicted structure of RBD showed that it is a protein with a positive charge and a random coil structure (69.51%). Four ligands were modeled in this entry, including one N-acetyl-D-glucosamine (NAG), one glycerol (GOL), and two sulfate ions (SO4 ), to which ICG desires to bind in the molecular docking analysis. Conclusion: Molecular modeling and simulation analysis showed that SARS-CoV-2-RBD could be a substrate for binding to ICG during aPDT to control the spread of COVID-19.

A combination of phototherapy modalities for extensive lip lesions in a patient with SARS-CoV-2 infection.

Many oral signs and symptoms related to the novel coronavirus disease (COVID-19) have been reported; however, both prevalence and etiology are still undetermined. Since the clinical features of the oral lesions seen in COVID-19 are highly heterogeneous and the treatments differ considerably in the literature, the present study aimed to report a clinical case in which a combination of antimicrobial photodynamic therapy (aPDT) and photobiomodulation therapy (PBMT) was used for extensive lip lesions in a patient suffering from COVID-19. Within 4 days and without any systemic drug administration, after two sessions of aPDT and one session of PBMT, the lip lesions were completely healed, and the patient recovered her orofacial functions satisfactorily. According to the current case report and taking into consideration the evident lack of information about many aspects of COVID-19 infection, this combination of phototherapy modalities seems to be a promising tool for managing COVID-19-related lip lesions; however, more studies are necessary.

Antimicrobial Photodynamic Therapy in the Control of COVID-19.

Antimicrobial photodynamic therapy (aPDT), using well known, safe and cost-effective photosensitizers, such as phenothiazines, e.g., methylene blue (MB), or porphyrins, e.g., protoporphyrin-IX (PP-IX), might help to mitigate the COVID-19 either to prevent infections or to develop photoactive fabrics (e.g., masks, suits, gloves) to disinfect surfaces, air and wastewater, under artificial light and/or natural sunlight.