RESUMEN

BACKGROUND: Photodynamic therapy (PDT) is an anticancer treatment that utilizes the interaction of light and a photosensitiser (PS), promoting tumour cell death mediated by generation of reactive oxygen species. In this study, we evaluated the in vitro photoactivity of four meso-substituted porphyrins and a porphyrin coupled to a fullerene. METHODS: The cell line employed was the LM3 mammary adenocarcinoma, and the PS with the best photokilling activity was administered to mice bearing the LM3 subcutaneously implanted adenocarcinoma. The TEMCP4+ porphyrin and its analogue TEMCC4+ chlorine contain four identical carbazoyl substituents at the meso positions of the tetrapyrrolic macrocycle and have A4 symmetry. The TAPP derivative also has A4 symmetry, and it is substituted at the meso positions by aminopropoxy groups. The DAPP molecule has ABAB symmetry with aminopropoxy and the trifluoromethyl substituents in trans positions. The TCP-C604+ dyad is formed by a porphyrin unit covalently attached to the fullerene C60. RESULTS: The PSs are taken up by the cells with the following efficiency: TAPP> TEMCP4+ = TEMCC4+ > DAPP >TCP-C604+, and the amount of intracellular PS correlates fairly with the photodamage degree, but also the quantum yields of singlet oxygen influence the PDT outcome. TAPP, DAPP, TEMCC4+ and TEMCP4+ exhibit high photoactivity against LM3 mammary carcinoma cells, being TAPP the most active. After topical application of TAPP on the skin of mice bearing LM3 tumours, the molecule is localized mainly in the stratum corneum, and at a lower extent in hair follicles and sebaceous glands. Systemic administration of TAPP produces a tumour: normal skin ratio of 31.4, and high accumulation in intestine and lung. CONCLUSION: The results suggest a potential use of topical TAPP for the treatment of actinic keratosis and skin adnexal neoplasms. In addition, selectivity for tumour tissue after systemic administration highlights the selectivity of and potentiality of TAPP as a new PS.

Asunto(s)

Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/uso terapéutico , Porfirinas/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Animales , Masculino , Ratones , Ratones Endogámicos BALB C , Microscopía Fluorescente , Fármacos Fotosensibilizantes/farmacocinética , Distribución Tisular

RESUMEN

PURPOSE: Melanoma is an invasive and very aggressive skin cancer due to its multi-drug resistance that results in poor patient survival. There is a need to test new treatment approaches to improve therapeutic efficacy and reduce side effects of conventional treatments. METHODS: PLA/PVA nanoparticles carrying both Dacarbazine and zinc phthalocyanine was produced by double emulsion technique. The characterization was performed by dynamic light scattering and atomic force microscopy. In vitro photodynamic therapy test assay using MV3 melanoma cells as a model has been performed. In vitro cell viability (MTT) was performed to measure cell toxicity of of nanoparticles with and without drugs using human endothelial cells as a model. The in vivo assay (biodistribution/tissue deposition) has been performed using radiolabeled PLA/PVA NPs. RESULTS: The nanoparticles produced showed a mean diameter of about 259 nm with a spherical shape. The in-vitro photodynamic therapy tests demonstrated that the combination is critical to enhance the therapeutic efficacy and it is dose dependent. The in vitro cell toxicity assay using endothelial cells demonstrated that the drug encapsulated into nanoparticles had no significant toxicity compared to control samples. In-vivo results demonstrated that the drug loading affects the biodistribution of the nanoparticle formulations (NPs). Low accumulation of the NPs into the stomach, heart, brain, and kidneys suggested that common side effects of Dacarbazine could be reduced. CONCLUSION: This work reports a robust nanoparticle formulation with the objective to leveraging the synergistic effects of chemo and photodynamic therapies to potentially suppressing the drug resistance and reducing side effects associated with Dacarbazine. The data corroborates that the dual encapsulated NPs showed better in-vitro efficacy when compared with the both compounds alone. The results support the need to have a dual modality NP formulation for melanoma therapy by combining chemotherapy and photodynamic therapy.

