RESUMO
Liposomes represent one of the most extensively studied nano-carriers due to their potential in targeted drug delivery. However, the complex in vivo fate, particularly under pathological conditions, presents challenges for clinical translation of liposomal therapeutics. Liver serves as the most important organ for liposome accumulation and metabolism. Unfortunately, the fate of liposomes under pathological liver conditions has been significantly overlooked. This study aimed to investigate the in vivo pharmacokinetic profile and biodistribution profile of liposomes under drug-induced liver injury (DILI) conditions. Two classic DILI animal models, i.e. acetaminophen-induced acute liver injury (AILI) and triptolide-induced subacute liver injury (TILI), were established to observe the effect of pathological liver conditions on the in vivo performance of liposomes. The study revealed significant changes in the in vivo fate of liposomes following DILI, including prolonged blood circulation and enhanced hepatic accumulation of liposomes. Changes in the composition of plasma proteins and mononuclear phagocyte system (MPS)-related cell subpopulations collectively led to the altered in vivo fate of liposomes under liver injury conditions. Despite liver injury, macrophages remained the primary cells responsible for liposomes uptake in liver, with the recruited monocyte-derived macrophages exhibiting enhanced ability to phagocytose liposomes under pathological conditions. These findings indicated that high capture of liposomes by the recruited hepatic macrophages not only offered potential solutions for targeted delivery, but also warned the clinical application of patients under pathological liver conditions.
Assuntos
Acetaminofen , Doença Hepática Induzida por Substâncias e Drogas , Diterpenos , Lipossomos , Fígado , Fenantrenos , Animais , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Acetaminofen/farmacocinética , Camundongos , Masculino , Fígado/metabolismo , Fígado/efeitos dos fármacos , Distribuição Tecidual , Fenantrenos/farmacocinética , Fenantrenos/administração & dosagem , Fenantrenos/toxicidade , Diterpenos/farmacocinética , Diterpenos/administração & dosagem , Compostos de Epóxi/farmacocinética , Compostos de Epóxi/administração & dosagem , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos/métodos , Camundongos Endogâmicos C57BLRESUMO
PURPOSE: Joint destruction is a major burden and an unsolved problem in rheumatoid arthritis (RA) patients. We designed an intra-articular mesoporous silica nanosystem (MSN-TP@PDA-GlcN) with anti-inflammatory and joint protection effects. The nanosystem was synthesized by encapsulating triptolide (TP) in mesoporous silica nanoparticles and coating it with pH-sensitive polydopamine (PDA) and glucosamine (GlcN) grafting on the PDA. The nano-drug delivery system with anti-inflammatory and joint protection effects should have good potency against RA. METHODS: A template method was used to synthesize mesoporous silica (MSN). MSN-TP@PDA-GlcN was synthesized via MSN loading with TP, coating with PDA and grafting of GlcN on PDA. The drug release behavior was tested. A cellular inflammatory model and a rat RA model were used to evaluate the effects on RA. In vivo imaging and microdialysis (MD) system were used to analyze the sustained release and pharmacokinetics in RA rats. RESULTS: TMSN-TP@PDA-GlcN was stable, had good biocompatibility, and exhibited sustained release of drugs in acidic environments. It had excellent anti-inflammatory effects in vitro and in vivo. It also effectively repaired joint destruction in vivo without causing any tissue toxicity. In vivo imaging and pharmacokinetics experiments showed that the nanosystem prolonged the residence time, lowered the Cmax value and enhanced the relative bioavailability of TP. CONCLUSIONS: These results demonstrated that MSN-TP@PDA-GlcN sustained the release of drugs in inflammatory joints and produced effective anti-inflammatory and joint protection effects on RA. This study provides a new strategy for the treatment of RA.
Assuntos
Anti-Inflamatórios , Artrite Reumatoide , Diterpenos , Liberação Controlada de Fármacos , Indóis , Nanopartículas , Fenantrenos , Polímeros , Dióxido de Silício , Animais , Dióxido de Silício/química , Artrite Reumatoide/tratamento farmacológico , Nanopartículas/química , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacocinética , Fenantrenos/química , Fenantrenos/administração & dosagem , Fenantrenos/farmacocinética , Fenantrenos/farmacologia , Ratos , Diterpenos/administração & dosagem , Diterpenos/química , Diterpenos/farmacocinética , Diterpenos/farmacologia , Indóis/administração & dosagem , Indóis/química , Indóis/farmacocinética , Indóis/farmacologia , Polímeros/química , Porosidade , Masculino , Compostos de Epóxi/química , Compostos de Epóxi/administração & dosagem , Glucosamina/química , Glucosamina/administração & dosagem , Ratos Sprague-Dawley , Portadores de Fármacos/química , Humanos , Camundongos , Preparações de Ação Retardada , Inflamação/tratamento farmacológico , Inflamação/prevenção & controleRESUMO
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-associated death worldwide. Beside early detection, early diagnosis, and early surgery, it is urgent to try new strategies for the treatment of HCC. Triptolide (TPL) has been employed to treat HCC. However, its clinical applications were restricted by the narrow therapeutic window, severe toxicity, and poor water-solubility. In this study, we developed cancer cell membrane-camouflaged biomimetic PLGA nanoparticles loading TPL (TPL@mPLGA) with the homologous targeting property for the treatment of HCC. The TPL@mPLGA was successfully prepared with particle size of 195.5 ± 7.5 nm and zeta potential at -21.5 ± 0.2 mV with good stability. The drug loading (DL) of TPL@mPLGA was 2.94%. After Huh-7 cell membrane coating, the natural Huh-7 cell membrane proteins were found to be retained on TPL@mPLGA, thus endowing the TPL@mPLGA with enhanced accumulation at tumor site, and better anti-tumor activity in vitro and in vivo when compared with TPL or TPL@PLGA. The TPL@mPLGA showed enhanced anti-tumor effects and reduced toxicity of TPL, which could be adopted for the treatment of HCC.
