Photodynamic therapy: a new treatment against COVID-19

In 2019, a new coronavirus (COVID-19) was discovered in Wuhan, China, which soon spread all over the world. The main hallmark of the disease includes fever, diarrhea, vomiting, and dry cough with dyspnea in half of the patients and acute respiratory distress syndrome (ARDS). Currently, no definitive treatment or prevention therapy exists for COVID-19 but scientists and researchers all over the world are relentlessly working to understand COVID-19 to discover novel therapeutic tools and vaccines. Today, photodynamic therapy (PDT) has been investigated as a noninvasive therapy for the treatment of this pandemic and was able to increase the healing process with the help of appropriate photosensitizers by targeting the pathogen inside the patient's body.

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

Photoactive conjugated polymer-based strategy to effectively inactivate RNA viruses

To efficiently combat viral infectious diseases, it is important to develop broadly applicable countermeasures, and efficient antiviral systems can be developed by elaborating the relationship of antiviral efficiency with the interactions between antiviral agents and viruses. In the present study, conjugated polymer (CP)-based photodynamic therapy was used to inhibit RNA virus infections. A severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pseudotyped virus composed of an SARS-CoV-2 envelope coated with the S protein and luciferase RNA genome was employed to assess antiviral efficiency. Three cationic CPs with different backbone structures, fluorene-co-phenylene (PFP), thiophene (PMNT), and phenylene vinylene (PPV), exhibit different photoinactivation effects. The highly efficient photoinactivation of PPV and PMNT is derived from the complete photodegradation of spike proteins, nucleocapsid proteins and nucleic acids of SARS-CoV-2 after binding to the viral spike proteins. Although PFP showed the highest efficiency in the photodegradation of spike proteins due to its strong binding affinity, ineffective viral inhibition was observed, which occurred because the viral gene was partially damaged under light irradiation and the process of delivering the viral gene to cells received assistance. This work preliminarily reveals the effect of CP-virus interactions on their photoinactivation activity and should be beneficial for further research on the development of highly efficient antiviral PDT agents.In this work, a photodynamic therapy system based on conjugated polymers (CPs) is developed to inhibit the infection of RNA viruses. Three cationic CPs with different backbone structures fluorene-co-phenylene (PFP), thiophene (PMNT), and phenylene vinylene (PPV) exhibit different photoinactivation effects. PPV and PMNT cause effective inactivation of viruses under light irradiation, while SARS-CoV-2 pseudotyped viruses keep infectious after treated by PFP, which is determined by the interactions between CPs with the proteins and gene of viruses. This work preliminarily reveals the effect of CP-virus interactions on their photoinactivation activity and would be beneficial to develop high-efficient antiviral PDT agents.

Daylight photodynamic therapy at home

Daylight photodynamic therapy (DPDT) is an established treatment for field-change actinic keratoses (AK) with high rates of satisfaction and success. In recent times there has been a push within the healthcare industry to reduce avoidable clinic time and complement it with community-based healthcare, including self-administration therapies. The importance of 'decentralized' healthcare and at-home therapies has been emphasized by the recent COVID-19 pandemic - access to treatments is restricted and many patients are not receiving the appropriate care in an attempt to minimize hospital-based treatments. In this project, we deconstructed DPDT and by utilizing principles of design and the concept of realistic medicine, transformed it into a user-friendly, environmentally conscious and engaging at-home therapeutic option. Information on protocols and best practice was obtained from clinical colleagues and a map of the patient pathway was outlined. The treatment was broken down and re-formed into simple steps, taking care with the number of instructions to prevent confusion. The physical form of the at-home kit was designed to facilitate the required materials for DPDT, while being simple and methodical to follow. Steps were separated into individual numbered sections, with only the materials needed at each step visible. Simple graphics are displayed alongside relevant instructions, with colouring to highlight importance. The at-home kit was iteratively improved with input from end users. As part of this initiative the DPDT athome kit is designed and prototyped in order to be posted directly to the user. In trialling this kit preclinically, the theoretical patient journey could be visualized, starting with the unboxing of the kit, then followed by the guides and directed procedure. Through feedback, iterations to the design have subsequently been made that efficiently translate the clinical procedure into a successful at-home design. One of the key principles of realistic medicine to consider is the reduction of waste. In this kit we have, where possible, used recycled and recyclable materials, and are in the process of incorporating medically approved biodegradable gloves, which will instantly reduce a high fraction of the nonrecyclable excess. Implementation of the kit in routine clinical practice will provide important feedback allowing further iterations to the design of the kit. Involving patients directly with the development work and continuously responding to the patient experience will significantly improve the final design of the at-home kit. Helping to implement an option to take this important treatment away from a hospitalized environment represents a paradigm shift in the possible delivery of DPDT and can be useful to optimize treatment delivery on a per-patient basis.

