Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.008
Filtrar
1.
Xenobiotica ; 50(2): 170-177, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30901299

RESUMO

1. 2-[1-Hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH), a second-generation photosensitizer, has been widely employed in photodynamic therapy (PDT) for the treatment of malignant lesions. The objective of this study was to characterize the pharmacokinetics of HPPH in Chinese patients using a population pharmacokinetic (PopPK) approach.2. For the first time, a PopPK model of HPPH for Chinese (n = 20) was developed (registration number: CTR20160425). The pharmacokinetics of HPPH was described by a three-compartment model with linear elimination. Through the stepwise addition (p < 0.05) and backward elimination (p < 0.001) approach, fat-free mass (FFM) was identified to be the most significant covariate and V1 increased with FFM. Visual predictive check (VPC) was employed for the evaluation of the final model. Subsequent full covariate analysis indicated that FFM has considerable impact (∼30%) on HPPH exposure and fat mass also has a modest (∼25%) impact.3. The simulations suggested that a dose adjustment of HPPH may be necessary for Chinese and the dose of 3 mg/m2 should be appropriate. HPPH exposure increases with fat mass while being inversely related to FFM. HPPH-PDT for overweight patients should be monitored with more caution and PDT conditions should be optimized if necessary.


Assuntos
Carcinoma/metabolismo , Clorofila/análogos & derivados , Neoplasias Esofágicas/metabolismo , Fármacos Fotossensibilizantes/farmacocinética , Grupo com Ancestrais do Continente Asiático , China , Clorofila/farmacocinética , Feminino , Humanos , Masculino , Modelos Teóricos , Fotoquimioterapia
2.
Spectrochim Acta A Mol Biomol Spectrosc ; 224: 117411, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31362187

RESUMO

The present study delves into the interaction of a potent cancer-cell photosensitizer Norharmane (NHM) with non-ionic triblock copolymer P123, followed by the assessment of the stability of the formed complex in the presence of ß-cyclodextrin (ß-CD). Spectroscopic results unveil the modulation of the prototropic equilibrium of NHM within the constrained microheterogeneous medium of the copolymer micelle to be favoured towards the neutral species of NHM over the cationic counterpart; which has been aptly rationalized invoking the key role of hydrophobic interaction in the association process and is further reinforced from steady-state and time-resolved spectroscopic measurements. The micropolarity of the probe-binding site has been evaluated by the archetypal ET(30) analysis revealing that the cationic probe remains in the corona region of the micelle instead of penetrating deeper into the micellar core. Moreover, the effect of ß-CD on the stability of the NHM-bound P123 aggregates has also been investigated, revealing that ß-CD can be used as a potential host for the release of the micelle-encapsulated drug through an inclusion complex formation with the P123 monomers. The result is expected to be of potential interest from medical perspective owing to the context of efficient drug release at their potential sites.


Assuntos
Antineoplásicos , Micelas , Fármacos Fotossensibilizantes , beta-Ciclodextrinas/química , Antineoplásicos/análise , Antineoplásicos/química , Antineoplásicos/farmacocinética , Liberação Controlada de Fármacos , Modelos Moleculares , Fármacos Fotossensibilizantes/análise , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacocinética , Espectrometria de Fluorescência
3.
Int J Nanomedicine ; 14: 8665-8683, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31806963

RESUMO

Background: The combination of chemo-photodynamic therapy based on nano-technology has emerged as a preferable and promising measure for synergetic antitumor therapy. Purpose: The aim of this study was expected to overcome most of the safety concerns from nano-carriers and improve the chemo-photodynamic synergistic antitumor efficacy. Methods: Herein, we reported a facile and effective approach based on the self-assembly of chemotherapeutic agent 10-hydroxycamptothecin (HCPT) and photosensitizer chlorin e6 (Ce6) for preparing stably dual-functional nanorods (NRs). Results: The chemical thermodynamic parameters obtained from isothermal titration calorimeter (ITC) and the microcosmic configuration snapshots acquired by molecular dynamics (MD) simulations verified that HCPT and Ce6 molecules tended to assemble with each other through various intermolecular forces. The as-prepared HCPT/Ce6 NRs possessed a relatively uniform size of around 165 nm and zeta potential of about -29 mV, together with good stability in aqueous solution and freeze-dried state. In addition, both the extra- and intracellular reactive oxygen species (ROS) generation capacity of the NRs under laser irradiation was significantly enhanced compared with Ce6 injections. Moreover, the dual-functional HCPT/Ce6 NRs exhibited a substantial in vitro/in vivo synergistic antitumor efficacy under laser irradiation due to the integration of the two therapeutic modalities into one drug delivery system. Besides, no obvious hepatic or renal toxicity was observed in the NRs treatment groups. Conclusion: Taken together, HCPT/Ce6 NRs demonstrated a powerful efficacy in chemo-photodynamic therapy for breast cancer. Therefore, the carrier-free dual-functional NRs prepared in a facile and effective strategy might give inspiration for the development of combined antitumor therapy.