Assuntos
Carcinoma Hepatocelular , Diterpenos , Compostos de Epóxi , Neoplasias Hepáticas , Nanopartículas , Fenantrenos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Diterpenos/administração & dosagem , Diterpenos/farmacologia , Diterpenos/química , Diterpenos/farmacocinética , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Compostos de Epóxi/química , Compostos de Epóxi/administração & dosagem , Compostos de Epóxi/farmacologia , Fenantrenos/administração & dosagem , Fenantrenos/farmacologia , Fenantrenos/química , Fenantrenos/farmacocinética , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Humanos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Nanopartículas/química , Animais , Linhagem Celular Tumoral , Camundongos , Membrana Celular/efeitos dos fármacos , Tamanho da Partícula , Portadores de Fármacos/química , Camundongos Nus , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacologia , Camundongos Endogâmicos BALB CRESUMO
Copaifera duckei oleoresin is a plant product extensively used by the Brazilian population for multiple purposes, such as medicinal and cosmetic. Despite its ethnopharmacological relevance, there is no pharmacokinetic data on this important medicinal plant. Due to this, we determined the pharmacokinetic profile of the major nonvolatile compounds of C. duckei oleoresin. The diterpenes ent-polyalthic acid and dihydro-ent-agathic acid correspond to approximately 40% of the total oleoresin. Quantification was performed using LC-MS/MS, and the validated analytical method showed to be precise, accurate, robust, reliable, and linear between 0.57 and 114.74 µg/mL plasma and 0.09 to 18.85 µg/mL plasma, respectively, for ent-polyalthic acid and dihydro-ent-agathic acid, making it suitable for application in preclinical pharmacokinetic studies. Wistar rats received a single 200 mg/kg oral dose (gavage) of C. duckei oleoresin, and blood was collected from their caudal vein through 48 h. Population pharmacokinetics analysis of ent-polyalthic and dihydro-ent-agathic acids in rats was evaluated using nonlinear mixed-effects modeling conducted in NONMEN software. The pharmacokinetic parameters of ent-polyalthic acid were absorption constant rate = 0.47 h-1, central and peripheral apparent volume of distribution = 0.04 L and 2.48 L, respectively, apparent clearance = 0.15 L/h, and elimination half-life = 11.60 h. For dihydro-ent-agathic acid, absorption constant rate = 0.28 h-1, central and peripheral apparent volume of distribution = 0.01 L and 0.18 L, respectively, apparent clearance = 0.04 L/h, and elimination half-life = 3.49 h. The apparent clearance, central apparent volume of distribution, and peripheral apparent volume of distribution of ent-polyalthic acid were approximately 3.75, 4.00-, and 13.78-folds higher than those of dihydro-ent-agathic.
Assuntos
Diterpenos , Ratos Wistar , Animais , Diterpenos/farmacocinética , Diterpenos/sangue , Diterpenos/química , Ratos , Masculino , Resinas Vegetais/farmacocinética , Resinas Vegetais/química , Espectrometria de Massas em Tandem , Fabaceae/química , Extratos Vegetais/farmacocinética , Extratos Vegetais/química , Cromatografia LíquidaRESUMO
To investigate the effect of retinoids, such as retinol (ROL), retinal (RAL), and retinyl palmitate (RP), on epidermal integrity, skin deposition, and bioconversion to retinoic acid (RA). 3-D human skin equivalent model (EpiDermFT™) was used. Epidermal cellular integrity measured by TEER values was significantly higher for a topical treatment of ROL and RAL than RP (p < 0.05). The skin deposition (µM) of ROL and RAL was approximately 269.54 ± 73.94 and 211.35 ± 20.96, respectively, greater than that of RP (63.70 ± 37.97) over 2 h incubation. Spectral changes were revealed that the CO maximum absorbance occurred between 1600â¼1800 cm-1 and was greater from ROL than that from RAL and RP, indicating conjugation of R-OH to R-CHO or R-COOH could strongly occur after ROL treatment. Subsequently, a metabolite from the bioconversion of ROL and RAL was identified as RA, which has a product ion of m/z 283.06, by using liquid a chromatography-mass spectrometry (LC-MS) - total ion chromatogram (TIC). The amount of bioconversion from ROL and RAL to RA in artificial skin was 0.68 ± 0.13 and 0.70 ± 0.10 µM at 2 h and 0.60 ± 0.04 and 0.57 ± 0.06 µM at 24 h, respectively. RA was not detected in the skin and the receiver compartment after RP treatment. ROL could be a useful dermatological ingredient to maintain epidermal integrity more effectively, more stably deposit on the skin, and more steadily metabolize to RA than other retinoids such as RAL and RP.