Asunto(s)

Antineoplásicos Alquilantes/administración & dosificación , Portadores de Fármacos/química , Melanoma/tratamiento farmacológico , Fármacos Fotosensibilizantes/administración & dosificación , Neoplasias Cutáneas/tratamiento farmacológico , Animales , Antineoplásicos Alquilantes/efectos adversos , Antineoplásicos Alquilantes/farmacocinética , Línea Celular Tumoral , Supervivencia Celular , Dacarbazina/administración & dosificación , Dacarbazina/farmacocinética , Composición de Medicamentos/métodos , Células Endoteliales , Humanos , Isoindoles/administración & dosificación , Isoindoles/farmacocinética , Masculino , Melanoma/patología , Ratones , Nanopartículas/química , Compuestos Organometálicos/administración & dosificación , Compuestos Organometálicos/farmacocinética , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/farmacocinética , Poliésteres/química , Alcohol Polivinílico/química , Neoplasias Cutáneas/patología , Distribución Tisular , Compuestos de Zinc/administración & dosificación , Compuestos de Zinc/farmacocinética

RESUMEN

Glioblastoma multiforme (GBM) is an extremely aggressive malignant brain tumor. Despite advances in treatment modalities, it remains largely incurable. This unfavorable prognosis for GBM is at least partly due to the lack of a successful drug delivery system across the blood-brain barrier (BBB). The delivery of drugs through nanomedicines combined with less invasive alternative therapies represents an important hope for the future of these incurable brain tumors. Whey protein nanocarriers represent promising strategy for targeted drug delivery to tumor cells by enhancing the drug's bioavailability and distribution, and reducing the body's response towards drug resistance. They have been extensively studied to find new alternatives for capacity to encapsulate different drugs and no need for cross-linkers. In this study, we report for the first time the incorporation and administration of Aluminum phthalocyanine chloride (AlClPc)-loaded whey protein drug delivery system (AlClPc-PDDS) for the treatment of glioblastoma brain cancer. This system was designed and optimized (with the use of the spray drying technique) to obtain the required particle size (in the range of 100 to 300 nm), zeta potential and drug loading. Our results suggest that we have developed a drug delivery system from a low-cost raw material and preparation method that is capable of incorporating hydrophobic drugs which, in combination with irradiation, cause photodamage to neoplasic cells, working as an effective adjuvant treatment for malignant glioma.

Asunto(s)

Neoplasias Encefálicas/tratamiento farmacológico , Portadores de Fármacos , Glioblastoma/tratamiento farmacológico , Nanopartículas , Fármacos Fotosensibilizantes , Proteína de Suero de Leche , Barrera Hematoencefálica/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacología , Glioblastoma/metabolismo , Glioblastoma/patología , Humanos , Indoles/química , Indoles/farmacocinética , Indoles/farmacología , Nanopartículas/química , Nanopartículas/uso terapéutico , Compuestos Organometálicos/química , Compuestos Organometálicos/farmacocinética , Compuestos Organometálicos/farmacología , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacocinética , Fármacos Fotosensibilizantes/farmacología , Proteína de Suero de Leche/química , Proteína de Suero de Leche/farmacocinética , Proteína de Suero de Leche/farmacología

RESUMEN

Monomeric zinc phthalocyanine has been studied as a promising active photosensitizer in photodynamic therapy against cancer, in which its aggregate form is non-active. This paper aimed to describe the monomer/aggregates equilibrium of zinc phthalocyanine in binary water/DMSO mixtures. To reach this aim theoretical calculation, electronic absorption, static and time-resolved fluorescence, and resonance light scattering was used. Zinc phthalocyanine shows a complex water dependence behavior in the mixture. At least three distinct steps were observed: (i) until 30% water zinc phthalocyanine is essentially in the monomeric form, changing to (ii) small slipped cofacial-aggregates around 30% to 40% water and finally to (iii) a staircase arrangement of large aggregates at higher water percent. The staircase arrangement is driven by the intermolecular coordination between the pyrrolic nitrogen lone-pairs and the central metal zinc. The water-Zn coordination governs the fluorescence quenching by a static mechanism. These results have direct relevance in the better understanding on the behavior of zinc phthalocyanine in vivo and when incorporated in drug delivery systems for clinical applications in photodynamic therapy.

Asunto(s)

Complejos de Coordinación/química , Indoles/química , Modelos Moleculares , Fármacos Fotosensibilizantes/química , Zinc/química , Complejos de Coordinación/farmacocinética , Complejos de Coordinación/farmacología , Sistemas de Liberación de Medicamentos , Humanos , Indoles/farmacocinética , Indoles/farmacología , Isoindoles , Fotoquimioterapia , Fármacos Fotosensibilizantes/farmacocinética , Fármacos Fotosensibilizantes/farmacología , Zinc/farmacocinética , Zinc/farmacología