Nanozyme: a New Approach for Anti-microbial Infections

Bacteria and viruses always posed a threat to human health. Most impressively, SARS-CoV-2 has raged around the world for almost three years, causing huge loss to human health. Facing increasing challenges of drug-resistance and poor treatment efficacy, new solutions are urgently needed to combat pathogenic microorganisms. Recently, nanozymes with intrinsic enzyme-like activities emerged as a promising new type of "antibiotics”. Nanozymes exhibit superior antibacterial and antiviral activities under physiological conditions by efficiently catalyzing generation of a large number of reactive oxygen species. Moreover, enhanced therapeutic effects are achieved in nanozyme-based therapy aided by the unique physicochemical properties of nanomaterials such as photothermal and photodynamic effects. This paper reviews the latest research progress in the field of anti-microbial nanozymes, systematically summarizes and analyzes the principles of nanozymes in the treatment of bacteria and viruses from a mechanistic point of view. An outlook on the future direction and the challenges of new anti-microbial infection nanomaterials are proposed to provide inspiration for developing next generation anti-microbial nanozymes. © 2023 Science Press. All rights reserved.

Recent Advances in Green Metallic Nanoparticles for Enhanced Drug Delivery in Photodynamic Therapy: A Therapeutic Approach.

Globally, cancer is one of the leading causes of death among men and women, it is characterized by the unregulated proliferation of tumor cells. Some of the common risk factors associated with cancer development include the consistent exposure of body cells to carcinogenic agents such as alcohol, tobacco, toxins, gamma rays and alpha particles. Besides the above-mentioned risk factors, conventional therapies such as radiotherapy, and chemotherapy have also been linked to the development of cancer. Over the past decade, tremendous efforts have been invested in the synthesis of eco-friendly green metallic nanoparticles (NPs), and their medical application. Comparatively, metallic NPs have greater advantages over conventional therapies. Additionally, metallic NPs can be functionalized with different targeting moieties e.g., liposomes, antibodies, folic acid, transferrin, and carbohydrates. Herein, we review and discuss the synthesis, and therapeutic potential of green synthesized metallic NPs for enhanced cancer photodynamic therapy (PDT). Finally, the advantages of green hybridized activatable NPs over conventional photosensitizers (PSs) and the future perspectives of nanotechnology in cancer research are discussed in the review. Furthermore, we anticipate that the insights offered in this review will inspire the design and development of green nano-formulations for enhanced image-guided PDT in cancer treatment.

Photodynamic nasal SARS-CoV-2 decolonization shortens infectivity and influences specific T-Cell responses.

Background: The main objective was to evaluate the efficacy of intranasal photodynamic therapy (PDT) in SARS-CoV-2 mildly symptomatic carriers on decreasing the infectivity period. SARS-CoV-2-specific immune-stimulating effects and safety were also analysed. Methods: We performed a randomized, placebo-controlled, clinical trial in a tertiary hospital (NCT05184205). Patients with a positive SARS-CoV-2 PCR in the last 48 hours were recruited and aleatorily assigned to PDT or placebo. Patients with pneumonia were excluded. Participants and investigators were masked to group assignment. The primary outcome was the reduction in in vitro infectivity of nasopharyngeal samples at days 3 and 7. Additional outcomes included safety assessment and quantification of humoral and T-cell immune-responses. Findings: Patients were recruited between December 2021 and February 2022. Most were previously healthy adults vaccinated against COVID-19 and most carried Omicron variant. 38 patients were assigned to placebo and 37 to PDT. Intranasal PDT reduced infectivity at day 3 post-treatment when compared to placebo with a ß-coefficient of -812.2 (CI95%= -478660 - -1.3, p<0.05) infectivity arbitrary units. The probability of becoming PCR negative (ct>34) at day 7 was higher on the PDT-group, with an OR of 0.15 (CI95%=0.04-0.58). There was a decay in anti-Spike titre and specific SARS-CoV-2 T cell immunity in the placebo group 10 and 20 weeks after infection, but not in the PDT-group. No serious adverse events were reported. Interpretation: Intranasal-PDT is safe in pauci-symptomatic COVID-19 patients, it reduces SARS-CoV-2 infectivity and decelerates the decline SARS-CoV-2 specific immune-responses.

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.

