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1.
Carbohydr Polym ; 231: 115733, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31888823

RESUMO

All-trans retinoic acid (ATRA) was grafted to hyaluronan (HA) via esterification. The reaction was mediated by mixed anhydrides. A perfect control of the degree of substitution (0.5-7.5%) was obtained by varying the molar ratio of retinoic acid in the feed. The degree of substitution plays a significant role in the long-term stability. The photodegradation of HA-ATRA upon UVA irradiation resulted in ß-ionone, ß-cyclocitral and 5,6-epoxy-(E)-retinoic acid. The photostability of the conjugate had increased with the combination with morin. The chemical structure of HA-ATRA and its degradation products was elucidated using NMR spectroscopy, SEC-MALLS, and gas chromatography-mass spectrometry (GC-MS). ATRA did not loss its biological activity after conjugation, as demonstrated by gene expression. The derivative was able to penetrate across the stratum corneum. Besides, HA-ATRA downregulated the expression of anti-inflammatory interleukins 6 and 8. HA-ATRA would be expected to be used for transdermal drug delivery or cosmetics.


Assuntos
Antioxidantes/farmacologia , Ácido Hialurônico/química , Pele/efeitos dos fármacos , Tretinoína/química , Administração Cutânea , Anidridos/química , Animais , Antioxidantes/química , Esterificação , Flavonoides/química , Ácido Hialurônico/síntese química , Ácido Hialurônico/farmacologia , Camundongos , Células NIH 3T3 , Norisoprenoides/química , Norisoprenoides/farmacologia , Fotólise/efeitos dos fármacos , Pele/efeitos da radiação , Tretinoína/síntese química , Tretinoína/farmacologia , Raios Ultravioleta
2.
J Fluoresc ; 29(6): 1277-1283, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31755049

RESUMO

Tretinoin or All-trans retinoic acid (ATRA) is an efficient medication in leukemia treatment. Arsenic trioxide (ATO) significantly improves the effectiveness of ATRA. In this study, the effect of ATO on ATRA binding to human serum albumin (HSA) was investigated. Fluorescence and UV-Vis spectroscopy and equilibrium dialysis technique were used to determine ATRA binding to HSA in the presence and absence of ATO and of two compounds, warfarin and ibuprofen, specific for binding to HSA sites I and II, respectively ("site markers"). The association constants for ATRA binding and the number of binding sites as well as the thermodynamic parameters of complex formation, were obtained at different temperatures. Fluorescence results showed a static quenching mechanism for ATRA binding to HSA. The calculated thermodynamic parameters revealed that the binding reaction is a spontaneous and exothermic process and also that hydrogen bonds and van der Waals forces have a central role in the binding of ATRA to HSA. Competitive experiments showed that none of markers seriously prevents ATRA binding to HSA. Interestingly, the fluorescence and equilibrium dialysis data showed that ATO increases the binding of ATRA to HSA, and converts the binding mode of ATRA from mainly hydrogen bonding to include hydrophobic interactions as well. These results suggest that ATO can prevent the metabolism of ATRA and keep it in the blood for longer by increasing the binding of ATRA to HSA.


Assuntos
Trióxido de Arsênio/química , Albumina Sérica Humana/química , Tretinoína/química , Sítios de Ligação , Transferência de Energia , Humanos , Albumina Sérica Humana/metabolismo , Espectrometria de Fluorescência , Termodinâmica , Tretinoína/metabolismo
3.
J Nanobiotechnology ; 17(1): 97, 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31526377

