The effect of erythrosine-B on the structuration of poloxamer 407 and cellulose derivative blends: in silico modelling supporting experimental studies

© 2021 Elsevier B.V. All rights reserved. This is the accepted manuscript version of an article which has been published in final form at https://doi.org/10.1016/j.msec.2021.112440Erythrosine is a dye approved for medical use that has shown promising photodynamic activity, allowing for the inactivation of microorganisms and activity against malignant cells. Despite the great photodynamic potential, erythrosine exhibits hydrophilicity, negatively impacting its action in biological membranes. Therefore, the incorporation of erythrosine in micellar polymeric systems, such as poloxamers, may overcome this limitation. Moreover, using bioadhesive and thermoresponsive polymers to combine in situ gelation and bioadhesion may enhance retention of this topically applied drug. In this work, mucoadhesive and thermoresponsive micellar systems were prepared containing erythrosine in two states: the native form (ERI) and the disodium salt (ERIs). The systems were evaluated based on the effect of ERI/ERIs on the micellar structure of the binary polymer mixtures. Optimised combinations of poloxamer 407 (polox407) and mucoadhesive sodium carboxymethylcellulose (NaCMC) or hydroxypropyl methylcellulose (HPMC) were used as micellar systems for ERI or ERIs delivery. The systems were studied with respect to theoretical interactions, qualitative composition, morphology, and micellar properties. In silico modelling indicated a higher interaction of the drug with poly(ethylene oxide) (PEO) than poly(propylene oxide) (PPO) fragments of polox407. Systems containing NaCMC displayed a repulsive effect in the presence of erythrosine, due to the polymer's charge density. Both systems could convert the photosensitizer in its monomeric form, ensuring photodynamic activity. In these mixtures, crystallinity, critical micellar temperature and enthalpy of polox407 micellisation were reduced, and micellar size, evaluated by transmission electron microscopy (TEM), showed low impact of ERI/ERIs in HPMC preparations. Aiming toward photodynamic applications, the findings showed how ERI or ERIs can affect the micellar formation of gels composed of 17.5% (w/w) polox407 and 3% (w/w) HPMC or 1% (w/w) NaCMC, important for understating their behaviour and future utilisation as erythrosine delivery systems.Peer reviewe

INTERAÇÃO DO LAPACHOL COM NANOPLATAFORMAS MICELARES DRUG DELIVERY

Este artigo contempla aspectos relacionados a capacidade de interação e monomerização do fármaco lapachol com os sistemas nanoestruturados micelares F127 e P123. Para isso, estudos prévios de agregação foram conduzidos para descrição da dinâmica agregacional do princípio ativo e sua influência nas propriedades espectroscópicas. A proposta deste trabalho é enriquecer o arsenal terapêutico atual com um novo formulado descrito pelo elevado potencial antimalárico, antitripanossômico, analgésico e antitinflamatório

Phenazines and Photoactive Formulations: Promising Photodrugs for Photodynamic Therapy

Photodynamic Therapy (PDT) is a therapeutic modality that can be applied with many photosensitizing compounds (PS). Photosensitization has shown promising results in damage against abnormal cell growth as cancer and inactivating a broad spectrum of microorganisms with no reported microbial resistance. Photodynamic processes occur by the light action at the appropriate wavelength in the presence of a PS that will be excited by the energy absorbed from the light source, where the interaction with the oxygen present in the cell will generate reactive oxygen species (ROS). The potential of phenazines as a photosensitizer is reviewed in this chapter as a practical guide to the future development of formulations that are effective for cancer treatment and microorganism control. Here we mainly summarize articles about phenazines from 2005 to 2021 when we performed a systematic search in the Science Direct, PubMed, Google Scholar, Web of Science, and Scopus databases. The carrier systems formed by micellar copolymers type Pluronic® have demonstrated effectiveness in incorporating several PS, ensuring its monomeric form for PDT applications. The fundamentals of the photosensitization mechanism are discussed. Studies have shown the beneficial impact of an appropriate incorporation technique to enhance the cellular uptake of phenazines compounds

REVISÃO DO FOTOSSENSIBILIZADOR FTALOCIANINA UTILIZADA NA TERAPIA FOTODINÂMICA E SUA APLICABILIDADE FRENTE AO TRATAMENTO DE DIVERSOS AGENTES PATOGÊNICOSrsos agentes patogênicos.

A terapia fotodinâmica (TFD) é uma modalidade de tratamento utilizada para amenizar e curar diversas doenças. Consiste na combinação de uma substância fotoativa denominada fotossensibilizador (FS) e a luz visível, com o objetivo de formar oxigênio singleto e outras espécies reativas de oxigênio (EROS), agentes precursores da morte celular por apoptose e/ou necrose. As ftalocianinas estão entre as substâncias FS mais utilizadas na TFD, mesmo em face de sua elevada hidrofobicidade e dificuldade de monomerização. Sua capacidade inibitória contra micro-organismos sua ação fotodinâmica frente a diversas linhagens de células cancerígenas, fizeram das ftalocianinas protagonistas em diversos artigos científicos. Este artigo de revisão tem como objetivo apresentar as características deste importante composto fotossensibilizador e as propriedades da Terapia Fotodinâmica, que tem conquistado espaço no Brasil. &nbsp

Boosting the photodynamic activity of erythrosine B by using thermoresponsive and adhesive systems containing cellulose derivatives for topical delivery

Erythrosine displays potential photodynamic activity against microorganisms and unhealthy cells. However, erythrosine has high hydrophilicity, negatively impacting on permeation through biological membranes. Combining biological macromolecules and thermoresponsive polymers may overcome these erythrosine-related issues, enhancing retention of topically applied drugs. The aim of this work was to investigate the performance of adhesive and thermoresponsive micellar polymeric systems, containing erythrosine in neutral (ERI) or disodium salt (ERIs) states. Optimized combinations of poloxamer 407 (polox407) and sodium carboxymethylcellulose (NaCMC) or hydroxypropyl methylcellulose (HPMC) were used as platforms for ERI/ERIs delivery. The rheological and mechanical properties of the systems was explored. Most of the formulations were plastic, thixotropic and viscoelastic at 37 °C, with suitable gelation temperature for in situ gelation. Mechanical parameters were reduced in the presence of the photosensitizer, improving the softness index. Bioadhesion was efficient for all hydrogels, with improved parameters for mucosa in contrast to skin. Formulations composed of 17.5 % polox407 and 3 % HPMC or 1 % NaCMC with 1 % (w/w) ERI/ERIs could release the photosensitizer, reaching different layers of the skin/mucosa, ensuring enough production of cytotoxic species for photodynamic therapy. Functional micelles could boost the photodynamic activity of ERI and ERIs, improving their delivery and contact time with the cells

Multifunctional Nanoparticles as High-Efficient Targeted Hypericin System for Theranostic Melanoma

Biotin, spermine, and folic acid were covalently linked to the F127 copolymer to obtain a new drug delivery system designed for HY-loaded PDT treatment against B16F10 cells. Chemical structures and binders quantification were performed by spectroscopy and spectrophotometric techniques (1NMR, HABA/Avidin reagent, fluorescamine assay). Critical micelle concentration, critical micelle temperature, size, polydispersity, and zeta potential indicate the hydrophobicity of the binders can influence the physicochemical parameters. Spermine-modified micelles showed fewer changes in their physical and chemical parameters than the F127 micelles without modification. Furthermore, zeta potential measurements suggest an increase in the physical stability of these carrier systems. The phototherapeutic potential was demonstrated using hypericin-loaded formulation against B16F10 cells, which shows that the combination of the binders on F127 copolymer micelles enhances the photosensitizer uptake and potentializes the photodynamic activity

Photo-Phytotherapeutic Gel Composed of Copaifera reticulata, Chlorophylls, and k-Carrageenan: A New Perspective for Topical Healing

Chronic wound healing represents an impactful financial burden on healthcare systems. In this context, the use of natural products as an alternative therapy reduces costs and maintains effectiveness. Phytotherapeutic gels applied in photodynamic therapy (PDT) have been developed to act as topical healing medicines and antibiotics. The bioactive system is composed of Spirulina sp. (source of chlorophylls) and Copaifera reticulata oil microdroplets, both incorporated into a polymeric blend constituted by kappa-carrageenan (k-car) and F127 copolymer, constituting a system in which all components are bioactive agents. The flow behavior and viscoelasticity of the formulations were investigated. The photodynamic activity was accessed from studies of the inactivation of Staphylococcus aureus bacteria, the main pathogen of hospital relevance. Furthermore, in vivo studies were conducted using eighteen rabbits with dermatitis (grade III and IV) in both paws. The gels showed significant antibiotic potential in vitro, eliminating up to 100% of S. aureus colonies in the presence or absence of light. The k-car reduced 41% of the viable cells; however, its benefits were enhanced by adding chlorophyll and copaiba oil. The animals treated with the phytotherapeutic medicine showed a reduction in lesion size, with healing and re-epithelialization verified in the histological analyses. The animals submitted to PDT displayed noticeable improvement, indicating this therapy’s viability for ulcerative and infected wounds. This behavior was not observed in the iodine control treatment, which worsened the animals’ condition. Therefore, gel formulations were a viable alternative for future pharmaceutical applications, aiming at topical healing

Thermo and Photoresponsive Emulgel Loaded with Copaifera reticulata Ducke and Chlorophylls: Rheological, Mechanical, Photodynamic and Drug Delivery Properties in Human Skin

Recently, the number of new cases of cutaneous leishmaniasis has been of concern among health agencies. Research that offers new therapeutic alternatives is advantageous, especially those that develop innovative drugs. Therefore, this paper presents the incorporation of Copaifera reticulata Ducke and chlorophyll extract into Pluronic®® F127 and Carbopol gels, under optimized polymer quantities. The chlorophyll extract (rich in photosensitizing compounds) was obtained by continuous-flow pressurized liquid extraction (PLE), a clean, environmentally friendly method. The system aims to act as as a leishmanicidal, cicatrizant, and antibiotic agent, with reinforcement of the photodynamic therapy (PDT) action. Rheological and mechanical analyses, permeation studies and bioadhesiveness analyses on human skin, and PDT-mediated activation of Staphylococcus aureus were performed. The emulgels showed gelation between 13° and 15 °C, besides pseudoplastic and viscoelastic properties. Furthermore, the systems showed transdermal potential, by releasing chlorophylls and C. reticulata Ducke into the deep layers of human skin, with good bioadhesive performance. The application of PDT reduced three logarithmic colony-forming units of S. aureus bacteria. The results support the potential of the natural drug for future clinical trials in treating wounds and cutaneous leishmania

Design and Optimization of a Natural Medicine from Copaifera reticulata Ducke for Skin Wound Care

In this study, we developed a bioadhesive emulsion-filled gel containing a high amount of Copaifera reticulata Ducke oil-resin as a veterinary or human clinical proposal. The phytotherapeutic system had easy preparation, low cost, satisfactory healing ability, and fly repellency, making it a cost-effective clinical strategy for wound care and myiasis prevention. Mechanical, rheological, morphological, and physical stability assessments were performed. The results highlight the crosslinked nature of the gelling agent, with three-dimensional channel networks stabilizing the Copaifera reticulata Ducke oil-resin (CrD-Ore). The emulgel presented antimicrobial activity, satisfactory adhesion, hardness, cohesiveness, and viscosity profiles, ensuring the easy spreading of the formulation. Considering dermatological application, the oscillatory responses showed a viscoelastic performance that ensures emulgel retention at the action site, reducing the dosage frequencies. In Vivo evaluations were performed using a case report to treat ulcerative skin wounds aggravated by myiasis in calves and heifers, which demonstrated healing, anti-inflammatory, and repellent performance for the emulsion-filled gel. The emulgel preparation, which is low in cost, shows promise as a drug for wound therapy

Copaiba Oil-Based Emulsion as a Natural Chemotherapeutic Agent for the Treatment of Bovine Mastitis: In Vivo Studies

Copaiba oil-resin (COR) extracted from Copaifera reticulata Ducke has been used as a natural chemotherapeutic agent for a wide range of therapeutic applications. This study presents an emulgel design with a high concentration of COR, designed to prevent and treat mastitis. The COR was stabilized in a gel matrix constituted by carbopol C934P and Pluronic® F127 (ECO formulation) ratios. The permeation study of ECO was accessed by Fourier transform infrared photoacoustic spectroscopy (FTIR-PAS). The results reveal a high capacity of ECO to permeate deep skin layers. Dairy cows with a history of mastitis were used as in vivo models and exposed to ECO treatment. Monitoring of the teat’s inflammatory response showed that ECO effectively prevents mastitis. Furthermore, the ECO formulation was able to form a thin film gel on the application side, preventing fly proliferation and significantly reducing the pathogen load. This study reveals a drug that can used as an alternative application for mastitis in human or veterinary clinics