RESUMEN

Oral therapy with 8-methoxypsoralen (8-MOP) may cause major side effects, whereas the topical treatment might not be much effective due to the low penetration induced by typical formulations. Therefore, the objectives of this work are the development and characterization of a nanoemulsion (NE) containing 8-MOP together with an ex vivo permeation study, monitored by a validated HPLC-Fluo method, to determine the amount of drug retained in viable skin (epidermis (E) and dermis (D)) and in stratum corneum (SC). The optimized conditions for NE formulation were achieved by full factorial designs (25 and 32): 60 s and 60% of ultrasound time and potency, respectively; 10 mL of final volume; 2% v/v of oil phase (clove essential oil); and 10% m/v of Poloxamer 407. The NE showed mean droplet diameter of 24.98 ±â€¯0.49 nm, polydispersity index (PDI) of 0.091 ±â€¯0.23, pH values of 6.54 ±â€¯0.06, refractive index of 1.3525 ±â€¯0.0001 and apparent viscosity of 51.15 ±â€¯3.66 mPa at 20 °C. Droplets with nanospherical diameters were also observed by transmission electron microscopy (TEM). Ex vivo permeation study showed that 8.5% of the applied 8-MOP dose permeated through the biological membranes, with flux (J) of 1.35 µg cm-2 h-1. The drug retention in E + D and in SC was 10.15 ±â€¯1.36 and 1.95 ±â€¯0.71 µg cm-2, respectively. Retention in viable skin induced by the NE was almost two-fold higher than a compounded cream (5.04 ±â€¯0.30 µg cm-2). These results suggested that the developed NE is a promising alternative for 8-MOP topical therapy when compared to commercial formulations.

Asunto(s)

Metoxaleno/administración & dosificación , Nanopartículas/administración & dosificación , Fármacos Fotosensibilizantes/administración & dosificación , Piel/metabolismo , Administración Cutánea , Animales , Aceite de Clavo/administración & dosificación , Aceite de Clavo/química , Aceite de Clavo/farmacocinética , Composición de Medicamentos , Sistemas de Liberación de Medicamentos , Estabilidad de Medicamentos , Emulsiones , Metoxaleno/química , Metoxaleno/farmacocinética , Nanopartículas/química , Permeabilidad , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacocinética , Poloxámero/administración & dosificación , Poloxámero/química , Poloxámero/farmacocinética , Absorción Cutánea , Solubilidad , Porcinos

RESUMEN

The use of layer-by-layer (LbL) deposition technique allows materials, such as drugs, to be self-assembled in multilayers with other electrolytes by combining their properties in a nanostructured system. Triclosan (TCS) is commonly used as a drug because of its bactericidal action, while erythrosine (ERY) has been used as a photosensitizer in photodynamic therapies because of its high light absorptivity in the visible region of the electromagnetic spectrum. The major advantage of investigating systems immobilized in LbL films is the benefit of characterizing the interaction through available substances in solid state techniques. It was possible to immobilize in LbL films, ERY, and ERY + TCS. The results show that the growth of the films was linear, indicating the deposition of the same amount of material from the first bilayer without substrate interference. The release analysis showed slow kinetics, which occurred more rapidly for ERY LbL films, probably due to apparent activation energy, which were higher for films with TCS. The combination of TCS, ERY, and laser light (532 nm) for photodynamic inactivation of the fungus Candida albicans was analyzed, and the results were promising for future studies in applications, such as coating surfaces of dental implants.

Asunto(s)

Candida albicans/efectos de los fármacos , Eritrosina/uso terapéutico , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/uso terapéutico , Triclosán/uso terapéutico , Preparaciones de Acción Retardada , Relación Dosis-Respuesta a Droga , Eritrosina/administración & dosificación , Eritrosina/farmacocinética , Luz , Fármacos Fotosensibilizantes/administración & dosificación , Fármacos Fotosensibilizantes/farmacocinética , Triclosán/administración & dosificación , Triclosán/farmacocinética

RESUMEN

Bacterial infections have been a major challenge to health. Increasing resistance to antimicrobial agents, according to World Health Organization, could be the major cause of death until 2050. Photodynamic therapy emerges as an alternative in microbial inactivation, due to its selectivity and to decreasing or dismissing antibiotic use. This study aimed at evaluating, in vitro, the internalization of the Methylene Blue and its photodynamic activity against a clinical and ATCC strain of Pseudomonas aeruginosa and Staphyloccocus aureus. Thus, the strains were incubated with MB in concentrations of 100, 300 e 500 µg/ml and then irradiated with a LED (±660 nm) at fluence of 10 and 25 J/cm2. The MB internalization was evaluated using a confocal microscope (Zeiss LSM 700), to capture the MB and the DAPI (for DNA staining). It was possible to observe that the MB was internalized by the bacterial cells, in all concentrations tested. The CFU/ml count demonstrated significant reduction (p ≤ 0,01) at the average 5.0 logs comparing with control group for the two species in all the tested concentrations. In conclusion, the strains tested were capable of internalizing the MB. PDT with MB was able to decrease the growth of the tested strains in vitro, being a promising alternative to the future treatment of infections caused by these species.

