Photodynamic therapy associated with nanomedicine strategies for treatment of human squamous cell carcinoma: A systematic review and meta-analysis.

A systematic review and meta-analysis were conducted about photodynamic therapy (PDT) associated with nanomedicine approaches in the treatment of human squamous cell carcinoma (HSSC). Independent reviewers conducted all steps in the systematic review. For evaluating the risk of bias, RoB 2, OHAT and SYRCLE tools were used. Meta-analysis was performed using a random-effect model (α = 0.05). For PDT against HSSC, Protoporphyrin IX was the photosensitizer, and liposomes were the nanomaterial more frequently used. Photosensitizers conjugated with nanoparticles exhibited positive results against HSSC. Tumors treated with PDT in combination with a nanotechnology drug-delivery system had an increased capacity for inhibiting the tumor growth rate (51.93%/P < 0.0001) when compared with PDT only. Thus, the PDT associated with nanomedicine approaches against HSCC could be a significant option for use in future clinical studies, particularly due to improved results in tumor growth inhibition.

Photodynamic and peptide-based strategy to inhibit Gram-positive bacterial biofilm formation.

The self-produced extracellular polymeric matrix of biofilms renders them difficult to eliminate once they are established. This makes the inhibition of biofilm formation key to successful treatment of biofilm infection. Antimicrobial photodynamic therapy (aPDT) and antimicrobial peptides offer a new approach as antibiofilm strategies. In this study sub-lethal doses of aPDT (with chlorin-e6 (Ce6-PDT) or methylene blue (MB-PDT)) and the peptides AU (aurein 1.2 monomer) or (AU)2K (aurein 1.2 C-terminal dimer) were combined to evaluate their ability to prevent biofilm development by Enterococcus faecalis. Biofilm formation was assessed by resazurin reduction, confocal microscopy, and infrared spectroscopy. All treatments successfully prevented biofilm development. The (AU)2K dimer had a stronger effect, both alone and combined with aPDT, while the monomer AU had significant activity when combined with Ce6-PDT. Additionally, it is shown that the peptides bind to the lipoteichoic acid of the E. faecalis cell wall, pointing to a possible key mechanism of biofilm inhibition.

Chlorin, Phthalocyanine, and Porphyrin Types Derivatives in Phototreatment of Cutaneous Manifestations: A Review.

Recent scientific research has shown the use of chlorin, phthalocyanines, and porphyrins derivatives as photosensitizers in photodynamic therapy in the treatment of various pathologies, including some of the major skin diseases. Thus, the main goal of this critical review is to catalog the papers that used these photosensitizers in the treatment of acne vulgaris, psoriasis, papillomavirus infections, cutaneous leishmaniasis, and skin rejuvenation, and to explore the photodynamic therapy mechanisms against these conditions alongside their clinical benefits.

Effect of Photodynamic Therapy on Microorganisms Responsible for Dental Caries: A Systematic Review and Meta-Analysis.

The aim of this study was to perform a systematic review of the literature followed by a meta-analysis about the efficacy of photodynamic therapy (PDT) on the microorganisms responsible for dental caries. The research question and the keywords were constructed according to the PICO strategy. The article search was done in Embase, Lilacs, Scielo, Medline, Scopus, Cochrane Library, Web of Science, Science Direct, and Pubmed databases. Randomized clinical trials and in vitro studies were selected in the review. The study was conducted according the PRISMA guideline for systematic review. A total of 34 articles were included in the qualitative analysis and four articles were divided into two subgroups to perform the meta-analysis. Few studies have achieved an effective microbial reduction in microorganisms associated with the pathogenesis of dental caries. The results highlight that there is no consensus about the study protocols for PDT against cariogenic microorganisms, although the results showed the PDT could be a good alternative for the treatment of dental caries.

DNA repair genes in astrocytoma tumorigenesis, progression and therapy resistance.