Assuntos
Camptotecina/análogos & derivados , Sistemas de Liberação de Medicamentos/métodos , Nanotubos/química , Fotoquimioterapia/métodos , Porfirinas/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Camptotecina/química , Camptotecina/farmacocinética , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Sinergismo Farmacológico , Feminino , Camundongos Endogâmicos BALB C , Simulação de Dinâmica Molecular , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacocinética , Porfirinas/farmacocinética , Espécies Reativas de Oxigênio
4.
J Nanobiotechnology ; 17(1): 113, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31699100

RESUMO

BACKGROUND: Synergistic therapy of tumor is a promising way in curing cancer and in order to achieve effective tumor therapy with real-time drug release monitoring, dynamic cellular imaging and antitumor activity. RESULTS: In this work, a polymeric nanoparticle with Forster resonance energy transfer (FRET) effect and chemo-photodynamic properties was fabricated as the drug vehicle. An amphiphilic polymer of cyclo(RGDfCSH) (cRGD)-poly(ethylene glycol) (PEG)-Poly(L-histidine) (PH)-poly(ε-caprolactone) (PCL)-Protoporphyrin (Por)-acting as both a photosensitizer for photodynamic therapy (PDT) and absorption of acceptor in FRET was synthesized and self-assembled into polymeric nanoparticles with epirubicin (EPI)-acting as an antitumor drug for chemotherapy and fluorescence of donor in FRET. Spherical EPI-loaded nanoparticles with the average size of 150 ± 2.4 nm was procured with negatively charged surface, pH sensitivity and high drug loading content (14.9 ± 1.5%). The cellular uptake of EPI-loaded cRGD-PEG-PH-PCL-Por was monitored in real time by the FRET effect between EPI and cRGD-PEG-PH-PCL-Por. The polymeric nanoparticles combined PDT and chemotherapy showed significant anticancer activity both in vitro (IC50 = 0.47 µg/mL) and better therapeutic efficacy than that of free EPI in vivo. CONCLUSIONS: This work provided a versatile strategy to fabricate nanoassemblies for intracellular tracking of drug release and synergistic chemo-photodynamic therapy.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Epirubicina/administração & dosagem , Nanopartículas/administração & dosagem , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/administração & dosagem , Animais , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/uso terapêutico , Liberação Controlada de Fármacos , Epirubicina/farmacocinética , Epirubicina/uso terapêutico , Transferência Ressonante de Energia de Fluorescência , Humanos , Concentração de Íons de Hidrogênio , Camundongos Endogâmicos BALB C , Nanopartículas/uso terapêutico , Fármacos Fotossensibilizantes/farmacocinética , Fármacos Fotossensibilizantes/uso terapêutico , Polímeros/administração & dosagem , Polímeros/farmacocinética , Polímeros/uso terapêutico
5.
Nat Commun ; 10(1): 4586, 2019 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-31594932

RESUMO

Upconversion nanoparticles (UCNPs) are the preferred choice for deep-tissue photoactivation, owing to their unique capability of converting deep tissue-penetrating near-infrared light to UV/visible light for photoactivation. Programmed photoactivation of multiple molecules is critical for controlling many biological processes. However, syntheses of such UCNPs require epitaxial growth of multiple shells on the core nanocrystals and are highly complex/time-consuming. To overcome this bottleneck, we have modularly assembled two distinct UCNPs which can individually be excited by 980/808 nm light, but not both. These orthogonal photoactivable UCNPs superballs are used for programmed photoactivation of multiple therapeutic processes for enhanced efficacy. These include sequential activation of endosomal escape through photochemical-internalization for enhanced cellular uptake, followed by photocontrolled gene knockdown of superoxide dismutase-1 to increase sensitivity to reactive oxygen species and finally, photodynamic therapy under these favorable conditions. Such programmed activation translated to significantly higher therapeutic efficacy in vitro and in vivo in comparison to conventional, non-programmed activation.