Assuntos
Retinaldeído , Retinoides , Pele , Tretinoína , Humanos , Tretinoína/metabolismo , Pele/metabolismo , Retinoides/metabolismo , Retinaldeído/metabolismo , Cinética , Ésteres de Retinil/metabolismo , Vitamina A/análogos & derivados , Vitamina A/metabolismo , Diterpenos/química , Diterpenos/farmacocinética , Espectrometria de Massas , Modelos Biológicos , Epiderme/metabolismo , Absorção CutâneaRESUMO
Background: Chemo-photodynamic combination therapy has demonstrated significant potential in the treatment of cancer. Triptolide (TPL), a naturally derived anticancer agent, when combined with the photosensitizer Chlorin e6 (Ce6), has shown to provide enhanced anti-tumor benefits. However, the development of stimuli-responsive nanovehicles for the co-delivery of TPL and Ce6 could further enhance the efficacy of this combination therapy. Methods: In this study, we synthesized a pH/ROS dual-responsive mPEG-TK-PBAE copolymer, which contains a pH-sensitive PBAE moiety and a ROS-sensitive thioketal (TK) linkage. Through a self-assembly process, TPL and Ce6 were successfully co-loaded into mPEG-TK-PBAE nanoparticles, hereafter referred to as TPL/Ce6 NPs. We evaluated the pH- and ROS-sensitive drug release and particle size changes. Furthermore, we investigated both the in vitro suppression of cellular proliferation and induction of apoptosis in HepG2 cells, as well as the in vivo anti-tumor efficacy of TPL/Ce6 NPs in H22 xenograft nude mice. Results: The mPEG-TK-PBAE copolymer was synthesized through a one-pot Michael-addition reaction and successfully co-encapsulated both TPL and Ce6 by self-assembly. Upon exposure to acid pH values and high ROS levels, the payloads in TPL/Ce6 NPs were rapidly released. Notably, the abundant ROS generated by the released Ce6 under laser irradiation further accelerated the degradation of the nanosystem, thereby amplifying the tumor microenvironment-responsive drug release and enhancing anticancer efficacy. Consequently, TPL/Ce6 NPs significantly increased PDT-induced oxidative stress and augmented TPL-induced apoptosis in HepG2 cells, leading to synergistic anticancer effects in vitro. Moreover, administering TPL/Ce6 NPs (containing 0.3 mg/kg of TPL and 4 mg/kg of Ce6) seven times, accompanied by 650 nm laser irradiation, efficiently inhibited tumor growth in H22 tumor-bearing mice, while exhibiting lower systemic toxicity. Conclusion: Overall, we have developed a tumor microenvironment-responsive nanosystem for the co-delivery of TPL and Ce6, demonstrating amplified synergistic effects of chemo-photodynamic therapy (chemo-PDT) for hepatocellular carcinoma (HCC) treatment.
Assuntos
Apoptose , Clorofilídeos , Diterpenos , Neoplasias Hepáticas , Camundongos Nus , Fenantrenos , Fotoquimioterapia , Fármacos Fotossensibilizantes , Porfirinas , Espécies Reativas de Oxigênio , Animais , Humanos , Fotoquimioterapia/métodos , Espécies Reativas de Oxigênio/metabolismo , Células Hep G2 , Neoplasias Hepáticas/tratamento farmacológico , Porfirinas/química , Porfirinas/farmacologia , Porfirinas/administração & dosagem , Porfirinas/farmacocinética , Diterpenos/química , Diterpenos/farmacologia , Diterpenos/farmacocinética , Diterpenos/administração & dosagem , Concentração de Íons de Hidrogênio , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/administração & dosagem , Apoptose/efeitos dos fármacos , Camundongos , Carcinoma Hepatocelular/tratamento farmacológico , Compostos de Epóxi/química , Compostos de Epóxi/farmacologia , Compostos de Epóxi/administração & dosagem , Nanopartículas/química , Ensaios Antitumorais Modelo de Xenoenxerto , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/administração & dosagem , Liberação Controlada de Fármacos , Proliferação de Células/efeitos dos fármacos , Polietilenoglicóis/química , Terapia CombinadaRESUMO
Acute lung injury (ALI) is a common and critical respiratory disorder caused by various factors, with viral infection being the leading contributor. Dehydroandrographolide (DAP), a constituent of the Chinese herbal plant Andrographis paniculata, exhibits a range of activities including anti-inflammatory, in vitro antiviral and immune-enhancing effects. This study evaluated the anti-inflammatory effects and pharmacokinetics (PK) profile of DAP in ALI mice induced by intratracheal instillation of Poly(I:C) (PIC). The results showed that oral administration of DAP (10-40â¯mg/kg) effectively suppressed the increase in lung wet-dry weight ratio, total cells, total protein content, accumulation of immune cells, inflammatory cytokines and neutrophil elastase levels in bronchoalveolar lavage fluid of PIC-treated mice. DAP concentrations, determined by an LC-MS/MS method, in plasma after receiving DAP (20â¯mg/kg) were unchanged compared to those in normal mice. However, DAP concentrations and relative PK parameters in the lungs were significantly altered in PIC-treated mice, exhibiting a relatively higher maximum concentration, larger AUC, and longer elimination half-life than those in the lungs of normal mice. These results demonstrated that DAP could improve lung edema and inflammation in ALI mice, and suggested that lung injury might influence the PK properties of DAP, leading to increased lung distribution and residence. Our study provides evidence that DAP displays significant anti-inflammatory activity against viral lung injury and is more likely to distribute to damaged lung tissue.
Assuntos
Lesão Pulmonar Aguda , Anti-Inflamatórios , Líquido da Lavagem Broncoalveolar , Diterpenos , Poli I-C , Animais , Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/farmacologia , Diterpenos/farmacocinética , Diterpenos/farmacologia , Masculino , Camundongos , Andrographis/química , Citocinas/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Elastase de Leucócito/metabolismoRESUMO
Yuanhuacine is a Daphne-type diterpene ortho-ester and is one of the main active ingredients of genkwa flos. Anticancer activity of yuanhuacine has been well investigated in various tumor cells and animal models, but information on metabolism and pharmacokinetics is limited. The aims of the present study were to investigate the metabolic and pharmacokinetic profiles of yuanhuacine in rat. The metabolic profile of yuanhuacine was obtained from rat plasma, urine, and feces using ultra-high-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry. A total of seven metabolites were detected, and the proposed metabolic pathways involved oxidation and glucuronidation. A simple and sensitive ultra-high-performance liquid chromatography-tandem mass spectrometry method was developed for the determination of yuanhuacine in rat plasma. The linear range of yuanhuacine was 1-1000 ng/ml (R2 = 0.998). The intra- and inter-precision (coefficient of variation %) of the assay was 3.86-6.18% and 2.65-5.75%, respectively, and the intra- and inter-accuracy (relative error %) was -3.83-4.77% and -3.03-5.11%, respectively. The extraction recovery, matrix effect, stability, and incurred sample reanalysis of yuanhuacine were within acceptable levels. The established method was validated and successfully applied to the preclinical pharmacokinetic study of yuanhuacine. The absolute oral bioavailability of yuanhuacine was calculated as 1.14%, and it reached the maximum plasma concentration of 28.21 ± 2.79 ng/ml in rat plasma at 2 h in the oral dosing group. The apparent volume of distribution of intravenous and intragastric administrations was 26.07 ± 6.45 and 21.83 ± 3.54 L/kg, respectively. The half-life of elimination of yuanhuacine was 9.64 ± 1.53 h in the intravenous dosing group.
Assuntos
Diterpenos , Espectrometria de Massas em Tandem , Ratos , Animais , Cromatografia Líquida , Disponibilidade Biológica , Espectrometria de Massas em Tandem/métodos , Ratos Sprague-Dawley , Cromatografia Líquida de Alta Pressão/métodos , Diterpenos/farmacocinética , Administração Oral , Reprodutibilidade dos TestesRESUMO
Triptolide (TP), a diterpenoid triepoxide, exhibits strong anti-cancer activities, especially against pancreatic cancer, but its clinical application is limited by organ toxicity. TP was combined with diammonium glycyrrhizinate (DG), as a cytoprotective agent, in a novel oral complex lipid emulsion (TP/DG-CLE) to increase the therapeutic index of TP against pancreatic cancer. The emulsion was produced by subjecting phospholipid and active components to high shear conditions using high-pressure homogenisation resulting in droplets of essentially neutral or small positive charge and consistent size below 200 nm. Pharmacokinetic studies in Sprague Dawley rats revealed an AUC(0-8 h) of TP following oral dosing of TP/DG-CLE that was fourfold higher than that achieved for TP/DG suspension, demonstrating significantly higher TP bioavailability and longer residence time in the bloodstream. Tissue distribution data obtained in mice demonstrated that TP/DG-CLE having a TP/DG weight ratio of 1:22.5 preferentially accumulated in the pancreas. Moreover, toxicology assays in rats provided indications of minor liver damage following daily administration of the emulsion for two weeks. Together these studies establish complex lipid emulsions containing TP and DG as a promising oral formulation for treatment of pancreatic cancer and establish a platform for developing new chemotherapeutic treatments.
Assuntos
Diterpenos , Neoplasias Pancreáticas , Ratos , Camundongos , Animais , Emulsões , Ratos Sprague-Dawley , Diterpenos/farmacocinética , Neoplasias Pancreáticas/tratamento farmacológico , Ácido Glicirrízico , Lipídeos , Neoplasias PancreáticasRESUMO
In this work, a series of water-soluble triptolide prodrugs were synthesized, and their triptolide release rate, pharmacokinetic characteristics and anti-tumor effect were measured. We found that inserting glycolic acid as a linker between triptolide and the cyclic amino acid accelerated the release of triptolide from prodrugs into the plasma while preserving its safety. Among them, prodrug TP-P1 was significantly better than Minnelide (the only water-soluble triptolide prodrug in clinical trials) in terms of release rate in plasma and synthetic yield. In mouse models of human acute myeloid leukemia (AML), TP-P1 was effective in reducing xenograft tumors at dose levels as low as 25 µg/kg, and eliminating tumors at dose 100 µg/kg. Furthermore, TP-P1 could significantly enhance the efficacy of FLT3 inhibitors in the treatment of AML. These experimental results showed the potential of TP-P1 as water-soluble prodrugs of triptolide.
Assuntos
Diterpenos , Leucemia Mieloide Aguda , Fenantrenos , Pró-Fármacos , Camundongos , Animais , Humanos , Pró-Fármacos/uso terapêutico , Água , Fenantrenos/uso terapêutico , Fenantrenos/farmacocinética , Diterpenos/uso terapêutico , Diterpenos/farmacocinética , Compostos de Epóxi/uso terapêutico , Compostos de Epóxi/farmacocinética , Leucemia Mieloide Aguda/tratamento farmacológicoRESUMO
Diterpene lactones have been identified as active compounds in several medicinal plants, including Andrographis paniculata (Burm. f.) Nees, which is a medicinal plant that has been used for centuries across the world. Andrographolide is the major diterpene from A. paniculata and the main bioactive constituent of this species. The effectiveness of diterpenes can be affected by factors that limit their oral bioavailability, such as their poor water solubility, slow dissolution rates, low gastrointestinal absorption, high chemical and metabolic instability, and rapid excretion. In this context, the purpose of the present review is to compile and compare literature data on the bioavailability of diterpene lactones from A. paniculata after oral administration in medicinal plant extracts or in their free forms and to highlight strategies that have been used to improve their oral bioavailability. Considering that medicinal plant extracts are commonly used as dried powder that is reconstituted in water before oral administration, novel pharmaceutical formulation strategies that are used to overcome difficulties with diterpene solubility are also compiled in this review. The use of self-microemulsifying drug delivery systems is a good strategy to enhance the dissolution and consequently the bioavailability of andrographolide after oral administration of A. paniculata extract formulations. On the other hand, herbosome technology, pH-sensitive nanoparticles, nanosuspensions, nanoemulsions, nanocrystal suspensions, nanocrystal-based solid dispersions, and solid dispersion systems are useful to formulate andrographolide in its free form and increase its oral bioavailability. The use of a suitable andrographolide delivery system is essential to achieve its therapeutic potential.
Assuntos
Andrographis paniculata , Diterpenos/farmacocinética , Lactonas/farmacocinética , Extratos Vegetais/farmacocinética , Administração Oral , Disponibilidade Biológica , Diterpenos/administração & dosagem , Composição de Medicamentos , Humanos , Lactonas/administração & dosagem , Fitoterapia , Extratos Vegetais/administração & dosagem , Plantas MedicinaisRESUMO
Andrographis paniculata (A. paniculata) is a traditional herbal medicine that has been widely used in Asian countries for hundreds of years. Andrographolide (AG) is a diterpene lactone extracted from A. paniculata. Owing to the in-depth study of pharmacological mechanisms, the therapeutic potential of AG, including its anti-inflammatory, anti-tumor, and immunoregulatory attributes, has attracted the attention of many researchers. Studies testing the therapeutic effects of AG have demonstrated desirable results in the treatment of a variety of clinical diseases. With high safety and various biological functions, AG might be a promising candidate for the treatment of musculoskeletal disorders. Here, we review all available literatures to summarize the pharmacological effects of AG and facilitate further researches on musculoskeletal diseases.
Assuntos
Diterpenos/farmacologia , Doenças Musculoesqueléticas/patologia , Andrographis paniculata , Animais , Artrite/patologia , Linhagem Celular , Diterpenos/efeitos adversos , Diterpenos/farmacocinética , Interações Medicamentosas , Humanos , Degeneração do Disco Intervertebral/patologia , Medicina Tradicional , Osteoporose/patologiaRESUMO
BACKGROUND: Attenuating inflammatory response and relieving pain are two therapeutic therapeutical goals for rheumatoid arthritis (RA). Anti-inflammatory and analgesic drugs are often associated with many adverse effects due to nonspecific distribution. New drug delivery systems with practical targeting ability and other complementary strategies urgently need to be explored. To achieve this goal, an acupoint drug delivery system that can target deliver anti-inflammatory drugs and simulate acupuncture in relieving pain was constructed, which can co-deliver triptolide (TP) and 2-chloro-N (6)-cyclopentyl adenosine (CCPA). RESULTS: We have successfully demonstrated that acupoint nanocomposite hydrogel composed of TP-Human serum album nanoparticles (TP@HSA NPs) and CCPA could effectively treat RA. The result shows that CCPA-Gel can enhance analgesic effects specifically at the acupoint, while the mechanical and thermal pain threshold was 4.9 and 1.6 times compared with non-acupoint, respectively, and the nanocomposite gel further enhanced. Otherwise, the combination of acupoint and nanocomposite hydrogel exerted synergetic improvement of inflammation, bone erosion, and reduction of systemic toxicity. Furthermore, it could regulate inflammatory factors and restore the balance of Th17/Treg cells, which provided a novel and effective treatment strategy for RA. Interestingly, acupoint administration could improve the accumulation of the designed nanomedicine in arthritic paws (13.5% higher than those in non-acupoint at 48 h), which may explain the better therapeutic efficiency and low toxicity. CONCLUSION: This novel therapeutic approach-acupoint nanocomposite hydrogel, builds a bridge between acupuncture and drugs which sheds light on the combination of traditional and modern medicine.