Glioblastoma (GBM) is the most common and malignant type of primary brain tumor, showing rapid development and resistance to therapies. On average, patients survive 14.6 months after diagnosis and less than 5% survive five years or more. Several pieces of evidence have suggested that the DNA damage signaling and repair activities are directly correlated with GBM phenotype and exhibit opposite functions in cancer establishment and progression. The functions of these pathways appear to present a dual role in tumorigenesis and cancer progression. Activation and/or overexpression of ATRX, ATM and RAD51 genes were extensively characterized as barriers for GBM initiation, but paradoxically the exacerbated activity of these genes was further associated with cancer progression to more aggressive stages. Excessive amounts of other DNA repair proteins, namely HJURP, EXO1, NEIL3, BRCA2, and BRIP, have also been connected to proliferative competence, resistance and poor prognosis. This scenario suggests that these networks help tumor cells to manage replicative stress and treatment-induced damage, diminishing genome instability and conferring therapy resistance. Finally, in this review we address promising new drugs and therapeutic approaches with potential to improve patient survival. However, despite all technological advances, the prognosis is still dismal and further research is needed to dissect such complex mechanisms.

Chitosan-Based Drug Delivery Systems for Optimization of Photodynamic Therapy: a Review.

Drug delivery systems (DDS) can be designed to enrich the pharmacological and therapeutic properties of several drugs. Many of the initial obstacles that impeded the clinical applications of conventional DDS have been overcome with nanotechnology-based DDS, especially those formed by chitosan (CS). CS is a linear polysaccharide obtained by the deacetylation of chitin, which has potential properties such as biocompatibility, hydrophilicity, biodegradability, non-toxicity, high bioavailability, simplicity of modification, aqueous solubility, and excellent chemical resistance. Furthermore, CS can prepare several DDS as films, gels, nanoparticles, and microparticles to improve delivery of drugs, such as photosensitizers (PS). Thus, CS-based DDS are broadly investigated for photodynamic therapy (PDT) of cancer and fungal and bacterial diseases. In PDT, a PS is activated by light of a specific wavelength, which provokes selective damage to the target tissue and its surrounding vasculature, but most PS have low water solubility and cutaneous photosensitivity impairing the clinical use of PDT. Based on this, the application of nanotechnology using chitosan-based DDS in PDT may offer great possibilities in the treatment of diseases. Therefore, this review presents numerous applications of chitosan-based DDS in order to improve the PDT for cancer and fungal and bacterial diseases.

Mucoadhesive In Situ Gelling Liquid Crystalline Precursor System to Improve the Vaginal Administration of Drugs.

The vaginal mucosa is a very promising route for drug administration due to its high permeability and the possibility to bypass first pass metabolism; however, current vaginal dosage forms present low retention times due to their dilution in vaginal fluids, which hampers the efficacy of many pharmacological treatments. In order to overcome these problems, this study proposes to develop a mucoadhesive in situ gelling liquid crystalline precursor system composed of 30% of oleic acid and cholesterol (7:1), 40% of ethoxylated and propoxylated cetyl alcohol, and 30% of a dispersion of 16% Poloxamer 407. The effect of the dilution with simulated vaginal fluid (SVF) on this system was evaluated by polarized light microscopy (PLM), small-angle X-ray scattering (SAXS), rheological studies, texture profile analysis (TPA), mucoadhesion study, in vitro drug release test using hypericin (HYP) as drug model, and cytotoxicity assay. PLM and SAXS confirmed the formation of an isotropic system. After the addition of three different concentrations of SVF (30, 50, and 100%), the resultant formulations presented anisotropy and characteristics of viscous lamellar phases. Rheology shows that formulations with SVF behaved as a non-Newtonian fluid with suitable shear thinning for vaginal application. TPA and mucoadhesion assays indicated the formation of long-range ordered systems as the amount of SVF increases which may assist in the fixation of the formulation on the vaginal mucosa. The formulations were able to control about 75% of the released HYP demonstrating a sustained release profile. Finally, all formulations acted as safe vaginal drug delivery systems.

Assessment of Chitosan-Based Hydrogel and Photodynamic Inactivation against Propionibacterium acnes.