RESUMO

BACKGROUND: Externally triggered drug delivery systems hold considerable promise for improving the treatment of many diseases, in particular, diseases where the spatial-temporal release of the drug is critical to maximize their biological effect whilst minimizing undesirable, off-target, side effects. RESULTS: Herein, we developed a light-triggerable formulation that takes advantage of host-guest chemistry to complex drugs functionalized with a guest molecule and release it after exposure to near infrared (NIR) light due to the disruption of the non-covalent host-guest interactions. The system is composed by a gold nanorod (AuNR), which generates plasmonic heat after exposure to NIR, a thin layer of hyaluronic acid immobilized to the AuNR upon functionalization with a macrocycle, cucurbit[6]uril (CB[6]), and a drug functionalized with a guest molecule that interacts with the macrocycle. For proof of concept, we have used this formulation for the intracellular release of a derivative of retinoic acid (RA), a molecule known to play a key role in tissue development and homeostasis as well as during cancer treatment. We showed that the formulation was able to conjugate approximately 65 µg of RA derivative per mg of CB[6] @AuNR and released it within a few minutes after exposure to a NIR laser. Importantly, the bioactivity of RA released from the formulation was demonstrated in a reporter cell line expressing luciferase under the control of the RA receptor. CONCLUSIONS: This NIR light-triggered supramolecular-based modular platform holds great promise for theranostic applications.


Assuntos
Química Farmacêutica/métodos , Sistemas de Liberação de Medicamentos/métodos , Bibliotecas de Moléculas Pequenas/química , Linhagem Celular Tumoral , Células Cultivadas , Liberação Controlada de Fármacos/efeitos dos fármacos , Ouro/química , Humanos , Ácido Hialurônico/química , Raios Infravermelhos , Nanotubos/química , Bibliotecas de Moléculas Pequenas/administração & dosagem , Tretinoína/química
4.
Mater Sci Eng C Mater Biol Appl ; 105: 110093, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31546364

RESUMO

Millions of people worldwide suffer from vision impairing conditions resulting from corneal injury or disease. Silk fibroin (SF) is an emerging biopolymer that has been used for several applications including the fabrication of bioengineered corneas and ocular prostheses. To improve the cell response to SF, riboflavin (RF) and all-trans retinoic acid (RA) were coupled onto SF matrices. RF is a photo-initiator that has previously been combined with ultraviolet light to crosslink corneal collagen while RA has been used to regulate the phenotype of corneal stromal cells and their extracellular matrix deposition. Different concentrations of RF and RA were respectively photo-crosslinked and covalently bound through carbodiimide coupling onto 2% SF matrices. The effect of incorporating these molecules on the physical, chemical and mechanical properties of the matrices was evaluated. The biological response of human corneal stromal cells to the matrices was examined using cellular adhesion assays, proliferation assays, cytoskeleton staining, gene expression analysis and immunocytochemical staining. RF and RA both led to changes in the surface nanostructure and hydrophilicity while just RF increased the material stiffness. Cells cultured on the matrices containing both biomolecules displayed improved cellular proliferation, increased GAG deposition and increased expression of keratocyte genes that are normally associated with healthy corneal stromal tissue. These in vitro studies serve as a starting point for the optimization of loading bioactive molecules on SF based matrices for formulating clinically relevant ocular implants.


Assuntos
Córnea/metabolismo , Ceratócitos da Córnea/metabolismo , Fibroínas/química , Riboflavina/química , Engenharia Tecidual , Tecidos Suporte/química , Tretinoína/química , Córnea/citologia , Ceratócitos da Córnea/citologia , Humanos
5.
Microbiol Immunol ; 63(10): 438-443, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31329291

RESUMO

The effects of chalcone and butein on the induction of the superoxide anion (O2 - )-generating system were studied in U937 cells by all-trans retinoic acid (RA). The chalcone skeleton, a common structural motif in them, significantly enhanced the transcription of gp91-phox in an epigenetic manner. In contrast, chalcone and butein showed opposite effects on the induction of the O2 - -generating activity by RA and the expression of gp91-phox protein. Chalcone inhibited, whereas butein promoted, the induction of O2 - -generating activity by RA and the expression of gp91-phox protein. These data raise the possibility that modification of the chalcone skeleton could produce more effective differentiation-promoting agents.


Assuntos
Chalcona/farmacologia , Chalconas/farmacologia , NADPH Oxidase 2/genética , NADPH Oxidase 2/metabolismo , Superóxidos/metabolismo , Humanos , Tretinoína/química , Células U937
6.
Methods Mol Biol ; 2000: 293-302, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31148023

RESUMO

Solid lipid nanoparticles (SLNs) have been extensively investigated for effective delivery of both hydrophilic and lipophilic drugs by topical route. There are several scalable techniques for the preparation of SLNs such as homogenization, microemulsion template, and solvent emulsification diffusion. This chapter describes step-wise methodology for the preparation and characterization of SLNs using solvent emulsification diffusion method. Tretinoin, a lipophilic entity, was chosen as a model drug. The critical aspects and the important interpretations with respect to the preparation and characterization of SLNs are reported in "Notes" section.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/química , Tretinoína/administração & dosagem , Administração Tópica , Emulsões , Interações Hidrofóbicas e Hidrofílicas , Tretinoína/química
7.
Biomed Pharmacother ; 115: 108857, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31048191

RESUMO

Gastric cancer which starts from the stomach is a fatal cancer with poor prognosis around the world. The recurrence and metastasis of gastric cancer may be attributed to gastric cancer stem cells. It is recognized that cancer usually possesses multiple populations of distinct cancer stem cells with different phenotypes, thus it will be imperative to target more subsets of cancer stem cells instead of targeting only one population of cancer stem cells. It is generally accepted that both CD44 and CD133 are gastric cancer stem cells markers, we hereby developed CD44/CD133-ATRA-PLPN (CD44 and CD133 antibody-conjugated all-trans retinoic acid-loaded poly(lactide-co-glycolide)-lecithin-PEG nanoparticles) to target both CD133+ and CD44+ gastric cancer stem cells. In this study, the therapeutic effect of CD44/CD133-ATRA-PLPN against gastric cancer stem cells was investigated. The results presented here confirmed that CD44/CD133-ATRA-PLPN was efficiently and specifically delivered to CD44+ or CD133+ gastric cancer stem cells, resulting in enhanced growth inhibitory effect towards gastric cancer stem cells compared with single targeted and non-targeted nanoparticles. As far as we know, we firstly reported the promotion of nanoparticle delivery to two populations of gastric cancer stem cells by antibodies. Since cancer usually contains distinct populations of cancer stem cells with multiple phenotypes, our dual targeting nanoparticles constitute an effective drug delivery platform for targeting multiple populations of cancer stem cells within the cancer.


Assuntos
Antígeno AC133/imunologia , Anticorpos/imunologia , Receptores de Hialuronatos/imunologia , Nanopartículas/química , Células-Tronco Neoplásicas , Neoplasias Gástricas/terapia , Animais , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Camundongos , Camundongos Nus , Neoplasias Experimentais , Polímeros/química , Tretinoína/administração & dosagem , Tretinoína/química
8.
Mol Neurobiol ; 56(10): 7074-7084, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30972628

RESUMO

Retinoic acid (RA) regulates numerous aspects of central nervous system function through modulation of gene transcription via retinoic acid receptors (RARs). However, RA has important roles independent of gene transcription (non-genomic actions) and in the brain a crucial regulator of homeostatic plasticity is RAR control of glutamate receptor subunit 1 (GluR1) translation. An assay to quantify RAR regulation of GluR1 translation would be beneficial both to study the molecular components regulating this system and screen drugs that influence this critical mechanism for learning and memory in the brain. A bioluminescence reporter assay was developed that expresses firefly luciferase under the control of the GluR1 5' untranslated region bound by RAR. This assay was introduced into SH-SY5Y cells and used to demonstrate the role of RARα in RA regulation of GluR1 translation. A screen of synthetic RAR and RXR ligands indicated that only a subset of these ligands activated GluR1 translation. The results demonstrate the practicality of this assay to explore the contribution of RARα to this pathway and that the capacity of RAR ligands to activate translation is a quality restricted to a limited number of compounds, with implications for their RAR selectivity and potentially their specificity in drug use.


Assuntos
Bioensaio , Genes Reporter , Luminescência , Biossíntese de Proteínas/efeitos dos fármacos , Receptores de AMPA/biossíntese , Tretinoína/farmacologia , Regiões 5' não Traduzidas/genética , Animais , Sequência de Bases , Linhagem Celular Tumoral , Humanos , Ligantes , Ratos , Receptor alfa de Ácido Retinoico/genética , Tretinoína/química
9.
Eur J Pharmacol ; 854: 201-212, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-30974104

RESUMO

Treatment of glioblastoma (GBM), as the most lethal type of brain tumor, still remains a major challenge despite the various therapeutic approaches developed over the recent decades. GBM is considered as one of the most therapy-resistant human tumors. Treatment with temozolomide (TMZ) chemotherapy and radiotherapy in GBM patients has led to 30% of two-year survival rate (American Brain Tumor Association), representing a demanding field to develop more effective therapeutic strategies. This study presents a novel method for local delivery of all-trans retinoic acid (ATRA) for targeting GBM cells as a possible adjuvant therapeutic strategy for this disease. We have used 3D bioprinting to fabricate hydrogel meshes laden with ATRA-loaded polymeric particles. The ATRA-loaded meshes have been shown to facilitate a sustained release of ATRA with tunable release rate. Cell viability assay was used to demonstrate the ability of fabricated meshes in reducing cell growth in U-87 MG cell line. We later showed that the developed meshes induced apoptotic cell death in U-87 MG. Furthermore, the use of hydrogel for embedding the ATRA-loaded particles can facilitate the immobilization of the drug next to the tumor site. Our current innovative approach has shown the potential to open up new avenues for treatment of GBM, benefiting patients who suffer from this debilitating disease.


Assuntos
Portadores de Fármacos/química , Glioblastoma/patologia , Hidrogéis/química , Impressão Tridimensional , Tretinoína/química , Tretinoína/farmacologia , Astrócitos/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Liberação Controlada de Fármacos , Elasticidade , Glioblastoma/tratamento farmacológico , Humanos , Hidrogéis/toxicidade , Porosidade , Análise de Sobrevida , Tretinoína/uso terapêutico , Viscosidade
10.
Carbohydr Polym ; 215: 8-19, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30981373

RESUMO

Novel chitosan-cystamine-retinoic acid conjugate (CS-SS-RA) was synthesized and could self-assemble into redox-sensitive micelles in aqueous environment with low critical micelle concentration value. CS-SS-RA micelles were characterized with spherical shape, desirable particle size, negative zeta potential, high paclitaxel (PTX) loading and encapsulation efficiency and redox-sensitivity. Hemolysis and cytotoxicity studies proved the safety of CS-SS-RA micelles for intravenous administration. Cytotoxicity study against HepG2 cells and the growth inhibition study on three-dimensional multicellular tumor spheroids (MCTSs) revealed that PTX-loaded CS-SS-RA micelles exhibited higher antitumor activity than free PTX. The in vitro cellular uptake profiles of FITC-labeled CS-SS-RA micelles evaluated via confocal laser scanning microscopy and flow cytometry indicated that CS-SS-RA micelles could enhance cellular uptake efficiency of PTX, and their internalization by HepG2 cells were mediated by clathrin-mediated endocytosis and macropinocytosis. These results demonstrated that CS-SS-RA micelles could be developed as a promising platform for intracellular delivery of hydrophobic antitumor agents.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/química , Quitosana/química , Portadores de Fármacos/química , Neoplasias/tratamento farmacológico , Tretinoína/química , Sobrevivência Celular/efeitos dos fármacos , Cistamina/química , Portadores de Fármacos/síntese química , Liberação Controlada de Fármacos , Células Hep G2 , Humanos , Micelas , Oxirredução , Paclitaxel/administração & dosagem , Tamanho da Partícula
12.
ACS Chem Biol ; 14(3): 369-377, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30707838

RESUMO

Retinoids, such as all- trans-retinoic acid (ATRA), are endogenous signaling molecules derived from vitamin A that influence a variety of cellular processes through mediation of transcription events in the cell nucleus. Because of these wide-ranging and powerful biological activities, retinoids have emerged as therapeutic candidates of enormous potential. However, their use has been limited, to date, due to a lack of understanding of the complex and intricate signaling pathways that they control. We have designed and synthesized a family of synthetic retinoids that exhibit strong, intrinsic, solvatochromatic fluorescence as multifunctional tools to interrogate these important biological activities. We utilized the unique photophysical characteristics of these fluorescent retinoids to develop a novel in vitro fluorometric binding assay to characterize and quantify their binding to their cellular targets, including cellular retinoid binding protein II (CRABPII). The dihydroquinoline retinoid, DC360, exhibited particularly strong binding ( Kd = 34.0 ± 2.5 nM), and we further used X-ray crystallography to determine the structure of the DC360-CRABPII complex to 1.8 Å, which showed that DC360 occupies the known hydrophobic retinoid binding pocket. Finally, we used confocal fluorescence microscopy to image the cellular behavior of the compounds in cultured human epithelial cells, highlighting a fascinating nuclear localization, and used RNA sequencing to confirm that the compounds regulate cellular processes similar to those of ATRA. We anticipate that the unique properties of these fluorescent retinoids can now be used to cast new light on the vital and highly complex retinoid signaling pathway.


Assuntos
Corantes Fluorescentes/química , Retinoides/metabolismo , Proteínas Celulares de Ligação ao Retinol/metabolismo , Tretinoína/química , Tretinoína/metabolismo , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Desenho de Fármacos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Imagem Óptica/métodos , Ligação Proteica , Conformação Proteica , Transdução de Sinais
13.
ACS Appl Mater Interfaces ; 11(9): 8779-8788, 2019 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-30714374

RESUMO

Nanoparticle-based cell differentiation therapy has attracted increasing research interest as it is a promising substitute for conventional cancer treatment methods. Here, the topological insulator bismuth selenide nanoparticle (Bi2Se3 NP) was core-shelled with silver (Ag@Bi2Se3) to represent remarkable biocompatibility and plasmonic features (ca. 2.3 times higher than those of Ag nanoparticle). Moreover, a newly developed RNA three-way junction (3WJ) structure was designed for the quad-functionalization of any type of nanoparticle and surface. One leg of the 3WJ was attached to the Ag@Bi2Se3, and the other leg harbored a cell-penetrating RNA and a florescence tag. The third leg was designed to inhibit micro-RNA-17 (miR-17) and to further release retinoic acid (RA). A new drug delivery mechanism was developed for the slow release of RA inside the cytosol based on the prerequisite inhibition of miR-17 using a strand displacement strategy. In this paper, we report a simple methodology for resolving the hydrophobicity challenges of RA by its conjugation with a RNA strand (RA/R) through a stimulus-responsive cross-linker. The developed nanobiohybrid material could fully differentiate SH-SY5Y cancer cells into neurons and stop their growth in 6 days without requiring sequential treatments which has not been reported yet. Using a surface-enhanced Raman spectroscopy technique, the RA delivery and the cell differentiation process were monitored nondestructively in real time. The fabricated nanobiohybrid material could open the new horizons in the fabrication of different diagnostic/therapeutic agents.


Assuntos
Nanopartículas Metálicas/química , MicroRNAs/metabolismo , Compostos Organosselênicos/química , Prata/química , Tretinoína/química , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Portadores de Fármacos/química , Endocitose , Humanos , MicroRNAs/antagonistas & inibidores , Microscopia Confocal , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Oligonucleotídeos/química , Povidona/química , Análise Espectral Raman , Tretinoína/metabolismo , Tretinoína/farmacologia
14.
J Drugs Dermatol ; 18(2): 178-188, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30811141

RESUMO

Background: Acne vulgaris (acne) is a common dermatological condition typically associated with adolescents, affecting about 85% of young people. However, it is also prevalent and persistent into adulthood, particularly in females. The efficacy of tretinoin in acne is well documented with large pivotal studies. The first lotion formulation of tretinoin was developed to provide an important alternative option to treat acne patients who may be sensitive to the irritant effects of other tretinoin formulations. Objective: To determine whether efficacy and safety of tretinoin 0.05% lotion was similar in adolescent (<18 years) and adult (>=18 years) women with moderate-to-severe acne. Methods: Post hoc analysis of two multicenter, randomized, double-blind, vehicle-controlled Phase 3 studies in moderate or severe acne. Female subjects (aged 9 to 58 years, N=909) randomized (1:1) to receive tretinoin 0.05% lotion or vehicle, once-daily for 12 weeks. Efficacy assessments included changes in baseline inflammatory and noninflammatory lesions and treatment success (at least 2-grade reduction in Evaluator's Global Severity Score [EGSS] and clear/almost clear). Safety, adverse events (AEs), and cutaneous tolerability were evaluated throughout. Results: At week 12, mean percent reduction in inflammatory and noninflammatory lesion counts in female subjects were 56.9% and 51.7%, respectively, compared with 47.1% and 34.9% with vehicle (P=<0.001). Similar results were seen in adult and adolescent females in terms of reduction in inflammatory lesion counts with tretinoin 0.05% lotion; reduction in noninflammatory lesions was significantly greater in adult females (P=0.002). Treatment success was achieved by 23.6% of female subjects by week 12, compared with 13.5% on vehicle (P<0.001). Although treatment success was somewhat greater in adult females (24.6% versus 21.6%), the difference was not significant. The majority of AEs were mild and transient. There were five serious AEs (SAEs) reported (4/1, adult/adolescent, respectively). The most frequently reported treatment related AEs with tretinoin 0.05% lotion were application site pain (3.0%/5.7%), and application site dryness (4.9%/6.4%). Local cutaneous safety and tolerability assessments were generally mild-to-moderate and improved by week 12. Slight increases in mean scores were observed for scaling, burning and stinging within the first four weeks and appeared to be transient. Conclusions: Tretinoin 0.05% lotion was significantly more effective than its vehicle in achieving treatment success and reducing inflammatory and noninflammatory lesions in female acne. Noninflammatory lesion count reduction was significantly greater in adult females compared with adolescent females. The new lotion formulation was well-tolerated. J Drugs Dermatol. 2019;18(2):178-188.


Assuntos
Acne Vulgar/diagnóstico , Acne Vulgar/tratamento farmacológico , Ceratolíticos/administração & dosagem , Índice de Gravidade de Doença , Tretinoína/administração & dosagem , Administração Tópica , Adolescente , Adulto , Criança , Método Duplo-Cego , Esquema de Medicação , Composição de Medicamentos , Feminino , Humanos , Ceratolíticos/química , Pessoa de Meia-Idade , Resultado do Tratamento , Tretinoína/química , Adulto Jovem
15.
Biomater Sci ; 7(3): 1028-1042, 2019 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-30608065

RESUMO

Gambogic acid (GA) is a natural antitumor drug candidate with advantages of broad-spectrum activity, low toxicity and multiple mechanisms. Its clinical application is hindered, however, by low aqueous solubility, instability and poor pharmacokinetic properties. In this research, core-shell hybrid nanoparticles have been developed to improve the druggability of GA. The nanoparticles are composed of a benzylamidated poly(γ-glutamic acid) (BzPGA) derivative as a core material and an amphiphilic hyaluronic acid derivative grafted with all-trans retinoic acid (HA-C6-ATRA) as a shell material. Through π-π stacking interactions, GA is encapsulated into BzPGA to form the "core" of the hybrid nanoparticle and the "shell" is formed by HA-C6-ATRA with a π-π stacking mediated "molecular fence". The nanovehicle, with sub 100 nm size, provides almost 100% encapsulation efficiency, a good protective effect and a sustained release profile for GA. A series of evaluations suggest that the core-shell nanoparticles provide a stable aqueous injection formulation (I), improved stability (II), prolonged circulation time and conferred tumor targeting properties (III) for GA. As a result, the anti-tumor activity of GA is significantly enhanced without causing higher toxicity, indicating that the designed nanoplatform dramatically improves the druggability of GA. This study may also provide inspiration for drug development research.


Assuntos
Antineoplásicos/química , Portadores de Fármacos/química , Nanopartículas/química , Xantonas/química , Animais , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Ácido Hialurônico/química , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Masculino , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos ICR , Tamanho da Partícula , Ácido Poliglutâmico/análogos & derivados , Ácido Poliglutâmico/química , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual , Tretinoína/química
16.
J Liposome Res ; 29(3): 283-290, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30501429

RESUMO

Acne vulgaris is the most common dermatological disorder affecting millions of individuals. Acne therapeutic solutions include topical treatment with retinoic acid (RA) which showed a good efficacy in treatment of mild and moderate cases. However, the high prevalence of adverse events, such as skin dryness, shedding and skin irritation affects the patient convenience and obstruct the acne treatment. Thus, the objective of this paper was to produce Span 60 based elastic vesicles enriched with penetration enhancers, and study their influence on the delivery of RA and its skin irritation. RA-loaded nanovesicles, enriched with Transcutol®/Labrasol®, were made using the thin film hydration technique, and assessed for entrapment efficiency, particle size and zeta potential. The optimized RA-loaded nanovesicles (composed of Span 60-Tween 20, and Transcutol®) were morphologically assessed via transmission electron microscopy. Moreover, RA deposition into newborn mice skin was assessed in vitro under non-occlusive conditions, where the optimized RA-loaded nanovesicles showed 2-fold higher RA deposition in the skin compared to the corresponding one lacking Transcutol. The optimized RA-loaded nanovesicles incorporated into 1% carbopol gel was evaluated for in-vivo clinical performance in acne patients, and showed appreciable advantages over the marketed formulation (Acretin®) in the treatment of acne regarding skin tolerability and patient's compliance.


Assuntos
Acne Vulgar/tratamento farmacológico , Fármacos Dermatológicos/administração & dosagem , Lipossomos/química , Pele/metabolismo , Tretinoína/administração & dosagem , Administração Tópica , Adolescente , Adulto , Animais , Fármacos Dermatológicos/química , Fármacos Dermatológicos/metabolismo , Etilenoglicóis/química , Glicerídeos/química , Hexoses/química , Humanos , Camundongos , Nanopartículas/química , Polissorbatos/química , Absorção Cutânea , Tretinoína/química , Tretinoína/metabolismo
17.
J Biomater Sci Polym Ed ; 30(1): 1-11, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29943678

RESUMO

Immunomodulatory function of all-trans retinoic acid (ATRA) has been gathering much attention for the therapy of autoimmune diseases. ATRA is a chemically unstable molecule which requires proper formulation for targeted delivery. Here we examined nanostructured lipid carrier (NLC) for the formulation of ATRA. NLC is a representative nanoparticle formulation especially suited for oral delivery. We established the preparation procedures of ATRA-containing NLC (NLC-RA) which minimizes the degradation of ATRA during the preparation process. NLC-RA thus obtained was taken up by macrophages and induced anti-inflammatory response via suppressing NF-κB signaling as well as via enhancing the production of anti-inflammatory cytokines. Moreover, NLC-RA enhanced differentiation of naïve T cells to regulatory T cells in the co-culture system with dendritic cells. These results suggest that NLC-RA is a promising alternative therapy for the autoimmune diseases especially intestinal bowel disease.


Assuntos
Portadores de Fármacos , Lipídeos , Macrófagos/efeitos dos fármacos , Nanocápsulas/química , Linfócitos T Reguladores/efeitos dos fármacos , Tretinoína/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Técnicas de Cocultura , Humanos , Ativação de Macrófagos/efeitos dos fármacos , Camundongos , Células RAW 264.7 , Tretinoína/química
18.
Int Immunopharmacol ; 65: 561-570, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30415163

RESUMO

Myelodysplastic syndromes (MDS) are a varied set of hematologic neoplasms and a high risk of progression to acute myeloid leukemia (AML). 4-Amino-2-trifluoromethyl-phenyl retinate (ATPR), a novel all-trans retinoic acid (ATRA) derivative, play an important role in various types of cancer cells as a tumor inhibitor. However, little is known concerning its antitumor effect on MDS. The cell viability and the percentage of apoptotic cells were used to measure MTT, Flow Cytometry and Hoechst 33342/PI staining. In addition, real-time quantitative RT-PCR (qRT-PCR) and western blotting were used to analyzed the expression of p53, as well as the levels of BNIP3, apoptosis proteins of Caspase-3, BAX and BCL-2. After SKM-1 cells were incubated with DAC, ATRA and ATPR, the viability of the SKM-1 cells was inhibited in a dose- and time-dependent manner. Both Hoechst staining and flow cytometry showed the apoptosis of SKM-1 cells was increased. Moreover, SKM-1 cells treated with ATPR unveiled elevated mRNA and protein levels of p53, BNIP3, BAX and Caspase-3 expression and decreased BCL-2 expression. However, silencing p53 suppressed the pro-apoptosis function of ATPR. Consequently, these data provide the first evidence for ATPR increased apoptosis in SKM-1 cells by p53 that is mutually dependent on and obligatorily linked to BNIP3 gene activation.


Assuntos
Síndromes Mielodisplásicas/tratamento farmacológico , Retinoides/uso terapêutico , Proteína Supressora de Tumor p53/metabolismo , Apoptose , Caspase 3/genética , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Regulação da Expressão Gênica , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Interferente Pequeno/genética , Retinoides/química , Transdução de Sinais , Tretinoína/química , Proteína Supressora de Tumor p53/genética , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
19.
Nat Commun ; 9(1): 3660, 2018 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-30202007

RESUMO

Kidney injury is a common complication of severe disease. Here, we report that injuries of the zebrafish embryonal kidney are rapidly repaired by a migratory response in 2-, but not in 1-day-old embryos. Gene expression profiles between these two developmental stages identify cxcl12a and myca as candidates involved in the repair process. Zebrafish embryos with cxcl12a, cxcr4b, or myca deficiency display repair abnormalities, confirming their role in response to injury. In mice with a kidney-specific knockout, Cxcl12 and Myc gene deletions suppress mitochondrial metabolism and glycolysis, and delay the recovery after ischemia/reperfusion injury. Probing these observations in zebrafish reveal that inhibition of glycolysis slows fast migrating cells and delays the repair after injury, but does not affect the slow cell movements during kidney development. Our findings demonstrate that Cxcl12 and Myc facilitate glycolysis to promote fast migratory responses during development and repair, and potentially also during tumor invasion and metastasis.


Assuntos
Quimiocina CXCL12/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Nefropatias/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/genética , Animais , Animais Geneticamente Modificados , Movimento Celular , Metabolismo Energético , Deleção de Genes , Perfilação da Expressão Gênica , Glicólise , Homeostase , Rim/lesões , Rim/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais , Tretinoína/química
20.
Skin Pharmacol Physiol ; 31(6): 316-323, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30199861

RESUMO

BACKGROUND AND AIM: Acne vulgaris is a common inflammatory skin condition which is treated using Tretinoin (TRE), a widely used retinoid. Nano emulations (NEs) are colloidal nano-sized particles that enhance the therapeutic efficacy of TRE and minimize adverse effects. This study is aimed at developing a TRE-loaded NE (NE-TRE) and at assessing the therapeutic effects of the formulation in acne vulgaris lesions, compared to conventional 0.05% TRE emulsion. METHOD: The high energy emulsification method was used to make NE-TRE. After obtaining stable NE, particle characterization and physicochemical properties were evaluated under accelerated conditions. Conducting a clinical study, we compared the therapeutic effects of NE-TRE and 0.05% TRE emulsion by comparing the number of acne lesions and porphyrin production in both sides of the face. RESULTS AND CONCLUSION: We successfully developed stable nanoparticles. It was a stable oil-in-water emulsion with particle size of about 150 nm, and containing circular and separated particles. In a pilot clinical study, the number of acne lesions as well as the size and intensity of porphyrin production significantly reduced after topical application of NE-TRE. This formula shows proper efficiency and good loading capacity of TRE in the drug delivery system.


Assuntos
Acne Vulgar/tratamento farmacológico , Fármacos Dermatológicos/administração & dosagem , Nanopartículas/administração & dosagem , Tretinoína/administração & dosagem , Adolescente , Adulto , Criança , Fármacos Dermatológicos/química , Sistemas de Liberação de Medicamentos , Emulsões , Feminino , Humanos , Masculino , Nanopartículas/química , Método Simples-Cego , Resultado do Tratamento , Tretinoína/química , Adulto Jovem
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