Assuntos
Pontos de Acupuntura , Anti-Inflamatórios , Artrite Reumatoide/metabolismo , Diterpenos , Nanogéis , Fenantrenos , Terapia por Acupuntura , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/farmacologia , Comportamento Animal/efeitos dos fármacos , Preparações de Ação Retardada , Diterpenos/química , Diterpenos/farmacocinética , Diterpenos/farmacologia , Sistemas de Liberação de Medicamentos , Compostos de Epóxi/química , Compostos de Epóxi/farmacocinética , Compostos de Epóxi/farmacologia , Humanos , Masculino , Nanomedicina , Fenantrenos/química , Fenantrenos/farmacocinética , Fenantrenos/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
Dengue fever is a dangerous infectious endemic disease that affects over 100 nations worldwide, from Africa to the Western Pacific, and is caused by the dengue virus, which is transmitted to humans by an insect bite of Aedes aegypti. Millions of citizens have died as a result of dengue fever and dengue hemorrhagic fever across the globe. Envelope (E), serine protease (NS3), RNA-directed RNA polymerase (NS5), and non-structural protein 1 (NS1) are mostly required for cell proliferation and survival. Some of the diterpenoids and their derivatives produced by nature possess anti-dengue viral properties. The goal of the computational study was to scrutinize the effectiveness of diterpenoids and their derivatives against dengue viral proteins through in silico study. Methods: molecular docking was performed to analyze the binding affinity of compounds against four viral proteins: the envelope (E) protein, the NS1 protein, the NS3 protein, and the NS5 protein. Results: among the selected drug candidates, triptolide, stevioside, alepterolic acid, sphaeropsidin A, methyl dodovisate A, andrographolide, caesalacetal, and pyrimethamine have demonstrated moderate to good binding affinities (-8.0 to -9.4 kcal/mol) toward the selected proteins: E protein, NS3, NS5, and NS1 whereas pyrimethamine exerts -7.5, -6.3, -7.8, and -6.6 kcal/mol with viral proteins, respectively. Interestingly, the binding affinities of these lead compounds were better than those of an FDA-approved anti-viral medication (pyrimethamine), which is underused in dengue fever. Conclusion: we can conclude that diterpenoids can be considered as a possible anti-dengue medication option. However, in vivo investigation is recommended to back up the conclusions of this study.
Assuntos
Antivirais/farmacologia , Vírus da Dengue/efeitos dos fármacos , Diterpenos/farmacologia , Antivirais/química , Antivirais/farmacocinética , Sítios de Ligação , Simulação por Computador , Dengue/tratamento farmacológico , Dengue/virologia , Diterpenos/química , Diterpenos/farmacocinética , Desenho de Fármacos , Humanos , Simulação de Acoplamento Molecular , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacocinética , Compostos Fitoquímicos/farmacologia , Ligação Proteica , RNA Helicases/química , RNA Helicases/efeitos dos fármacos , RNA Helicases/metabolismo , Serina Endopeptidases/química , Serina Endopeptidases/efeitos dos fármacos , Serina Endopeptidases/metabolismo , Proteínas do Envelope Viral/química , Proteínas do Envelope Viral/efeitos dos fármacos , Proteínas do Envelope Viral/metabolismo , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/efeitos dos fármacos , Proteínas não Estruturais Virais/metabolismoRESUMO
BACKGROUND: The prognosis of patients with advanced gastric cancer (GC) remains unsatisfactory owing to distant metastasis and resistance to concurrent systemic therapy. Cancer-associated fibroblasts (CAFs), as essential participators in the tumor microenvironment (TME), play a vital role in tumor progression. Thus, CAFs-targeting therapy is appealing for remodeling TME and sensitizing GC to conventional systemic therapy. METHODS: Amphiphilic SN38 prodrug polymeric micelles (PSN38) and encapsulated the hydrophobic esterase-responsive prodrug of Triptolide (TPL), triptolide-naphthalene sulfonamide (TPL-nsa), were synthesized to form PSN38@TPL-nsa nanoparticles. Then, CAFs were isolated from fresh GC tissues and immortalized. TPL at low dose concentration was used to investigate its effect on CAFs and CAFs-induced GC cells proliferation and migration. The synergistic mechanism and antitumor efficiency of SN38 and TPL co-delivery nanoparticle were investigated both in vitro and in vivo. RESULTS: Fibroblast activation protein (FAP), a marker of CAFs, was highly expressed in GC tissues and indicated poorer prognosis. TPL significantly reduced CAFs activity and inhibited CAFs-induced proliferation, migration and chemotherapy resistance of GC cells. In addition, TPL sensitized GC cells to SN38 treatment through attenuated NF-κB activation in both CAFs and GC cells. PSN38@TPL-nsa treatment reduced the expression of collagen, FAP, and α-smooth muscle actin (α-SMA) in tumors. Potent inhibition of primary tumor growth and vigorous anti-metastasis effect were observed after systemic administration of PSN38@TPL-nsa to CAFs-rich peritoneal disseminated tumor and patient-derived xenograft (PDX) model of GC. CONCLUSION: TPL suppressed CAFs activity and CAFs-induced cell proliferation, migration and chemotherapy resistance to SN38 of GC. CAFs-targeted TPL and SN38 co-delivery nanoparticles exhibited potent efficacy of antitumor and reshaping TME, which was a promising strategy to treat advanced GC.