Clinical effectiveness and prospects of methylene blue A systematic review

Methylene blue (MB) is a well-known pharmaceutical ingredient that is thought to have a multi-targeted therapeutic effect as an anti-malarial and neuroprotective agent and has recently been identified as a treatment for coronavirus disease 2019 (COVID-19). In this review, we present an overview of relevant clinical trials, including ongoing trials, on the therapeutic uses of MB. A search for clinical trials on clinicaltrials.gov was performed using the terms "methylene blue" and "methylthionine chloride." This review focuses on clinical trials of MB-based therapies applied to brain diseases, cancer imaging and diagnosis, infectious diseases such as malaria or COVID-19, and cardiovascular diseases. Nanoparticle-based delivery techniques have also been briefly discussed in addition to common delivery methods.

Photodynamic therapy: A new treatment against Covid-19

In 2019, a new coronavirus (COVID-19) was discovered in Wuhan, China, which soon spread all over the world. The main hallmark of the disease includes fever, diarrhea, vomiting, and dry cough with dyspnea in half of the patients and acute respiratory distress syndrome (ARDS). Currently, no definitive treatment or prevention therapy exists for COVID-19 but scientists and researchers all over the world are relentlessly working to understand COVID-19 to discover novel therapeutic tools and vaccines. Today, photodynamic therapy (PDT) has been investigated as a noninvasive therapy for the treatment of this pandemic and was able to increase the healing process with the help of appropriate photosensitizers by targeting the pathogen inside the patient's body. Copyright © 2022, Semnan University of Medical Sciences. All rights reserved.

Photodynamic Therapy: A Prospective Therapeutic Approach for Viral Infections and Induced Neoplasia.

The recent COVID-19 pandemic outbreak and arising complications during treatments have highlighted and demonstrated again the evolving ability of microorganisms, especially viral resistance to treatment as they develop into new and strong strains. The search for novel and effective treatments to counter the effects of ever-changing viruses is undergoing. Although it is an approved procedure for treating cancer, photodynamic therapy (PDT) was first used against bacteria and has now shown potential against viruses and certain induced diseases. PDT is a multi-stage process and uses photosensitizing molecules (PSs) that accumulate in diseased tissues and eradicates them after being light-activated in the presence of oxygen. In this review, studies describing viruses and their roles in disrupting cell regulation mechanisms and signaling pathways and facilitating tumorigenesis were described. With the development of innovative "or smart" PSs through the use of nanoparticles and two-photon excitation, among other strategies, PDT can boost immune responses, inactivate viral infections, and eradicate neoplastic cells. Visualization and monitoring of biological processes can be achieved in real-time with nanomedicines and better tissue penetration strategies. After photodynamic inactivation of viruses, signaling pathways seem to be restored but the underlying mechanisms are still to be elucidated. Light-mediated treatments are suitable to manage both oncogenic viral infections and induced neoplasia.

Optimization of Anti-SARS-CoV-2 Treatments Based on Curcumin, Used Alone or Employed as a Photosensitizer.

Curcumin, the bioactive compound of the spice Curcuma longa, has already been reported as a potential COVID-19 adjuvant treatment due to its immunomodulatory and anti-inflammatory properties. In this study, SARS-CoV-2 was challenged with curcumin; moreover, curcumin was also coupled with laser light at 445 nm in a photodynamic therapy approach. Curcumin at a concentration of 10 µM, delivered to the virus prior to inoculation on cell culture, inhibited SARS-CoV-2 replication (reduction >99%) in Vero E6 cells, possibly due to disruption of the virion structure, as observed using the RNase protection assay. However, curcumin was not effective as a prophylactic treatment on already-infected Vero E6 cells. Notably, when curcumin was employed as a photosensitizer and blue laser light at 445 nm was delivered to a mix of curcumin/virus prior to the inoculation on the cells, virus inactivation was observed (>99%) using doses of curcumin that were not antiviral by themselves. Photodynamic therapy employing crude curcumin can be suggested as an antiviral option against SARS-CoV-2 infection.

Harnessing Human Papillomavirus' Natural Tropism to Target Tumors.

Human papillomaviruses (HPV) are small non-enveloped DNA tumor viruses established as the primary etiological agent for the development of cervical cancer. Decades of research have elucidated HPV's primary attachment factor to be heparan sulfate proteoglycans (HSPG). Importantly, wounding and exposure of the epithelial basement membrane was found to be pivotal for efficient attachment and infection of HPV in vivo. Sulfation patterns on HSPG's become modified at the site of wounds as they serve an important role promoting tissue healing, cell proliferation and neovascularization and it is these modifications recognized by HPV. Analogous HSPG modification patterns can be found on tumor cells as they too require the aforementioned processes to grow and metastasize. Although targeting tumor associated HSPG is not a novel concept, the use of HPV to target and treat tumors has only been realized in recent years. The work herein describes how decades of basic HPV research has culminated in the rational design of an HPV-based virus-like infrared light activated dye conjugate for the treatment of choroidal melanoma.