Asunto(s)

Azul de Metileno/farmacología , Fármacos Fotosensibilizantes/farmacología , Pseudomonas aeruginosa/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Azul de Metileno/farmacocinética , Viabilidad Microbiana , Microscopía Confocal , Fotoquimioterapia , Fármacos Fotosensibilizantes/farmacocinética

RESUMEN

Metal phthalocyanines are promising components in photodynamic therapy. Aluminum phthalocyanine chloride (AlClPc) has been used to treat oral cancer in mice, human carious tissue, lung cancer cells and other conditions. To overcome the high hydrophobicity of AlClPc, phthalocyanine is often encapsulated in nanoformulations. Despite increased usage, little is known about the pharmacokinetics and biodistribution of AlClPc. The aim of this study was the development and validation of a UHPLC-MS method for the determination of AlClPc in solution after extraction from nanoformulations and biological matrices such as plasma and tissue. The described method has been assayed as to selectivity, linearity, limits of detection and quantification, precision and recovery. The present study is the first to describe the behavior of AlClPc in biological matrices with mass spectrometry as well as the first to describe the chromatographic behavior of AlClPc contaminants. Molecular mass analysis identified dechlorination of AlClPc by both LC/MS and MALDI-MS and an adduct formation in LC/MS. The parameters observed indicated that the method has applicability and robustness for use in biodistribution studies.

Asunto(s)

Cromatografía Líquida de Alta Presión/normas , Indoles/sangre , Nanoestructuras/química , Compuestos Organometálicos/sangre , Fármacos Fotosensibilizantes/sangre , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/normas , Animales , Disponibilidad Biológica , Biotransformación , Aceite de Ricino/química , Sistemas de Liberación de Medicamentos , Emulsiones , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Indoles/farmacocinética , Indoles/farmacología , Riñón/efectos de los fármacos , Riñón/metabolismo , Límite de Detección , Hígado/efectos de los fármacos , Hígado/metabolismo , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Ratones , Ratones Endogámicos BALB C , Nanoestructuras/administración & dosificación , Compuestos Organometálicos/farmacocinética , Compuestos Organometálicos/farmacología , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/farmacocinética , Fármacos Fotosensibilizantes/farmacología , Polietilenglicoles/química , Bazo/efectos de los fármacos , Bazo/metabolismo , Distribución Tisular

RESUMEN

BACKGROUND: Photodynamic therapy (PDT) may have topical indications. In those cases it is important for a topical photosensitizer to penetrate into the tissue to which it has been applied. This study aimed to compare the penetration of two different concentrations of erythrosine into intact and in vitro decayed dentin samples. METHODS: This in vitro study evaluated erythrosine (0.3 and 5%) penetration into sound (intact) and decayed dentin. A total of 11 dentin discs were prepared and divided into two equal halves, in order to keep one half sound while the other half was submitted to sterilization and an in vitro demineralization model for 5 days. Before erythrosine application, the organic and inorganic composition of all samples was evaluated by Fourier Transform Raman spectroscopy, and after erythrosine application for 30 min, the penetration depth was determined by Photoacoustic spectroscopy technique. RESULTS: The results indicated that 0.3% erythrosine showed a higher penetration depth into sound dentin (p = 0.002); and 5% erythrosine higher penetration into decayed dentin (p < 0.001). However considering clinical parameters, no statistically significant difference was found between any of the conditions tested. CONCLUSIONS: Erythrosine demonstrated ability to penetrate into dentin, irrespective of sound or decayed condition. Photoacoustic spectroscopy can be considered a method for estimating the penetration into hard tissues, and in conjunction with Raman spectroscopy, these are effective methods for evaluating the spectral response of dentin. Considering that erythrosine is capable of penetrating into decayed dentin, clinical trials are needed to test the effectiveness of this photosensitizer in Photodynamic therapy and Antimicrobial Photodynamic therapy.

Asunto(s)

Dentina/metabolismo , Eritrosina/farmacocinética , Técnicas Fotoacústicas/métodos , Fármacos Fotosensibilizantes/farmacocinética , Análisis Espectral/métodos , Biopelículas/efectos de los fármacos , Caries Dental/patología , Relación Dosis-Respuesta a Droga , Humanos , Tercer Molar , Espectrometría Raman/métodos

RESUMEN

In vivo spectrofluorometric analysis during photodynamic therapy (PDT) is a fundamental tool to obtain information about drug bleaching kinetics. Using a portable spectrofluorometer with an excitation source emitting at 400nm wavelength and a spectral analyzer ranging from 500nm to 800nm, the evolution of the meta-tetra(hydroxyphenyl) chlorin (m-THPC) photosensitizer fluorescence spectrum at the tumoral tissue of BALB/c murines with fibrosarcoma located at their flank was followed up. Ex vivo fluorescence measurements of the tumor and skin were also performed with the aim of better characterizing the in vivo signal at different parts of the tumor. PDT was performed employing a LED 637nm light source. Fluorescence at different parts of the tumor and at the tail and armpit of mice was measured immediately after injection and followed daily. The average fluorescence intensity in the tumor reached a maximum after 24-72h. Subsequently, illuminations 24, 48, 72 and 96h post-injection were performed, and the fluorescence was measured immediately before and after each illumination. Eventually, 24h post-illumination, the fluorescence at certain parts of the tumor increased in comparison with that measured immediately after illumination. This effect, named "rebound effect", was due to the new local accumulation of the drug, and was used to perform a second illumination on some mice to increase the amount of photodynamic reaction and significantly improve the PDT outcome. These results are encouraging to optimize PDT in the proposed animal model, thinking about the possible translation to humans.

Asunto(s)

Fibrosarcoma/tratamiento farmacológico , Mesoporfirinas/uso terapéutico , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/uso terapéutico , Animales , Modelos Animales de Enfermedad , Mesoporfirinas/farmacocinética , Ratones , Ratones Endogámicos BALB C , Fármacos Fotosensibilizantes/farmacocinética

RESUMEN

BACKGROUND: Photodynamic therapy (PDT) has been established in several countries as an alternative therapy for the treatment of various malignancies. This therapy involves the incorporation of a photosensitizer (PS) that is activated by visible light and form reactive oxygen species leading to target cell death by apoptosis or necrosis. Previously, our group has demonstrated that CHL-T (semi-synthesized from chlorophyll a and containing a linked solubilizing group TRISMA®) presented a pronounced potential to induce death in HeLa cell line after PDT. In the present study, besides confirm the high cytotoxicity in another cell line, we have further investigated the cell death mechanisms caused by CHL-T as a photosensitizer in laryngeal carcinoma cells. METHODS: Cells were exposed to different concentrations of three photosensitizers, namely, hypericin (HY), unmodified chlorin (CHL) and a synthesized amphiphilic chlorin derivative (CHL-T). PSs accumulation and localization were accessed by fluorescence assays. Photosensitization was induced at 6Jcm-2 using red LEDs (630±10nm). Viability was assessed by mitochondrial function (MTT); whereas apoptosis/necrosis was evaluated by fluorescence microscopy and flow cytometry. Expression of pro-apoptotic p53 protein was studied by Western blot. RESULTS AND CONCLUSIONS: All PS showed similar localization profile in the HEp-2 cells. The use of CHL-T increased the percentage of apoptotic cells and also p53 expression in comparison with the use of HY and CHL as photosensitizers. This study shows a significant effect of CHLT associated with red light (630±10nm and 18mWcm-2) irradiation on a cancer cell line, indicating the potential of this amphiphilic chlorin in enhancing the therapeutic effectiveness of Photodynamic Therapy (PDT).

Asunto(s)

Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/farmacología , Antracenos , Apoptosis/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Humanos , Perileno/análogos & derivados , Perileno/farmacología , Fármacos Fotosensibilizantes/farmacocinética , Porfirinas/farmacología

RESUMEN

Hypericin (Hyp) is a natural photoactive pigment utilized in the treatment of different types of cancer and antimicrobial inactivation using photodynamic therapy (PDT). Hyp is poorly soluble in water leading to problems of administration, getting close contact with the site, and bio-availability. Therefore, this study aimed to develop bioadhesive thermoresponsive system containing Hyp for local PDT. Carbomer 934P, poloxamer 407, and Hyp were used to prepare the thermoresponsive bioadhesive formulations. They were characterized for sol-gel transition temperature, mechanical, mucoadhesive, rheological (continuous flow and oscillatory) and dielectric properties, syringeability, in vitro Hyp release kinetics, ex vivo permeability, and photodynamic activity. The formulations displayed suitable gelation temperature and rheological characteristics. The compressional, mechanical and mucoadhesive properties, as well the syringeability showed the easiness of administration and the permanence of the system adhered to the mucosa or skin. The dielectric analysis helped to understand the Hyp availability, and its release presented an anomalous behavior. The system did not permeate the pig skin nor rat intestine and showed good biological photodynamic activity. Therefore, data obtained from the bioadhesive system indicate a potentially useful role as a platform for local hypericin delivery in PDT, suggesting it is worthy of in vivo evaluation.

Asunto(s)

Sistemas de Liberación de Medicamentos/métodos , Perileno/análogos & derivados , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/administración & dosificación , Resinas Acrílicas/química , Animales , Antracenos , Liberación de Fármacos , Geles/química , Absorción Intestinal/fisiología , Fenómenos Mecánicos , Perileno/administración & dosificación , Perileno/farmacocinética , Fármacos Fotosensibilizantes/farmacocinética , Poloxámero/química , Ratas , Reología , Absorción Cutánea/fisiología , Porcinos , Adherencias Tisulares

RESUMEN

INTRODUCTION: Nanomedicine development allowed the discovery of new photosensitizers (PS) and drug delivery systems (DDS) to overcome current issues on phototherapy. Nano-engineered materials have the potential to improve the solubility of PS, control drug pharmacokinetics, decreasing side effects, increasing bioavailability, and overcoming multidrug resistance. A recent approach is the co-delivery of PS with other therapeutic agents in a multimodal platform for synergic and improved results. Areas covered: This paper discusses the delivery of PS-nanostructured platforms for conventional, photothermal, and antimicrobial photodynamic therapies, as well as in a recent therapeutic modality for photobiomodulation, covering applications of cancer diagnosis, targeting to skin pathogens, photoregeneration and wound healing. The focus of the present review is to describe the use of different DDS to enhance the therapeutic outcomes triggered by the combination of delivered PS, light, and oxygen. Expert opinion: Nanotechnology allowed the development of site-specific delivery of PS molecules, expanding possibilities poorly explored before to enhance photodynamic efficacy and extrapolate the concept to other treatment protocols. Research in this area embraces potential and pitfalls of PS delivery, allowing new clinical phase outcomes and long-term issues to be established, which will impact on several biomedical applications.

Asunto(s)

Sistemas de Liberación de Medicamentos/métodos , Nanoestructuras/química , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/administración & dosificación , Resistencia a Medicamentos , Quimioterapia Combinada , Humanos , Fármacos Fotosensibilizantes/farmacocinética

RESUMEN

Candida albicans biofilm is a main cause of infections associated with medical devices such as catheters, contact lens and artificial joint prosthesis. The current treatment comprises antifungal chemotherapy that presents low success rates. Photodynamic inactivation (PDI) involves the combination of a photosensitizing compound (PS) and light to generate oxidative stress that has demonstrated effective antimicrobial activity against a broad-spectrum of pathogens, including C. albicans. This fungus senses glucose inducing an upregulation of membrane transporters that can facilitate PS uptake into the cell. The aim of this study was to evaluate the effects of glucose on methylene blue (MB) uptake and its influence on PDI efficiency when combined to a red LED with central wavelength at λ=660nm. C. albicans biofilms were grown on hydrogel disks. Prior to PDI assays, MB uptake tests were performed with and without glucose-sensitization. In this system, the optimum PS administration was determined as 500µM of MB in contact with the biofilm during 30min before irradiation. Irradiation was performed during 3, 6, 9, 12, 15 and 18min with irradiance of 127.3mW/cm2. Our results showed that glucose was able to increase MB uptake in C. albicans cells. In addition, PDI without glucose showed a higher viability reduction until 6min; after 9min, glucose group demonstrated a significant decrease in cell viability when compared to glucose-free group. Taken together, our data suggest that glucose is capable to enhance MB uptake and modulate photodynamic inactivation of C. albicans biofilm.

Asunto(s)

Biopelículas/efectos de los fármacos , Candida albicans/efectos de los fármacos , Glucosa/farmacología , Azul de Metileno/farmacocinética , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/farmacocinética , Técnicas Bacteriológicas , Azul de Metileno/farmacología , Fármacos Fotosensibilizantes/farmacología

RESUMEN

The search for alternatives to control microorganisms is necessary both in clinical and agricultural areas. Antimicrobial photodynamic treatment (APDT) is a promising light-based approach that can be used to control both human and plant pathogenic fungi. In the present study, we evaluated the effects of photodynamic treatment with red light and four phenothiazinium photosensitizers (PS): methylene blue (MB), toluidine blue O (TBO), new methylene blue N (NMBN) and the phenothiazinium derivative S137 on ungerminated and germinated microconidia of Fusarium oxysporum, F. moniliforme, and F. solani. APDT with each PS killed efficiently both the quiescent ungerminated microconidia and metabolically active germinated microconidia of the three Fusarium species. Washing away the unbound PS from the microconidia (both ungerminated and germinated) before red light exposure reduced but did not prevent the effect of APDT. Subcelullar localization of PS in ungerminated and germinated microconidia and the effects of photodynamic treatment on cell membranes were also evaluated in the three Fusarium species. APDT with MB, TBO, NMBN or S137 increased the membrane permeability in microconidia and APDT with NMBN or S137 increased the lipids peroxidation in microconidia of the three Fusarium species. These findings expand the understanding of photodynamic inactivation of filamentous fungi with phenothiazinium PS.