Assuntos
Portadores de Fármacos/química , Nanopartículas/química , Processos Fotoquímicos/efeitos da radiação , Animais , Compostos de Cálcio/química , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/efeitos da radiação , Desenho de Fármacos , Endossomos/efeitos dos fármacos , Técnicas de Inativação de Genes , Células HeLa , Humanos , Indóis/administração & dosagem , Indóis/farmacocinética , Raios Infravermelhos , Camundongos , Nanopartículas/efeitos da radiação , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Compostos Organometálicos/administração & dosagem , Compostos Organometálicos/farmacocinética , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/administração & dosagem , Fármacos Fotossensibilizantes/farmacocinética , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , Silicatos/química , Superóxido Dismutase-1/genética , Distribuição Tecidual , Raios Ultravioleta
6.
Molecules ; 24(17)2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31470637

RESUMO

Metastatic melanoma (MM) has a poor prognosis and is attributed to late diagnoses only when metastases has already occurred. Thus, early diagnosis is crucial to improve its overall treatment efficacy. The standard diagnostic tools for MM are incisional biopsies and/or fine needle aspiration biopsies, while standard treatments involve surgery, chemotherapy, or irradiation therapy. The combination of photodynamic diagnosis (PDD) and therapy (PDT) utilizes a photosensitizer (PS) that, when excited by light of a low wavelength, can be used for fluorescent non-destructive diagnosis. However, when the same PS is activated at a higher wavelength of light, it can be cytotoxic and induce tumor destruction. This paper focuses on PS drugs that have been used for PDD as well as PDT treatment of MM. Furthermore, it emphasizes the need for continued investigation into enhanced PS delivery via active biomarkers and passive nanoparticle systems. This should improve PS drug absorption in MM cells and increase effectiveness of combinative photodynamic methods for the enhanced diagnosis and treatment of MM can become a reality.


Assuntos
Melanoma/diagnóstico por imagem , Melanoma/tratamento farmacológico , Fármacos Fotossensibilizantes/uso terapêutico , Neoplasias Cutâneas/diagnóstico por imagem , Neoplasias Cutâneas/tratamento farmacológico , Ácido Aminolevulínico/química , Ácido Aminolevulínico/farmacocinética , Ácido Aminolevulínico/uso terapêutico , Biópsia por Agulha Fina , Portadores de Fármacos/síntese química , Diagnóstico Precoce , Humanos , Indóis/química , Indóis/farmacocinética , Indóis/uso terapêutico , Luz , Metástase Linfática , Melanoma/patologia , Imagem Molecular/métodos , Nanopartículas/administração & dosagem , Nanopartículas/química , Perileno/análogos & derivados , Perileno/química , Perileno/farmacocinética , Perileno/uso terapêutico , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacocinética , Neoplasias Cutâneas/patologia
7.
Chemistry ; 25(55): 12801-12809, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31381210

RESUMO

Photodynamic therapy (PDT) is a promising cancer ablation method, but its efficiency is easily affected by several factors, such as the insufficient delivery of photosensitizers, low oxygen levels as well as long distance between singlet oxygen and intended organelles. A multifunctional nanohybrid, named MGAB, consisting of gelatin-coated manganese dioxide and albumin-coated gold nanoclusters, was designed to overcome these issues by improving chlorin e6 (Ce6) delivery and stimulating oxygen production in lysosomes. MGAB were quickly degraded in a high hydrogen peroxide, high protease activity, and low pH microenvironment, which is closely associated with tumor growth. The Ce6-loaded MGAB were picked up by tumor cells through endocytosis, degraded within the lysosomes, and released oxygen and photosensitizers. Upon near-infrared light irradiation, the close proximity of oxygen with photosensitizer within lysosomes enabled the production of cytotoxic singlet oxygen, resulting in more effective PDT.


Assuntos
Portadores de Fármacos/química , Endocitose/fisiologia , Lisossomos/química , Compostos de Manganês/química , Óxidos/química , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/química , Oxigênio Singlete/metabolismo , Humanos , Raios Infravermelhos , Oxigênio , Fármacos Fotossensibilizantes/farmacocinética , Porfirinas/metabolismo , Oxigênio Singlete/química
8.
Molecules ; 24(14)2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31340553

RESUMO

The synthesis and application of porphyrins has seen a huge shift towards research in porphyrin bio-molecular based systems in the past decade. The preferential localization of porphyrins in tumors, as well as their ability to generate reactive singlet oxygen and low dark toxicities has resulted in their use in therapeutic applications such as photodynamic therapy. However, their inherent lack of bio-distribution due to water insolubility has shifted research into porphyrin-nanomaterial conjugated systems to address this challenge. This has broadened their bio-applications, viz. bio-sensors, fluorescence tracking, in vivo magnetic resonance imaging (MRI), and positron emission tomography (PET)/CT imaging to photo-immuno-therapy just to highlight a few. This paper reviews the unique theranostic role of porphyrins in disease diagnosis and therapy. The review highlights porphyrin conjugated systems and their applications. The review ends by bringing current challenges and future perspectives of porphyrin based conjugated systems and their respective applications into light.