Current status of alginate lyase from bacteria associated with marine brown algae as a combat agent against biofilm-related infection

Infection diseases are still the leading cause of death in lower and middle-income countries in the last decades. This as we know today is worsen by COVID-19, placing infectious disease as the global leading cause of death today.Onthe other hand, the morbidity and mortality of infection diseases on children around theworld is still alarming. In children, infectious disease is also the leading cause of death where lower respiratory infections are the more common, followed byDiarrhea and HIV/AIDS. The lower respiratory infections are often caused by biofilm forming bacteria such as Streptococcus pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. Bacteria in biofilms are inherently more tolerant to antimicrobial treatment when compared directly to planktonic cells of the same strain. Many studies have shown that bacteria growing in biofilms are often thousands of times more tolerant to antimicrobial treatment than their planktonic counterparts. Therefore, degradation of biofilm produced by pathogenic bacteria is very important for lower respiratory infection treatment. It urges development of alginate lyase enzyme from bacteria associated with brown algae as antibiofilm agent. In the world, costs to eradicate bacterial biofilm are continuously increased while the market for products required in biofilm treatment is steadily growing. The large share of this segment in various areas of the world attributed to microbial products to remove, prevent, and manage biofilm. Current strategies in Combating bacterial biofilm infection includes quorum sensing inhibition, drug delivery system, photothermal therapy, photodynamic therapy, catalytic therapy, nano-agent, theranostics, and matrix destruction. A natural antibiofilm agent is alginate lyase (an enzyme), which can destroy the main part of biofilm. Marine brown algae are a source of bacteria producing natural depolymerization agent of antibiofilm. This is due to the high alginate content of brown algae compared to red or green algae. Alginate is the substrate of alginate lyase produced by marine bacteria. Administration of alginate lyase can disrupt or destroy biofilm, when traced using electron micrograph before and after treatment. Most studies on application of alginate lyase as antibiofilm agent in the world is focused on cystic fibrosis case of infection caused by Pseudomonas aeruginosa. Unspecified brown algae, followed by Sargassum sp. and Laminaria sp. have been mostly studied as source of bacterial alginate lyase without regards to their alginate contents. Hopefully the use of alginate lyase from bacteria associated with broader range of marine brown algae as antibiofilm agent could be expanded. The application should be enhanced to broader cases of biofilm-related infections in theworld, not only limited to cystic fibrosis cases.

The concept of multimodal prevention and treatment of new coronavirus infection COVID-19 by drug photosensitizers and photodynamic therapy on their basis

A study of antiviral low-dose photodynamic therapy with pharmacopoeia photosensitizers in the form of methylene blue and chloride E6 (Radachlorin) solutions in vitro demonstrated complete inactivation of SARS-CoV-2 in suspension and protection of Vero E6 cells even 3.5 hours after their infection with coronavirus at concentrations of photosensitizers 100-1000 times lower than the recommended pharmacopoeia forms of these drugs. © 2022 IEEE.

Methylene blue applied to N95 respirators and medical masks for SARS-CoV-2 decontamination: What is the likelihood of inhaling methylene blue?

BACKGROUND: Global shortage of personal protective equipment (PPE), as consequence of the COVID-19 global pandemic, has unmasked significant resource inequities prompting efforts to develop methods for safe PPE decontamination for reuse. The World Health Organization (WHO) in their Rational Use of PPE bulletin cited the use of a photodynamic dye, methylene blue, and light exposure as a viable option for N95 respirator decontamination. Because WHO noted that methylene blue (MB) would be applied to surfaces through which health care workers breathe, we hypothesized that little to no MB will be detectable by spectroscopy when the PPE is subjected to MB at supraphysiologic airflow rates. METHODS: A panel of N95 respirators, medical masks, and cloth masks were sprayed with 5 cycles of 1,000 uM MB solution. Mask coupons were subjected to the equivalent of 120 L/min of 100% humidified air flow. Effluent gas was trapped in an aqueous solution and the resultant fluid was sampled for MB absorbance with a level of detection of 0.004 mg/m3. RESULTS: No detectable MB was identified for any mask using Ultraviolet-Visible spectroscopy. CONCLUSIONS: At 500-fold the amount of MB applied to N95 respirators and medical masks as were used for the decontamination study cited in the WHO Rational Use of PPE bulletin, no detectable MB was observed, thus providing safety evidence for the use of methylene blue and light exposure for mask decontamination.