Asunto(s)

Fusarium/efectos de los fármacos , Fenotiazinas/farmacología , Fotoquimioterapia , Fármacos Fotosensibilizantes/farmacología , Fusarium/clasificación , Fusarium/fisiología , Germinación , Fenotiazinas/farmacocinética , Fármacos Fotosensibilizantes/farmacocinética , Especificidad de la Especie , Fracciones Subcelulares/metabolismo

RESUMEN

This study examined the potential of iontophoresis in topical photodynamic therapy (PDT) of human invasive squamous cells carcinomas (SCC). SCC was induced in nude BALB/c mice by subcutaneous injection of A431 cells. Tumor penetration and distribution of the photosensitizer tetrasulfonated zinc phthalocyanine (ZnPcS4) was investigated after 10 and 30 min of in vivo iontophoresis of a gel containing ZnPcS4. PDT was performed immediately after iontophoresis using laser at 660 nm with a dose of irradiation of 100 J/cm(2) and irradiance of 48 mW/cm(2) while tumor growth was measured for 30 days. Iontophoresis increased ZnPcS4 penetration into tumors by 6-fold after 30 min when compared with passive delivery. Confocal microscopy analysis showed that ZnPcS4 was homogeneous distributed within deep regions of the tumor after iontophoresis. Irradiation of the tumors immediately after iontophoresis showed reduction in tumor size by more than 2-fold when compared to non-treated tumors. Iontophoretic-PDT treated tumors presented large areas of necrosis. The study concluded that iontophoretic delivery of photosensitizers could be a valuable strategy for topical PDT of invasive SCC.

Asunto(s)

Carcinoma de Células Escamosas/tratamiento farmacológico , Indoles/farmacología , Iontoforesis/métodos , Compuestos Organometálicos/farmacología , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/farmacología , Neoplasias Cutáneas/tratamiento farmacológico , Animales , Transporte Biológico , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Femenino , Humanos , Indoles/metabolismo , Indoles/farmacocinética , Ratones , Ratones Desnudos , Necrosis , Compuestos Organometálicos/metabolismo , Compuestos Organometálicos/farmacocinética , Permeabilidad , Fármacos Fotosensibilizantes/metabolismo , Fármacos Fotosensibilizantes/farmacocinética , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Resultado del Tratamiento , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

The development and manufacture of novel nanocarriers for drug delivery has proved challenging with regards to scale-up and pharmaceutical quality. Polymeric nanocarriers composed of poly(lactic-co-glycolic acid)-b-poly(ethylene glycol) (PLGA-PEG) were prepared and the photosensitizer meso-tetrakis(3-hydroxyphenyl) chlorin (mTHPC) was effectively encapsulated. Furthermore, the interplay of various process and formulation parameters and their impact on the most important product specifications were investigated by using a factorial design and a central composite design in a microfluidic manufacturing process. These nanoparticles for intravenous administration with a size of 97 ± 0.13 nm, narrow size distribution, and an encapsulation efficiency of more than 80% were produced at high throughput. In vitro stability and in vitro drug release testing were applied for quality control purposes. Finally, the toxicity of the photosensitizer was tested in vitro. The cytotoxicity was successfully reduced while the efficacy of the formulation was maintained. First observations using in vivo imaging suggest effective distribution of the nanocarrier system after injection into rodents. Thus, further in vivo testing of the beneficial effects of nanoencapsulation into the matrix system and its formulation will be considered for the delivery of mTHPC to tumor tissues during photodynamic therapy.

Asunto(s)

Portadores de Fármacos/química , Nanoestructuras/química , Fotoquimioterapia , Fármacos Fotosensibilizantes/química , Administración Intravenosa , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Química Farmacéutica , Composición de Medicamentos , Diseño de Fármacos , Industria Farmacéutica/métodos , Humanos , Mesoporfirinas/química , Ratones , Técnicas Analíticas Microfluídicas , Tamaño de la Partícula , Fármacos Fotosensibilizantes/farmacocinética , Fármacos Fotosensibilizantes/toxicidad , Poliésteres/química , Polietilenglicoles/química , Distribución Tisular

RESUMEN

Poly(D,L lactic-co-glycolic acid) (PLGA) based nanoparticles (NPs) are proposed for topical delivery of Protoporphyrin IX (PpIX) in Photodynamic Therapy of skin cancers. PpIX loaded into PLGA NPs showed nanometric average diameter (-280 nm), spherical forms and pH - 5.7, conditions suitable for topical application. In vitro release of PpIX from NPs was sustained up to 24 hr with a burst release effect of about 37.0% at 2 hr. Penetration and distribution of PpIX in hairless mice skin was determined by fluorescence microscopy 8 or 24 hrs after application of PpIX-NPs in the animals. At 24 hours, areas located in deeper regions of the skin were found to have greater fluorescence intensity. The finding indicates a localized effect of PpIX-NPs in the epidermis plus dermis--a site of action for topical PDT--and suggests a potential use of PpIX-NPs in PDT associated to skin cancer treatments.

Asunto(s)

Ácido Láctico/química , Nanopartículas , Fotoquimioterapia , Fármacos Fotosensibilizantes/administración & dosificación , Ácido Poliglicólico/química , Protoporfirinas/administración & dosificación , Piel/metabolismo , Animales , Ratones , Ratones Pelados , Microscopía Electrónica de Rastreo , Microscopía Fluorescente , Fármacos Fotosensibilizantes/farmacocinética , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Protoporfirinas/farmacocinética

RESUMEN

We report the development of D, L lactic co-glycolic acid) (PLGA)-based nanoparticles (NPs) for topical delivery of protoporphyrin IX (PpIX), a photosensitizer (PS), in treatments like photodynamic therapy (PDT) of skin cancers. PpIX-NPs were obtained in ~75.0% yield, encapsulation efficiency of 67.7%, drug content of 50.3 µg mg(-1), average diameter of 290 nm maintained up to 30 days and a zeta potential of 32.3 mV. Sustained in vitro release of PpIX through artificial membranes following Higuchi kinetics was kept up to 10 days. In vitro retentions of PpIX both in stratum corneum (SC) and epidermis + dermis ([EP + D]) were higher from NPs (23.0 and 10.0 times, respectively) compared to control solutions at all times. Quantification of PpIX by extraction, after in vivo skin application of NPs-PpIX on hairless mice, showed higher retention of the PS both in SC and in [EP + D] (3.0 and 2.0 times, respectively) compared to control solutions. Taken together, the results indicate that NPs are suitable for PpIX encapsulation showing minimal permeation through the skin and a localized effect, characteristics of a potential and promising delivery system for PDT-associated treatments of skin cancers, photodiagnosis and their off-label uses.

Asunto(s)

Portadores de Fármacos , Ácido Láctico/química , Nanopartículas , Fármacos Fotosensibilizantes/administración & dosificación , Ácido Poliglicólico/química , Protoporfirinas/administración & dosificación , Piel/metabolismo , Animales , Técnicas In Vitro , Ratones , Ratones Pelados , Permeabilidad , Fármacos Fotosensibilizantes/farmacocinética , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Protoporfirinas/farmacocinética

RESUMEN

Topical photodynamic therapy (PDT) is an excellent treatment option for various non-melanoma skin cancers and precancerous lesions, including actinic keratosis, Bowen's disease, and basal cell carcinoma. The clinical use of PDT includes a broad range of neoplastic, inflammatory, and infectious skin diseases. There is also anecdotal evidence suggesting the efficacy of PDT for the treatment of keratoacanthomas (KA). We report a case-series of four patients with solitary KA confirmed by histology, treated with topical PDT with methylaminolevulinic acid (MAL) cream. After three sessions of PDT, the lesions completely disappeared. There was no evidence of recurrence and excellent cosmetic outcome was achieved after three years of follow-up. Topical photodynamic therapy with MAL can be a therapeutic alternative for KA with good clinical and cosmetic outcomes.

Asunto(s)

Queratoacantoma/tratamiento farmacológico , Fotoquimioterapia/métodos , Enfermedades de la Piel/tratamiento farmacológico , Administración Tópica , Anciano , Anciano de 80 o más Años , Ácido Aminolevulínico/administración & dosificación , Ácido Aminolevulínico/análogos & derivados , Ácido Aminolevulínico/farmacocinética , Femenino , Humanos , Queratoacantoma/patología , Masculino , Fármacos Fotosensibilizantes/administración & dosificación , Fármacos Fotosensibilizantes/farmacocinética , Enfermedades de la Piel/patología , Resultado del Tratamiento