Assuntos
Glicoconjugados/síntese química , Neoplasias/diagnóstico por imagem , Neoplasias/terapia , Fármacos Fotossensibilizantes/síntese química , Porfirinas/síntese química , Animais , Glicoconjugados/farmacocinética , Glicoconjugados/farmacologia , Humanos , Imagem por Ressonância Magnética/métodos , Camundongos , Neoplasias/patologia , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacocinética , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/farmacocinética , Porfirinas/farmacologia , Tomografia por Emissão de Pósitrons/métodos , Oxigênio Singlete/química , Oxigênio Singlete/metabolismo , Nanomedicina Teranóstica/métodos , Água/química , Água/metabolismo
9.
Photodiagnosis Photodyn Ther ; 26: 436-441, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31054334

RESUMO

Indocyanine green lactosome (ICG-lactosome) is an attractive new-generation agent for photodynamic therapy (PDT) that is characterized by a near-infrared excitation wavelength and high stability in the bloodstream. Fluorescence imaging has been used to examine its pharmacokinetics in vivo, but no depth-resolved information can be obtained with this method. In this study, we applied photoacoustic (PA) imaging to visualize the depth distribution of ICG-lactosome in a mouse subcutaneous tumor model. With this method, the depth distribution of blood vessels can also be visualized, enabling detection of vascular shutdown effects due to PDT. We performed PA imaging of both the distributions of ICG-lactosome and blood vessels in a tumor before and after PDT, and we found that PA signals originating from ICG-lactosome were greatly increased at 18 h after drug injection but rapidly decreased after PDT. These results indicate efficient accumulation of ICG-lactosome and rapid photobleaching due to the PDT reaction in the tumor, respectively. After PDT, PA amplitudes of hemoglobin were significantly decreased, being attributable to vascular shutdown effects. These results show the usefulness of PA imaging for monitoring not only photosensitizer accumulation and bleaching but also vascular responses in PDT with ICG-lactosome. This method can be applied to the diagnosis of many types of PDT processes.


Assuntos
Neoplasias de Cabeça e Pescoço/diagnóstico por imagem , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Verde de Indocianina/farmacologia , Técnicas Fotoacústicas , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Modelos Animais de Doenças , Feminino , Verde de Indocianina/farmacocinética , Camundongos , Camundongos Nus , Fármacos Fotossensibilizantes/farmacocinética
10.
Biomater Sci ; 7(7): 2812-2825, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31066391

RESUMO

Among brain tumors, glioblastoma multiforme (GBM) is the most common and aggressive form (WHO grade IV) with a median survival of only 14.6 months in adults. Photodynamic therapy (PDT) is a combination of a photosensitizer (PS), light and molecular oxygen, and considered a promising treatment for GBM. Therapeutic outcomes of PDT rely on ROS generation in a tumor microenvironment, which can be controlled with dual selectivity by localization of the photosensitizer and confinement of light to the targeted tumor microenvironment. We previously demonstrated the photodynamic anticancer efficacy of mitochondrial-targeted photosensitizer-loaded albumin nanoparticles (PS@chol-BSA NPs). In this study, the photodynamic therapeutic effect of PS@chol-BSA NPs was further enhanced by confinement of light using a fiber optic cannula in orthotopic GBM-xenografted mice. In vitro cellular uptake and phototoxicity of PS@chol-BSA NPs were evaluated in brain tumor (U87MG) and endothelial (bEnd.3) cells. In vivo biodistribution was determined by an in vivo imaging system (IVIS) and the photodynamic efficacy was evaluated with confined laser irradiation. PS@chol-BSA NPs showed higher cellular uptake and phototoxicity in U87MG cells than in bEnd.3 cells. PS@chol-BSA NPs showed a brain tumor accumulation of 0.2%ID within 2 h and remain in the brain tumor for 22 h. When compared to the control group, there was remarkable suppression in tumor growth by laser irradiation with and without the fiber optic cannula at a dose of 1 mg kg-1, in which significant tumor suppression up to 40% was observed with confined laser irradiation. Together, dual-selective photodynamic therapy with a mitochondria-targeted photosensitizer and fiber optic cannula provides a promising therapeutic strategy for malignant brain tumors.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Cânula , Glioblastoma/tratamento farmacológico , Mitocôndrias/metabolismo , Fibras Ópticas , Fotoquimioterapia/instrumentação , Fármacos Fotossensibilizantes/farmacologia , Animais , Neoplasias Encefálicas/patologia , Bovinos , Linhagem Celular Tumoral , Portadores de Fármacos/química , Glioblastoma/patologia , Humanos , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/efeitos da radiação , Nanopartículas/química , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacocinética , Soroalbumina Bovina/química , Distribuição Tecidual
11.
Invest Ophthalmol Vis Sci ; 60(6): 2140-2145, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31099830