Chitosan (CH) is a biopolymer that exhibits a number of interesting properties such as anti-inflammatory and antibacterial activity and is also a promising platform for the incorporation of photosensitizing agents. This study aimed to evaluate the efficacy of antimicrobial activity of chitosan hydrogel formulation alone and in combination with the methylene blue (MB) associated with antimicrobial photodynamic therapy (aPDT) against planktonic and biofilm phase of Propionibacterium acnes. Suspensions were sensitized with 12.5, 25.0, 37.5, 50.0 µg/mL of MB for 10 min and biofilms to 75, 100 and 150 µg/mL for 30 min then exposed to red light (660 nm) at 90 J/cm² and 150 J/cm² respectively. After treatments, survival fractions were calculated by counting the number of colony-forming units. The lethal effect of aPDT associated with CH hydrogel in planktonic phase was achieved with 12.5 µg/mL MB and 1.9 log10 biofilm reduction using 75 µg/mL MB. Rheological studies showed that formulations exhibited pseudoplastic non-Newtonian behavior without thixotropy. Bioadhesion test evidenced that the formulations are highly adhesive to skin and the incorporation of MB did not influence the bioadhesive force of the formulations.

Photodynamic therapy combined to cisplatin potentiates cell death responses of cervical cancer cells.

BACKGROUND: Photodynamic therapy (PDT) has proven to be a promising alternative to current cancer treatments, especially if combined with conventional approaches. The technique is based on the administration of a non-toxic photosensitizing agent to the patient with subsequent localized exposure to a light source of a specific wavelength, resulting in a cytotoxic response to oxidative damage. The present study intended to evaluate in vitro the type of induced death and the genotoxic and mutagenic effects of PDT alone and associated with cisplatin. METHODS: We used the cell lines SiHa (ATCC® HTB35™), C-33 A (ATCC® HTB31™) and HaCaT cells, all available at Dr. Christiane Soares' Lab. Photosensitizers were Photogem (PGPDT) and methylene blue (MBPDT), alone or combined with cisplatin. Cell death was accessed through Hoechst and Propidium iodide staining and caspase-3 activity. Genotoxicity and mutagenicity were accessed via flow cytometry with anti-gama-H2AX and micronuclei assay, respectively. Data were analyzed by one-way ANOVA with Tukey's posthoc test. RESULTS: Both MBPDT and PGPDT induced caspase-independent death, but MBPDT induced the morphology of typical necrosis, while PGPDT induced morphological alterations most similar to apoptosis. Cisplatin predominantly induced apoptosis, and the combined therapy induced variable rates of apoptosis- or necrosis-like phenotypes according to the cell line, but the percentage of dead cells was always higher than with monotherapies. MBPDT, either as monotherapy or in combination with cisplatin, was the unique therapy to induce significant damage to DNA (double strand breaks) in the three cell lines evaluated. However, there was no mutagenic potential observed for the damage induced by MBPDT, since the few cells that survived the treatment have lost their clonogenic capacity. CONCLUSIONS: Our results elicit the potential of combined therapy in diminishing the toxicity of antineoplastic drugs. Ultimately, photodynamic therapy mediated by either methylene blue or Photogem as monotherapy or in combination with cisplatin has low mutagenic potential, which supports its safe use in clinical practice for the treatment of cervical cancer.

Polymeric Nanoparticle-Based Photodynamic Therapy for Chronic Periodontitis in Vivo.

Antimicrobial photodynamic therapy (aPDT) is increasingly being explored for treatment of periodontitis. Here, we investigated the effect of aPDT on human dental plaque bacteria in suspensions and biofilms in vitro using methylene blue (MB)-loaded poly(lactic-co-glycolic) (PLGA) nanoparticles (MB-NP) and red light at 660 nm. The effect of MB-NP-based aPDT was also evaluated in a clinical pilot study with 10 adult human subjects with chronic periodontitis. Dental plaque samples from human subjects were exposed to aPDT-in planktonic and biofilm phases-with MB or MB-NP (25 µg/mL) at 20 J/cm² in vitro. Patients were treated either with ultrasonic scaling and scaling and root planing (US + SRP) or ultrasonic scaling + SRP + aPDT with MB-NP (25 µg/mL and 20 J/cm²) in a split-mouth design. In biofilms, MB-NP eliminated approximately 25% more bacteria than free MB. The clinical study demonstrated the safety of aPDT. Both groups showed similar improvements of clinical parameters one month following treatments. However, at three months ultrasonic SRP + aPDT showed a greater effect (28.82%) on gingival bleeding index (GBI) compared to ultrasonic SRP. The utilization of PLGA nanoparticles encapsulated with MB may be a promising adjunct in antimicrobial periodontal treatment.

Femtosecond Laser Patterning of the Biopolymer Chitosan for Biofilm Formation.