Assuntos
Antineoplásicos , Micelas , Pró-Fármacos , Neoplasias Gástricas/metabolismo , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Fibroblastos Associados a Câncer/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Diterpenos/química , Diterpenos/farmacocinética , Diterpenos/farmacologia , Sinergismo Farmacológico , Compostos de Epóxi/química , Compostos de Epóxi/farmacocinética , Compostos de Epóxi/farmacologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Fenantrenos/química , Fenantrenos/farmacocinética , Fenantrenos/farmacologia , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Pró-Fármacos/farmacologia , Microambiente Tumoral/efeitos dos fármacosRESUMO
In addition to early detection, early diagnosis, and early surgery, it is of great significance to use new strategies for the treatment of hepatocellular carcinoma (HCC). Studies showed that the combination of sorafenib (SFN) and triptolide (TPL) could reduce the clinical dose of SFN and maintain good anti-HCC effect. But the solubility of SFN and TPL in water is low and both drugs have certain toxicity. Therefore, we constructed a biomimetic nanosystem based on cancer cell-platelet (PLT) hybrid membrane camouflage to co-deliver SFN and TPL taking advantage of PLT membrane with long circulation functions and tumor cell membrane with homologous targeting. The biomimetic nanosystem, SFN and TPL loaded cancer cell-PLT hybrid membrane-camouflaged liquid crystalline lipid nanoparticles ((SFN + TPL)@CPLCNPs), could simultaneously load SFN and TPL at the molar ratio of SFN to TPL close to 10:1. (SFN + TPL)@CPLCNPs achieved long circulation function and tumor targeting at the same time, promoting tumor cell apoptosis, inhibiting tumor growth, and achieving a better "synergy and attenuation effect", which provided new ideas for the treatment of HCC.
Assuntos
Carcinoma Hepatocelular/metabolismo , Diterpenos , Lipossomos , Neoplasias Hepáticas/metabolismo , Nanopartículas , Fenantrenos , Sorafenibe , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Materiais Biomiméticos/química , Plaquetas/química , Linhagem Celular Tumoral , Membrana Celular/química , Diterpenos/química , Diterpenos/farmacocinética , Diterpenos/farmacologia , Compostos de Epóxi/química , Compostos de Epóxi/farmacocinética , Compostos de Epóxi/farmacologia , Humanos , Lipossomos/química , Lipossomos/farmacocinética , Lipossomos/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Nanomedicina , Nanopartículas/química , Nanopartículas/toxicidade , Fenantrenos/química , Fenantrenos/farmacocinética , Fenantrenos/farmacologia , Células RAW 264.7 , Sorafenibe/química , Sorafenibe/farmacocinética , Sorafenibe/farmacologiaRESUMO
The aim of this study was to develop and evaluate a triptolide phospholipid complex (TPCX) for the treatment of rheumatoid arthritis (RA) by transdermal delivery. TPCX was prepared and characterized by differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FTIR) analysis, transmission electron microscope (TEM), and scanning electron microscope (SEM). The solubility of TPCX was determined. Then, a TPCX cream was prepared to evaluate its percutaneous permeability and the antiarthritis effect. The transdermal permeability was determined using the Franz method, and a microdialysis system was used for skin pharmacokinetic study. A rat model of RA was prepared to evaluate the pharmacological effects. TPCX increased the solubility of triptolide in water, and the percutaneous permeability of TPCX cream was greatly enhanced compared with triptolide cream. The skin pharmacokinetic study indicated that TPCX cream has a longer biological half-life (t1/2) and mean residence time (MRT), but it has a shorter Tmax than that of triptolide cream in vivo. The area under the curve (AUC0-t)/AUC0-∞) and the peak concentration (Cmax) of TPCX cream were obviously higher than those of triptolide cream. The TPCX-loaded cream alleviated paw swelling and slowed down the progression of arthritis by inhibiting the inflammatory response by down regulating the TNF-α, IL-1ß, and IL-6 levels, thus exhibiting excellent antiarthritic effects. In summary, the prepared TPCX effectively increases the hydrophilicity of triptolide, which is good for its percutaneous absorption and enhances its effect on RA rats. TPCX can be a good candidate for the transdermal delivery to treat RA.