RESUMO

Purpose: To determine the riboflavin concentration in the posterior corneal stroma, Descemet's membrane, and endothelium prior to UV irradiation in corneal cross-linking (CXL) in humans. Methods: Five human deepithelialized cadaver corneas were mounted into artificial anterior chambers. After the establishment of stable physiological hydration, two-photon imaging with a certified multiphoton tomograph was used to determine fluorescence intensity and second harmonic generation signals from collagen throughout each cornea by optical sectioning, with a step size of 2.5 µm. Afterward, 0.1% riboflavin solution was applied to the anterior corneal surface, similar to the standard CXL protocol. To determine the absolute riboflavin concentration immediately before UV irradiation, corneas were measured by two-photon imaging just at the end of the riboflavin imbibition and after riboflavin saturation. Results: The topical application of 0.1% riboflavin results in a riboflavin concentration that decreases to 0.035% in the posterior stroma. Inside Descemet's membrane and endothelium, the concentration drops further to only approximately 0.015% at the endothelial level. Local riboflavin distribution indicates a predominantly paracellular passive diffusion of riboflavin into the anterior chamber. Conclusion: The experimentally determined riboflavin concentration of 0.015% at the endothelium shows a substantial discrepancy of a factor of 1.7 to the previously theoretically calculated 0.025%. A lower riboflavin concentration at the endothelium may enable higher radiant exposures and further improve the efficacy of CXL.


Assuntos
Reagentes para Ligações Cruzadas , Epitélio Posterior/metabolismo , Fármacos Fotossensibilizantes/farmacocinética , Riboflavina/farmacocinética , Cadáver , Colágeno/metabolismo , Substância Própria/metabolismo , Lâmina Limitante Posterior/metabolismo , Humanos , Raios Ultravioleta
12.
Int J Pharm ; 562: 313-320, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30898641

RESUMO

Photosensitizer-based photodynamic therapy (PDT) has attracted great attention in cancer treatment. However, achieving efficient delivery of photosensitizers is still a great challenge for their clinical applications. The photosensitizer-encapsulating delivery nanosystem usually suffers from poor stability, complex preparation process and low drug loading. Herein, we utilize a surfactant-like chemotherapeutic agent, mitoxantrone (MTX), as a nanocarrier to deliver a photosensitizer pyropheophorbide a (PPa) for antitumor therapy. MTX consists of aromatic rings (hydrophobic part) and two amino-groups and two hydroxyl-groups (hydrophilic part) with planar structure, which could interact with PPa via π-π stacking, hydrophobic interactions, intermolecular hydrogen bonding and electrostatic interactions. This system (PPa@MTX) spontaneously forms near-spherical nanostructures (∼150 nm), has a high loading capacity for PPa (56.5%) and exhibits a pH-responsive drug release manner in vitro. In vivo antitumor efficacy evaluations show that the pegylated PPa@MTX nanosystem has increased accumulation in tumor tissues and enhanced antitumor efficacy in female BALB/c mice bearing murine mammary carcinoma (4T1) tumor cells, compared to free PPa. Employing the surfactant-like drug as nanocarriers, our results show that the "drug-delivering-drug" strategy is a good foundation for the development of novel PDT-based drug delivery system against cancer.


Assuntos
Antineoplásicos , Clorofila/análogos & derivados , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Mitoxantrona , Nanoestruturas , Fármacos Fotossensibilizantes , Tensoativos , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Clorofila/administração & dosagem , Clorofila/química , Clorofila/farmacocinética , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos , Feminino , Camundongos Endogâmicos BALB C , Mitoxantrona/administração & dosagem , Mitoxantrona/química , Mitoxantrona/farmacocinética , Nanoestruturas/administração & dosagem , Nanoestruturas/química , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Fármacos Fotossensibilizantes/administração & dosagem , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacocinética , Tensoativos/administração & dosagem , Tensoativos/química , Tensoativos/farmacocinética
13.
Proc Natl Acad Sci U S A ; 116(14): 6618-6623, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30894484