Controlling microbial growth is crucial for many biomedical, pharmaceutical and food industry applications. In this paper, we used a femtosecond laser to microstructure the surface of chitosan, a biocompatible polymer that has been explored for applications ranging from antimicrobial action to drug delivery. The influence of energy density on the features produced on chitosan was investigated by optical and atomic force microscopies. An increase in the hydrophilic character of the chitosan surface was attained upon laser micromachining. Patterned chitosan films were used to observe Staphylococcus aureus (ATCC 25923) biofilm formation, revealing an increase in the biofilm formation in the structured regions. Our results indicate that fs-laser micromachining is an attractive option to pattern biocompatible surfaces, and to investigate basic aspects of the relationship between surface topography and bacterial adhesion.

Nanotechnology-Based Drug Delivery Systems for Photodynamic Therapy of Cancer: A Review.

Photodynamic therapy (PDT) is a promising alternative approach for improved cancer treatment. In PDT, a photosensitizer (PS) is administered that can be activated by light of a specific wavelength, which causes selective damage to the tumor and its surrounding vasculature. The success of PDT is limited by the difficulty in administering photosensitizers (PSs) with low water solubility, which compromises the clinical use of several molecules. Incorporation of PSs in nanostructured drug delivery systems, such as polymeric nanoparticles (PNPs), solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), gold nanoparticles (AuNPs), hydrogels, liposomes, liquid crystals, dendrimers, and cyclodextrin is a potential strategy to overcome this difficulty. Additionally, nanotechnology-based drug delivery systems may improve the transcytosis of a PS across epithelial and endothelial barriers and afford the simultaneous co-delivery of two or more drugs. Based on this, the application of nanotechnology in medicine may offer numerous exciting possibilities in cancer treatment and improve the efficacy of available therapeutics. Therefore, the aim of this paper is to review nanotechnology-based drug delivery systems for photodynamic therapy of cancer.

Peptide KSL-W-Loaded Mucoadhesive Liquid Crystalline Vehicle as an Alternative Treatment for Multispecies Oral Biofilm.

Decapeptide KSL-W shows antibacterial activities and can be used in the oral cavity, however, it is easily degraded in aqueous solution and eliminated. Therefore, we aimed to develop liquid crystalline systems (F1 and F2) for KSL-W buccal administration to treat multispecies oral biofilms. The systems were prepared with oleic acid, polyoxypropylene (5) polyoxyethylene (20) cetyl alcohol (PPG-5-CETETH-20), and a 1% poloxamer 407 dispersion as the oil phase (OP), surfactant (S), and aqueous phase (AP), respectively. We characterized them using polarized light microscopy (PLM), small-angle X-ray scattering (SAXS), rheology, and in vitro bioadhesion, and performed in vitro biological analysis. PLM showed isotropy (F1) or anisotropy with lamellar mesophases (F2), confirmed by peak ratio quantification using SAXS. Rheological tests demonstrated that F1 exhibited Newtonian behavior but not F2, which showed a structured AP concentration-dependent system. Bioadhesion studies revealed an AP concentration-dependent increase in the system's bioadhesiveness (F2 = 15.50 ± 1.00 mN·s) to bovine teeth blocks. Antimicrobial testing revealed 100% inhibition of multispecies oral biofilm growth after KSL-W administration, which was incorporated in the F2 aqueous phase at a concentration of 1 mg/mL. Our results suggest that this system could serve as a potential vehicle for buccal administration of antibiofilm peptides.

Bacterial resistance to antimicrobial photodynamic therapy: A critical update.

Bacterial antibiotic resistance is one of the most significant challenges for public health. The increase in bacterial resistance, mainly due to microorganisms harmful to health, and the need to search for alternative treatments to contain infections that cannot be treated by conventional antibiotic therapy has been aroused. An alternative widely studied in recent decades is antimicrobial photodynamic therapy (aPDT), a treatment that can eliminate microorganisms through oxidative stress. Although this therapy has shown satisfactory results in infection control, it is still controversial in the scientific community whether bacteria manage to develop resistance after successive applications of aPDT. Thus, this work provides an overview of the articles that performed successive aPDT applications in models using bacteria published since 2010, focusing on sublethal dose cycles, highlighting the main PSs tested, and addressing the possible mechanisms for developing tolerance or resistance to aPDT, such as efflux pumps, biofilm formation, OxyR and SoxRS systems, catalase and superoxide dismutase enzymes and quorum sensing.

A 12-month follow-up of hypopigmentation after laser hair removal.

INTRODUCTION: Laser hair removal is becoming an increasingly popular alternative to traditional methods such as shaving, waxing, among other methods. Semiconductor diode lasers are considered the most efficient light sources available and are especially well suited for clinical applications including hair reduction. The effectiveness of laser hair reduction depends on many variables, including the skin type of the patient. MATERIAL AND METHODS: A patient with Fitzpatrick Skin Type IV was submitted to laser hair removal of the arms with a high-power diode laser system with long pulses with a wavelength of 800 nm, a fluence of 40 J/cm(2) and a pulse width of 20 ms. A 12-month follow-up assessment was performed and included photography and questionnaire. RESULTS: Hypopigmentation was observed after a single laser hair removal section. After 6 months with the area totally covered, a gradual suntan with a sun screen lotion with an SPF of 15 was prescribed by the dermatologist. After 12 months of the initial treatment, a complete recovery of the hypopigmentation was achieved. CONCLUSION: Although a safe procedure, lasers for hair removal may be associated with adverse side effects including undesired pigment alterations. Before starting a laser hair removal treatment, patients seeking the eradication of hair should be informed that temporary, and possibly permanent, pigmentary changes may occur.

Assessment of synergism between enzyme inhibition of Cu/Zn-SOD and antimicrobial photodynamic therapy in suspension and E. coli biofilm.

BACKGROUND: Antimicrobial Photodynamic Therapy (aPDT) is a treatment based on the interaction between a photosensitizer (PS), oxygen and a light source, resulting in the production of reactive oxygen species (ROS). There are two main types of reactions that can be triggered by this interaction: type I reaction, which can result in the production of hydrogen peroxide, superoxide anion and hydroxyl radical, and type II reaction, which is the Photodynamic Reaction, which results in singlet oxygen production. Antioxidant enzymes (e.g., catalase and superoxide dismutase) are agents that help prevent the damage caused by ROS and, consequently, reduce the effectiveness of aPDT. The aim of this study was to evaluate a possible synergism of the combined inhibition therapy of the enzyme Cu/Zn-Superoxide dismutase (SOD) and the methylene blue- and curcumin-mediated aPDT against Escherichia coli ATCC 25922, in suspension and biofilm. METHODS: Kinetic assay of antimicrobial activity of diethydithiocarbamate (DDC) and Minimum Bactericidal Concentration (MIC) of DDC were performed to evaluate the behavior of the compound on bacterial suspension. Inhibition times of Cu/Zn-SOD, as well as DDC concentration, were evaluated via bacterial susceptibility to combined therapy in suspension and biofilm. RESULTS: DDC did not present MIC at the evaluated concentrations. The inhibition time and Cu/Zn-SOD concentration with the highest bacterial reductions were 30 minutes and 1.2 µg/mL, respectively. Synergism occurred between DDC and MB-mediated aPDT, but not with CUR-mediated aPDT. CONCLUSIONS: The synergism between Cu/Zn-SOD inhibition and aPDT has been confirmed, opening up a new field of study full of possibilities.

Photodynamic Therapy Can Modulate the Nasopharyngeal Carcinoma Microenvironment Infected with the Epstein-Barr Virus: A Systematic Review and Meta-Analysis.

Nasopharyngeal carcinoma is a malignancy from epithelial cells predominantly associated with the Epstein-Barr virus (EBV) infection, and it is responsible for 140,000 deaths annually. There is a current need to develop new strategies to increase the efficacy of antineoplastic treatment and reduce side effects. Thus, the present study aimed to perform a systematic review and meta-analysis of the ability of photodynamic therapy (PDT) to modulate the tumor microenvironment and PDT efficacy in nasopharyngeal carcinoma treatment. The reviewers conducted all steps in the systematic review. PubMed, Science Direct, Scopus, Scielo, Lilacs, EMBASE, and the Cochrane library databases were searched. The OHAT was used to assess the risk of bias. Meta-analysis was performed with a random-effects model (α = 0.05). Nasopharyngeal carcinoma cells treated with PDT showed that IL-8, IL-1α, IL-1ß, LC3BI, LC3BII, MMP2, and MMP9 levels were significantly higher than in groups that did not receive PDT. NF-ĸB, miR BART 1-5p, BART 16, and BART 17-5p levels were significantly lower in the PDT group than in the control group. Apoptosis levels and the viability of nasopharyngeal carcinoma cells (>70%) infected with EBV were effective after PDT. This treatment also increased LMP1 levels (0.28-0.50/p < 0.05) compared to the control group. PDT showed promising results for efficacy in killing nasopharyngeal carcinoma cells infected with EBV and modulating the tumor microenvironment. Further preclinical studies should be performed to validate these results.

Potential Use of Brazilian Green Propolis Extracts as New Photosensitizers for Antimicrobial Photodynamic Therapy against Cariogenic Microorganisms.

The synergic effect of Streptococcus mutans and Candida albicans increases dental caries severity. Antimicrobial photodynamic therapy (aPDT) is a non-invasive treatment for antimicrobial aspects. However, the current photosensitizers (PS) have many downsides for dental applications. This study aimed to evaluate the efficiency of two different Brazilian green propolis (BGP-AF and BGP-AG) as PS for aPDT against these microorganisms. A single-species biofilm was irradiated with crude extracts and their fractions and controls. Such extracts showed the best results and were evaluated in dual-species biofilms. Photodegradation, reactive oxygen species (ROS), cytotoxicity, and color stability assays were also investigated. Reductions higher than 3 log10 CFU/mL (p < 0.0001) occurred for crude BGP in single- and dual-species biofilms. Singlet oxygen was produced in BGP (p < 0.0001). BGP-mediated aPDT delayed S. mutans and C. albicans regrowth after 24 h of treatment (p < 0.0001). Both BGP did not change the color of dental materials (p > 0.05). BGP-AF-mediated aPDT showed 72.41% of oral keratinocyte viability (p < 0.0001). BGP extracts may be used in aPDT against S. mutans and C. albicans. Specifically, BGP-AF may represent a promising PS for dental applications.

Nanocarriers for photodynamic-gene therapy.

The use of nanotechnology in medicine has important potential applications, including in anticancer strategies. Nanomedicine has made it possible to overcome the limitations of conventional monotherapies, in addition to improving therapeutic results by means of synergistic or cumulative effects. A highlight is the combination of gene therapy (GT) and photodynamic therapy (PDT), which are alternative anticancer approaches that have attracted attention in the last decade. In this review, strategies involving the combination of PDT and GT will be discussed, together with the role of nanocarriers (nonviral vectors) in this synergistic therapeutic approach, including aspects related to the design of nanomaterials, responsiveness, the interaction of the nanomaterial with the biological environment, and anticancer performance in studies in vitro and in vivo.

In Vitro Evaluation of Photodynamic Activity of Plant Extracts from Senna Species against Microorganisms of Medical and Dental Interest.

Background: Bacterial resistance requires new treatments for infections. In this context, antimicrobial photodynamic therapy (aPDT) is an effective and promising option. Objectives: Three plant extracts (Senna splendida, Senna alata, and Senna macranthera) were evaluated as photosensitizers for aPDT. Methods: Cutibacterium acnes (ATCC 6919), Streptococcus mutans (ATCC 35668), Staphylococcus aureus (ATCC 25923), Escherichia coli (ATCC 25922), and Candida albicans (ATCC 90028) were evaluated. Reactive oxygen species production was also verified. Oral keratinocytes assessed cytotoxicity. LC-DAD-MS analysis identified the chemical components of the evaluated extracts. Results: Most species cultured in the planktonic phase showed total microbial reduction (>6 log10 CFU/mL/p < 0.0001) for all extracts. C. albicans cultured in biofilm showed total microbial reduction (7.68 log10 CFU/mL/p < 0.0001) for aPDT mediated by all extracts. Extracts from S. macranthera and S. alata produced the highest number of reactive oxygen species (p < 0.0001). The S. alata extract had the highest cell viability. The LC-DAD-MS analysis of active extracts showed one naphthopyrone and seven anthraquinones as potential candidates for photoactive compounds. Conclusion: This study showed that aPDT mediated by Senna spp. was efficient in microbial suspension and biofilm of microorganisms of medical and dental interest.