Assuntos
Artrite Reumatoide/tratamento farmacológico , Diterpenos/farmacologia , Imunossupressores/farmacologia , Fenantrenos/farmacologia , Fosfolipídeos/química , Administração Cutânea , Animais , Área Sob a Curva , Química Farmacêutica , Diterpenos/administração & dosagem , Diterpenos/farmacocinética , Relação Dose-Resposta a Droga , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Compostos de Epóxi/administração & dosagem , Compostos de Epóxi/farmacocinética , Compostos de Epóxi/farmacologia , Meia-Vida , Imunossupressores/administração & dosagem , Imunossupressores/farmacocinética , Mediadores da Inflamação/metabolismo , Masculino , Fenantrenos/administração & dosagem , Fenantrenos/farmacocinética , Ratos , Ratos WistarRESUMO
Erinacine A, derived from the mycelia of Hericium erinaceus, has attracted much attention due to its neuroprotective properties. However, very few studies have been conducted on the bioavailability, tissue distribution, and protein binding of erinacine A. This study aimed to investigate the bioavailability, tissue distribution, and protein binding of erinacine A in Sprague-Dawley rats. After oral administration (po) and intravenous administration (iv) of 2.381 g/kg BW of the H. erinaceus mycelia extract (equivalent to 50 mg/kg BW of erinacine A) and 5 mg/kg BW of erinacine A, respectively, the absolute bioavailability of erinacine A was estimated as 24.39%. Erinacine A was detected in brain at 1 h after oral dosing and reached the peak at 8 h. Protein binding assay showed unbound erinacine A fractions in brain to blood ratio is close to unity, supporting passive diffusion as the dominating transport. Feces was the major route for the elimination of erinacine A. This study is the first to show that erinacine A can penetrate the blood-brain barrier of rats by the means of passive diffusion and thus support the development of H. erinaceus mycelia for the improvement of neurohealth.
Assuntos
Diterpenos/metabolismo , Diterpenos/farmacocinética , Hericium/química , Micélio/química , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacocinética , Espectrometria de Massas em Tandem/métodos , Administração Intravenosa , Administração Oral , Animais , Disponibilidade Biológica , Barreira Hematoencefálica/metabolismo , Cromatografia Líquida/métodos , Diterpenos/administração & dosagem , Fezes/química , Masculino , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Distribuição TecidualRESUMO
AIM: Retinyl palmitate (RP), the most stable vitamin A derivative, is used to treat photoaging and other skin disorders. The need to minimize the adverse effects of topical drug administration has led to an enhanced interest in loading RP on ethosomes for topical drug delivery. The aim of the current study was to prepare and compare the performance of RP decorated ethosomal hydrogel with tretinoin cream in the treatment of acne vulgaris as an approach to improve drug efficacy and decrease its side effects. METHODS: RP-loaded ethosomes were prepared using the injection sonication technique. A Box-Behnken design using Design Expert® software was used for the optimization of formulation variables. Particle size, zeta potential (ZP), entrapment efficiency percent (EE%), % drug release, and permeation over 24 h of different formulations were determined. The optimal formulation was incorporated into a hydrogel. Finally, the efficacy and tolerability of the optimized RP ethosomal hydrogel were clinically evaluated for acne treatment using a split-face comparative clinical study. RESULTS: The optimized ethosomal RP showed particle size of 195.8±5.45 nm, ZP of -62.1±2.85 mV, EE% of 92.63±4.33%, drug release % of 96.63±6.81%, and drug permeation % of 85.98 ±4.79%. Both the optimized RP ethosomal hydrogel and tretinoin effectively reduced all types of acne lesions (inflammatory, non-inflammatory, and total lesions). However, RP resulted in significantly lower non-inflammatory and total acne lesion count than the marketed tretinoin formulation. Besides, RP-loaded ethosomes showed significantly improved tolerability compared to marketed tretinoin with no or minimal skin irritation symptoms. CONCLUSION: RP ethosomal hydrogel is considerably effective in controlling acne vulgaris with excellent skin tolerability. Therefore, it represents an interesting alternative to conventional marketed tretinoin formulation for topical acne treatment.
Assuntos
Acne Vulgar/tratamento farmacológico , Diterpenos/administração & dosagem , Hidrogéis/química , Hidrogéis/farmacologia , Ésteres de Retinil/administração & dosagem , Administração Cutânea , Adulto , Animais , Diterpenos/efeitos adversos , Diterpenos/química , Diterpenos/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Feminino , Humanos , Hidrogéis/efeitos adversos , Masculino , Tamanho da Partícula , Estudos Prospectivos , Ratos Wistar , Ésteres de Retinil/efeitos adversos , Ésteres de Retinil/química , Ésteres de Retinil/farmacocinética , Absorção Cutânea/efeitos dos fármacos , Testes de Irritação da Pele , Tretinoína/administração & dosagem , Tretinoína/farmacologiaRESUMO
PURPOSE: Cyclodextrin (CD) is commonly used to enhance the solubility of oral drugs. However, with the increase of CD concentrations, the fraction of free drug molecules decreases, which may potentially impede drug absorption. This study aims to predict the optimal ratio between drug and CD to achieve the best absorption efficiency by computational simulation. METHODS: First, a physiologically based pharmacokinetic (PBPK) model was developed. This model can continuously adjust absorption according to free drug fraction and was validated against two model drugs, progesterone (PG) and andrographolide (AG). The further analysis involves 3-D surface graphs to investigate the relationship between free drug amount, theoretically absorbable concentration, and contents of drug and CD in the formulation. RESULTS: The PBPK model predicted the PK behavior of two drugs well. The concentration ratio of drug to CD, leading to maximal free drug amount and the best absorption efficiency, is nearly the same as the slope determined in the phase solubility test. The new modified PBPK model and 3-D surface graph can easily predict the absorption difference of formulations with various drug/CD ratios. CONCLUSION: This PBPK model and 3-D surface graph can predict the absorption and determine the optimal concentration ratio of CD formulation, which could accelerate the R&D of CD formulation.