RESUMO

Although platinum-based anticancer drugs prevail in cancer treatment, their clinical applications are limited by the severe side effects as well as their ineffectiveness against drug resistant cancers. A precise combination of photodynamic therapy (PDT) and chemotherapy can synergistically improve the therapeutic outcome and thereby may overcome drug resistance through a multipronged assault. Herein, we employ the well-defined cavity of a discrete organoplatinum(II) metallacage (M) to encapsulate octaethylporphine (OEP), a photosensitizer, forming a dual-functionalized system M⊃OEP that is wrapped into the hydrophobic core of the nanoparticles (MNPs) self-assembled from an amphiphilic diblock copolymer. Using a copper-free click reaction, a targeting ligand is conjugated on the surface of the MNPs, aiming to specifically deliver a chemotherapeutic drug and a photosensitizer to cancer cells. Benefiting from the enhanced permeability and retention effect and active targeting capability, high tumor accumulation of MNPs is achieved, leading to an improved therapeutic outcome and reduced side effects. In vivo studies demonstrate that the combination of chemotherapy and PDT exhibits a superior antitumor performance against a drug-resistant tumor model attributed to their synergistic anticancer efficacy.


Assuntos
Antineoplásicos , Nanopartículas , Neoplasias Experimentais , Compostos Organoplatínicos , Fotoquimioterapia , Fármacos Fotossensibilizantes , Porfirinas , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Química Click , Humanos , Camundongos , Camundongos Nus , Nanopartículas/química , Nanopartículas/uso terapêutico , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Compostos Organoplatínicos/farmacocinética , Compostos Organoplatínicos/farmacologia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacocinética , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/química , Porfirinas/farmacocinética , Porfirinas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Photodiagnosis Photodyn Ther ; 26: 116-123, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30822565

RESUMO

BACKGROUND: Hemoporfin is a porphyrin-based photosensitizer and has been used for photodynamic therapy of port wine stain birthmarks in China. This study assessed the pharmacokinetics and cutaneous photosensitization of Hemoporfin in healthy volunteers. METHODS: Sixteen healthy subjects received a single intravenous infusion injection of Hemoporfin (5 mg/kg). The concentrations of Hemoporfin (MHD) and its metabolite Haematoporphyrin (HP) in plasma, urine and faeces were determined. The pharmacokinetic parameters were calculated. In addition, the cutaneous photosensitization was evaluated under the irradiation of solar simulator, 532 nm laser, and sunlight. RESULTS: The Cmax of MHD and HP were 46.7 ± 8.41 and 1.04 ± 0.265 µg/ml, respectively. The t1/2 of MHD and HP were 5.09 ± 0.945 and 5.71 ± 2.65 h, respectively. The AUC0-24h of MHD and HP were 29.8 ± 6.19 and 0.757 ± 0.285 h·µg/ml, respectively. The AUC0-∞ of MHD and HP were 29.8 ± 6.2 and 0.792 ± 0.308 h·µg/ml, respectively. The cumulative fecal excretion rate of MHD and HP were 45.3% and 1.05% at 96 h, respectively. Whereas, the cumulative urinary excretion rate of MHD was only 0.132% at 96 h. The concentration of HP in urine was less than 10% of MHD. After 52 h of administration, the cutaneous photosensitization associated with the exposure to various light sources was minimal. CONCLUSION: MHD and HP were excreted mainly through the faeces after intravenous infusion. Hemoporfin associated cutaneous photosensitization was insignificant.


Assuntos
Hematoporfirinas/farmacocinética , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacocinética , Adolescente , Adulto , Feminino , Voluntários Saudáveis , Hematoporfirinas/administração & dosagem , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Fármacos Fotossensibilizantes/administração & dosagem
15.
Spectrochim Acta A Mol Biomol Spectrosc ; 214: 513-521, 2019 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-30818150

RESUMO

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.


Assuntos
Complexos de Coordenação/química , Indóis/química , Modelos Moleculares , Fármacos Fotossensibilizantes/química , Zinco/química , Complexos de Coordenação/farmacocinética , Complexos de Coordenação/farmacologia , Sistemas de Liberação de Medicamentos , Humanos , Indóis/farmacocinética , Indóis/farmacologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacocinética , Fármacos Fotossensibilizantes/farmacologia , Zinco/farmacocinética , Zinco/farmacologia
16.
Nanoscale ; 11(12): 5474-5488, 2019 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-30855625

RESUMO

Clinical chemotherapy for cancer is limited by the physiological barrier of tumors, resulting in low drug delivery to tumors, poor efficacy of drugs and inability to block tumor metastasis. Here we developed an intelligent switchable nitric oxide (NO)-releasing nanoparticle, IPH-NO, which loads a photosensitizer (IR780) and the chemotherapy drug paclitaxel (PTX) into NO donor-S-nitrosated human serum albumin (HSA-NO). NO exhibits two effects based on its concentration: enhancement of chemotherapy by increasing the enhanced permeability and retention (EPR) effect at low concentrations and direct killing of cancer cells at high concentrations. IPH-NO can slowly release NO in the presence of glutathione to boost tumor vascular permeability and improve drug accumulation. Near-infrared light irradiation was utilized to induce a quick release of NO that can directly kill cancer cells at high concentrations. This combination of phototherapy and NO gas therapy activated by NIR together with chemotherapy showed significant effects in tumor inhibition. Furthermore, IPH-NO blocked tumor metastasis by inhibiting epithelial mesenchymal transition. PH-NO provides a novel strategy to control NO release at tumor site for drug accumulation and combination therapies, consequently potentiating the anticancer efficacy and inhibiting tumor metastasis.


Assuntos
Nanomedicina , Nanopartículas/química , Óxido Nítrico/metabolismo , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Glutationa/química , Meia-Vida , Humanos , Hipotermia Induzida , Raios Infravermelhos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Paclitaxel/química , Paclitaxel/farmacocinética , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacocinética , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Albumina Sérica Humana/química , Oxigênio Singlete/análise
17.
Theranostics ; 9(3): 884-899, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30809315

RESUMO

Cancer cell expresses abundant surface receptors. These receptors are important targets for cancer treatment and imaging applications. Our goal here is to develop nanoparticles with cargo loading and tumor targeting capability. Methods: A peptide targeting at cancer cell surface receptor (urokinase receptor, uPAR) was expressed in fusion with albumin (diameter of ~7 nm), and the fusion protein was assembled into nanoparticles with diameter of 40 nm, either in the presence or absence of cargo molecules, by a novel preparation method. An important feature of this method is that the nanoparticles were stabilized by hydrophobic interaction of the fusion protein and no covalent linking agent was used in the preparation. The stability, the cargo release, in vitro and in vivo properties of such formed nanoparticles were characterized by transmission electron microscopy, dynamic light scattering, gel shift assay, laser scanning confocal microscopy and 3D fluorescent molecular tomography. Results: The nanoparticles were stable for more than two weeks in aqueous buffer, even in the buffer containing 10% fetal bovine serum. Interestingly, in the presence of urokinase receptor, the uPAR-targeting nanoparticle disintegrated into 7.5 nm fragments and released its cargo, but not the non-targeting nanoparticles made from albumin by the same preparation method. Such nanoparticles also showed higher uptake and cytotoxicity to the receptor-expressing cancer cells in vitro and higher tumor accumulation in xenografted tumor-bearing mice in vivo compared to the non-targeting nanoparticles. Conclusion: Our results demonstrate a new function of cell surface receptor as a responsive trigger to disassemble nanoparticles, besides its common use to enrich targeting agents. Such nanoparticles were thus named receptor-responsive nanoparticles (RRNP).


Assuntos
Carcinoma Hepatocelular/terapia , Portadores de Fármacos/administração & dosagem , Terapia de Alvo Molecular/métodos , Nanopartículas/administração & dosagem , Fármacos Fotossensibilizantes/administração & dosagem , Receptores de Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Proteínas Recombinantes de Fusão/administração & dosagem , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Humanos , Camundongos , Transplante de Neoplasias , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacocinética , Ligação Proteica , Transplante Heterólogo , Resultado do Tratamento
18.
J Photochem Photobiol B ; 191: 128-134, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30616037

RESUMO

Photobiological properties of phthalocyanine photosensitizers, namely, clinically approved Photosens and new compounds Holosens and Phthalosens were analyzed on transitional cell carcinoma of the urinary bladder (T24) and human hepatic adenocarcinoma (SK-HEP-1). Photosens is a sulfated aluminum phthalocyanine with the number of sulfo groups 3.4, which is characterized by a high degree of hydrophilicity, slow cellular uptake, localization in lysosomes and the lowest photodynamic activity. Holosens is an octacholine zinc phthalocyanine, a cationic compound with significant charge. Holosens more efficiently enters the cells; it is localized in Golgi apparatus in addition to lysosomes and exhibits a significant inhibitory effect on cell viability upon irradiation. The highest photodynamic activity was demostrated by Phthalosens. Phthalosens is a metal-free analog of Photosens with a number of sulfo groups 2.5, which determines its amphiphilicity. Phthalosens is characterized by the highest rate of cellular uptake through the outer cell membrane, localization in cell membrane as well as in lysosomes and Golgi apparatus, and the highest activity upon irradiation among the photosensitizers studied. In general, changes in the physicochemical properties of Holosens and Phthalosens ensured an increase in their efficiency in vitro compared to Photosens. The features of accumulation, intracellular distribution and their interrelation with photodynamic activity, revealed in this work, indicate the prospects of Phthalosens and Holosens for clinical practice.


Assuntos
Indóis/farmacologia , Fármacos Fotossensibilizantes/química , Linhagem Celular Tumoral , Complexo de Golgi/metabolismo , Humanos , Indóis/farmacocinética , Lisossomos/metabolismo , Organelas/metabolismo , Compostos Organometálicos/farmacocinética , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacocinética
19.
Photodiagnosis Photodyn Ther ; 25: 425-435, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30685548

RESUMO

BACKGROUND: Daylight-activated PDT has seen increased support in recent years as a treatment method for actinic keratosis and other non-melanoma skin cancers. The inherent variability observed in broad-spectrum light used in this methodology makes it difficult to plan and monitor light dose, or compare to lamp light doses. METHODS: The present study expands on the commonly used PpIX-weighted effective surface irradiance metric by introducing a Monte Carlo method for estimating effective fluence rates into depths of the skin. The fluence rates are compared between multiple broadband and narrowband sources that have been reported in previous studies, and an effective total fluence for various treatment times is reported. A dynamic estimate of PpIX concentration produced during pro-drug incubation and treatment is used with the fluence estimates to calculate a photodynamic dose. RESULTS: Even when there is up to a 5x reduction between the effective surface irradiance of the broadband light sources, the effective fluence below 250 µm depth is predicted to be relatively equivalent. An effective threshold fluence value (0. 70Jeff/cm2) is introduced based on a meta-analysis of previously published ALA-PpIX induced cell death. This was combined with a threshold PpIX concentration (50 nM) to define a threshold photodynamic dose of 0.035 u M Jeff/cm2. CONCLUSIONS: The threshold was used to generate lookup tables to prescribe minimal treatment times to achieve depth-dependent cytotoxic effect based on incubation times and irradiance values for each light source.


Assuntos
Ácido Aminolevulínico/farmacologia , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Pró-Fármacos/farmacologia , Protoporfirinas/metabolismo , Pele/efeitos dos fármacos , Ácido Aminolevulínico/administração & dosagem , Ácido Aminolevulínico/farmacocinética , Morte Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Ceratose Actínica/tratamento farmacológico , Modelos Biológicos , Método de Monte Carlo , Fármacos Fotossensibilizantes/administração & dosagem , Fármacos Fotossensibilizantes/farmacocinética , Pró-Fármacos/administração & dosagem , Pró-Fármacos/farmacocinética , Valores de Referência , Neoplasias Cutâneas/tratamento farmacológico , Fatores de Tempo
20.
Eur J Pharm Sci ; 129: 68-78, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30597205

RESUMO

2-[1-Hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH), a second-generation photosensitizer, is employed in photodynamic therapy (PDT) for the treatment of various malignant lesions. PDT is a drug-device combined targeted treatment, and the clinical responses depend to a large extent on the photosensitizer distribution in target tissues and light exposure. In the present study, we aimed to give some suggestion for the development of HPPH-PDT from the perspective of photosensitizer biodistribution. For the first time, a PBPK model of HPPH was developed, which adequately described HPPH concentration-time profiles in rats plasma and various tissues. The rat PBPK model was further extrapolated to simulate the HPPH disposition in mouse and human. The simulated HPPH human serum concentrations yield a satisfactory agreement with observations at multiple dosing levels. It turned out that overweight may have a significant influence on HPPH exposure in human. Model simulated concentration-time profiles in human target tissues were also obtained. The appropriate time window to conduct light exposure for the treatment of digestive cancer and skin cancer could be 24-48 h and 48-96 h post-dose, respectively. Model simulations can explain the relevant clinical responses to some extent. The incorporation of the PBPK model into PDT could provide the photosensitizer concentrations not only in blood but also in target tissues, which may accelerate the development of this kind of treatment.


Assuntos
Clorofila/análogos & derivados , Animais , Clorofila/farmacocinética , Feminino , Humanos , Masculino , Camundongos , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacocinética , Ratos , Ratos Sprague-Dawley , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/metabolismo , Distribuição Tecidual/fisiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA