RESUMO
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
BACKGROUND: Melanoma is the most malignant skin tumor and is difficult to cure with the alternative treatments of chemotherapy, biotherapy, and immunotherapy. Our previous study showed that triptolide (TP) exhibited powerful tumoricidal activity against melanoma. However, the clinical potential of TP is plagued by its poor aqueous solubility, short half-life, and biotoxicity. Therefore, developing an ideal vehicle to efficiently load TP and achieving targeted delivery to melanoma is a prospective approach for making full use of its antitumor efficacy. RESULTS: We applied exosome (Exo) derived from human umbilical cord mesenchymal stromal cells (hUCMSCs) and engineered them exogenously with a cyclic peptide, arginine-glycine-aspartate (cRGD), to encapsulate TP to establish a bionic-targeted drug delivery system (cRGD-Exo/TP), achieving synergism and toxicity reduction. The average size of cRGD-Exo/TP was 157.34 ± 6.21 nm, with a high drug loading of 10.76 ± 1.21%. The in vitro antitumor results showed that the designed Exo delivery platform could be effectively taken up by targeted cells and performed significantly in antiproliferation, anti-invasion, and proapoptotic activities in A375 cells via the caspase cascade and mitochondrial pathways and cell cycle alteration. Furthermore, the biodistribution and pharmacokinetics results demonstrated that cRGD-Exo/TP possessed superior tumor targetability and prolonged the half-life of TP. Notably, cRGD-Exo/TP significantly inhibited tumor growth and extended survival time with negligible systemic toxicity in tumor-bearing mice. CONCLUSION: The results indicated that the functionalized Exo platform provides a promising strategy for targeted therapy of malignant melanoma.
Assuntos
Exossomos , Integrina alfaVbeta3/metabolismo , Melanoma , Neoplasias Cutâneas , Animais , Linhagem Celular Tumoral , Diterpenos , Compostos de Epóxi , Exossomos/metabolismo , Humanos , Integrinas/metabolismo , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Camundongos , Peptídeos Cíclicos/metabolismo , Fenantrenos , Neoplasias Cutâneas/tratamento farmacológico , Distribuição Tecidual , Melanoma Maligno CutâneoRESUMO
The application of nanoparticles in the diagnosis and treatment of diseases has undergone different developmental stages, but phagocytosis and nonspecific distribution have been the main factors restricting the transformation of nanobased drugs into clinical practice. In the past decade, the design of membrane-coated nanoparticles has gained increasing attention. It is hoped that the combination of the cell membrane's natural biological properties and the functional integration of synthetic nanoparticle systems can compensate for the shortage of traditional nanoparticles. The membrane coating gives the nanoparticles unique biological functions such as immune evasion and targeting capability. However, when the encapsulation of monotypic membranes does not meet the diverse demands of biomedicine, the combination of different cell membranes may offer more possibilities. In this review, the composition, preparation, and advantages of biomimetic nanoparticles coated with hybrid cell membranes are summarized, and the applications of hybrid membrane-coated biomimetic nanoparticles (HM@BNPs) in drug delivery, phototherapy, liquid biopsy, tumor vaccines, immune therapy, and detoxification are reviewed. Finally, the current challenges and opportunities with regard to HM@BNPs are discussed.
Assuntos
Materiais Biomiméticos , Nanopartículas , Biomimética , Membrana Celular , Sistemas de Liberação de Medicamentos , FototerapiaRESUMO
Exosomes are described as nanoscale extracellular vesicles (EVs) secreted by multiple cell types and extensively distributed in various biological fluids. They contain multifarious bioactive molecules and transfer them to adjoining or distal cells through systemic circulation, participating in intracellular and intercellular communication, and modulating host-tumor cell interactions. Recent research has indicated that exosomes obtained from different biological fluids and their contents (proteins, nucleic acids, glycoconjugates, and lipids) can serve as biomarkers for cancer diagnosis, prognosis, and therapeutic response. Furthermore, the discovery of exosomes as therapeutic delivery vehicles has drawn much attention in antineoplastic drug delivery. They can be utilized for therapeutic delivery of proteins, genetic drugs, and chemotherapeutic drugs. Herein, this review summarizes the biogenesis, structure, and components of exosomes, focusing primarily on their two possible applications as diagnostic biomarkers and therapeutic delivery vehicles for cancers.
Assuntos
Antineoplásicos/administração & dosagem , Biomarcadores Tumorais/análise , Sistemas de Liberação de Medicamentos/métodos , Exossomos , Neoplasias/tratamento farmacológico , Humanos , Biópsia Líquida/métodos , Neoplasias/diagnóstico , Neoplasias/mortalidade , Neoplasias/patologia , PrognósticoRESUMO
Ectonucleotide pyrophosphatase-phosphodiesterase 3 (ENPP3), a protein detected in the human uterus, has been found to play an important role in the development and invasion of tumours. It was recently discovered that ENPP3 was upregulated during the window of implantation in the human endometrium but its functional relevance remains elusive. The objective was to determine ENPP3 expression in human endometrium and its roles in endometrial receptivity and embryo implantation. ENPP3 expression was analysed using immunohistochemistry and western blot assay. The effects of ENPP3 on embryo implantation were evaluated using a BeWo cell (a human choriocarcinoma cell line) spheroid attachment assay and BeWo cells were dual cultured with Ishikawa cells transfected with lentiviral vectors (LV5-NC or LV5-ENPP3) to mimic embryo implantation in a Transwell model. The effects of endometrial ENPP3 on factors related to endometrial receptivity were also determined. The results showed that ENPP3 was expressed in human endometrial epithelial cells and its expression levels changed during the menstrual cycle, peaking in the mid-secretory phase, corresponding to the time of embryo implantation. The overexpression of endometrial ENPP3 not only increased the embryo implantation rate but also had positive effects on the expression of factors related to endometrial receptivity in human endometrial cells. The results indicate that ENPP3 levels undergo cyclic changes in the endometrium and affect embryo adhesion and invasion via altering the expression of implantation factors in the human endometrium. Therefore, ENPP3 may play an important role in embryo implantation and may be a unique biomarker of endometrial receptivity.
Assuntos
Implantação do Embrião/fisiologia , Endométrio/metabolismo , Diester Fosfórico Hidrolases/metabolismo , Pirofosfatases/metabolismo , Adulto , Biomarcadores/metabolismo , Western Blotting , Adesão Celular , Linhagem Celular , Movimento Celular , Implantação do Embrião/genética , Células Epiteliais/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Ciclo Menstrual/genética , Ciclo Menstrual/metabolismo , Modelos Biológicos , Diester Fosfórico Hidrolases/genética , Gravidez , Pirofosfatases/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Esferoides Celulares/metabolismoRESUMO
BACKGROUND: In recent years, nanoparticles (NPs) including nanostructured lipid carries (NLC) and solid lipid nanoparticles (SLN) captured an increasing amount of attention in the field of transdermal drug delivery system. However, the mechanisms of penetration enhancement and transdermal transport properties of NPs are not fully understood. Therefore, this work applied different platforms to evaluate the interactions between skin and NPs loading triptolide (TPL, TPL-NLC and TPL-SLN). Besides, NPs labeled with fluorescence probe were tracked after administration to investigate the dynamic penetration process in skin and skin cells. In addition, ELISA assay was applied to verify the in vitro anti-inflammatory effect of TPL-NPs. RESULTS: Compared with the control group, TPL-NPs could disorder skin structure, increase keratin enthalpy and reduce the SC infrared absorption peak area. Besides, the work found that NPs labeled with fluorescence probe accumulated in hair follicles and distributed throughout the skin after 1 h of administration and were taken into HaCaT cells cytoplasm by transcytosis. Additionally, TPL-NLC could effectively inhibit the expression of IL-4, IL-6, IL-8, IFN-γ, and MCP-1 in HaCaT cells, while TPL-SLN and TPL solution can only inhibit the expression of IL-6. CONCLUSIONS: TPL-NLC and TPL-SLN could penetrate into skin in a time-dependent manner and the penetration is done by changing the structure, thermodynamic properties and components of the SC. Furthermore, the significant anti-inflammatory effect of TPL-NPs indicated that nanoparticles containing NLC and SLN could serve as safe prospective agents for transdermal drug delivery system.
Assuntos
Diterpenos/administração & dosagem , Portadores de Fármacos/química , Imunossupressores/administração & dosagem , Lipídeos/química , Nanopartículas/química , Fenantrenos/administração & dosagem , Administração Cutânea , Linhagem Celular , Diterpenos/farmacocinética , Compostos de Epóxi/administração & dosagem , Compostos de Epóxi/farmacocinética , Humanos , Imunossupressores/farmacocinética , Nanopartículas/ultraestrutura , Fenantrenos/farmacocinética , Pele/metabolismo , Absorção CutâneaRESUMO
BACKGROUND: This work aimed to provide useful information on the use of nanoemulsions for the percutaneous administration of triptolide. Lipid nanosystems have great potential for transdermal drug delivery. Nanoemulsions and nanoemulsion gels were prepared to enhance percutaneous permeation. Microstructure and in vitro/in vivo percutaneous delivery characteristics of triptolide (TPL)-nanoemulsions and TPL-nanoemulsion gels were compared. The integrity of the nanoemulsions and nanoemulsion gels during transdermal delivery and its effects on the surface of skin were also investigated. The penetration mechanisms of nanoemulsions and nanoemulsion gels were investigated by differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR). The transport characteristics of fluorescence-labelled nanoemulsions were probed using laser scanning confocal microscopy. A chronic dermatitis/eczema model in mice ears and the pharmacodynamic of the TPL-nanoemulsion gels were also investigated. RESULTS: Compared to TPL gels, significantly greater cumulative amounts of TPL-nanoemulsion gels and TPL-nanoemulsions penetrated rat skin in vitro. The in vivo microdialysis showed the concentration-time curve AUC0-t for TPL-NPs is bigger than the TPL-gels. At the same time, TPL-NPs had a larger effect on the surface of skin. By hydrating keratin and changing the structure of both the stratum corneum lipids and keratin, nanoemulsions and nanoemulsion gels influence skin to promote percutaneous drug penetration. Both hairfollicles and the stratum corneum are also important in this transdermal drug delivery system. Moderate and high dosages of the TPL-nanoemulsion gels can significantly improve the symptoms of dermatitis/eczema inflammation and edema erythematic in mice ears and can reduce the expression of IFN-γ and IL-4. Moreover, the TPL-nanoemulsion gels cause less gastrointestinal damage than that of the Tripterygium wilfordii oral tablet does. CONCLUSIONS: Nanoemulsions could be suitable for transdermal stably releasing drugs and maintaining the effective drug concentration. The TPL-nanoemulsion gels provided higher percutaneous amounts than other carriers did. These findings suggest that nanoemulsion gels could be promising percutaneous carriers for TPL. The TPL-nanoemulsion gels have a significant treatment effect on dermatitis/eczema in the mice model and is expected to provide a new, low-toxicity and long-term preparation for the clinical treatment of dermatitis/eczema in transdermal drug delivery systems.
Assuntos
Antineoplásicos Alquilantes/química , Diterpenos/química , Portadores de Fármacos/química , Géis/química , Nanoestruturas/química , Fenantrenos/química , Administração Cutânea , Animais , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/farmacocinética , Varredura Diferencial de Calorimetria , Dermatite/tratamento farmacológico , Dermatite/patologia , Dermatite/veterinária , Diterpenos/administração & dosagem , Diterpenos/farmacocinética , Liberação Controlada de Fármacos , Emulsões/química , Compostos de Epóxi/administração & dosagem , Compostos de Epóxi/química , Compostos de Epóxi/farmacocinética , Meia-Vida , Masculino , Permeabilidade/efeitos dos fármacos , Fenantrenos/administração & dosagem , Fenantrenos/farmacocinética , Ratos , Ratos Sprague-Dawley , Pele/efeitos dos fármacos , Pele/metabolismo , Pele/patologia , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Compound Yangshe granule is a characteristic Chinese preparation against cervical cancer used at Fudan University Shanghai Cancer Center, and it consists of Hedyotis Diffusae Herba, Solani Lyrati Herba, Rubiae Radix et Rhizoma, Echinopsis Radix, Angelicae Sinensis Radix, Codonopsis Radix and Atractylodis Macrocephalae Rhizoma. AIM OF THE STUDY: The objective of the current study was to investigate the preclinical efficacy of compound Yangshe granule against cervical cancer and elucidate the underlying mechanisms. MATERIALS AND METHODS: Antitumor effect of the preparation was investigated in U14 cells in vitro and subcutaneous xenograft mice in vivo. The underlying mechanisms were investigated by through network pharmacological analysis and identified by in vitro study. The components of compound Yangshe granule were collected from the Traditional Chinese Medicine Systems Pharmacology database, and the corresponding targets were predicted by the SwissTargetPrediction database. The targets involved in cervical cancer were collected from the GeneCards, Online Mendelian Inheritance in Man and DrugBank databases. A proteinâprotein interaction network was constructed by using the String platform. The drug-disease-target network was plotted by Cytoscape software. Kyoto Encyclopedia of Genes and Genomes and Gene Ontology enrichment analyses were performed to investigate hub targets. RESULTS: After treatment with 0.5-10 mg/mL compound Yangshe granule, the survival rates of U14 cells gradually declined to 53.32% for 24 h, 23.62% for 48 h, and 12.81% for 72 h. The apoptosis rates of U14 cells gradually increased to 15.52% for 24 h, 23.87% for 48 h, and 65.01% for 72 h after treatment with 2-10 mg/mL compound Yangshe granule. After oral administration of compound Yangshe granule by xenograft mice, the tumor inhibition rates reached 52.27%, 74.62%, and 82.70% in the low, middle, and high dose groups, respectively. According to the network pharmacological analysis, quercetin, luteolin and naringenin were the most bioactive ingredients of the preparation. Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that compound Yangshe granule may combat cervical cancer through the PI3K/AKT pathway. CONCLUSION: In summary, network pharmacology combined with biological experiments demonstrated that the main bioactive components including quercetin, luteolin and naringenin could inhibit the tumor growth by regulating the PI3K/AKT pathway and Bcl-2 family. Thus, compound Yangshe granule may be a promising adjuvant therapy for cervical cancer.
Assuntos
Medicamentos de Ervas Chinesas , Neoplasias do Colo do Útero , Feminino , Humanos , Camundongos , Animais , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Quercetina/farmacologia , Luteolina/farmacologia , Farmacologia em Rede , Transdução de Sinais , China , Medicina Tradicional Chinesa , Neoplasias do Colo do Útero/tratamento farmacológico , Simulação de Acoplamento MolecularRESUMO
Extracellular vesicles (EVs) are phospholipid bilayer vesicles actively secreted by cells, that contain a variety of functional nucleic acids, proteins, and lipids, and are important mediums of intercellular communication. Based on their natural properties, EVs can not only retain the pharmacological effects of their source cells but also serve as natural delivery carriers. Among them, plant-derived nanovesicles (PNVs) are characterized as natural disease therapeutics with many advantages such as simplicity, safety, eco-friendliness, low cost, and low toxicity due to their abundant resources, large yield, and low risk of immunogenicity in vivo. This review systematically introduces the biogenesis, isolation methods, physical characterization, and components of PNVs, and describes their administration and cellular uptake as therapeutic agents. We highlight the therapeutic potential of PNVs as therapeutic agents and drug delivery carriers, including anti-inflammatory, anticancer, wound healing, regeneration, and antiaging properties as well as their potential use in the treatment of liver disease and COVID-19. Finally, the toxicity and immunogenicity, the current clinical application, and the possible challenges in the future development of PNVs were analyzed. We expect the functions of PNVs to be further explored to promote clinical translation, thereby facilitating the development of a new framework for the treatment of human diseases.
RESUMO
UNLABELLED: Assessment of Ventricular Electrophysiological Characteristics. INTRODUCTION: The aim of this study was to investigate the characteristics of ventricular electrophysiology following stellate ganglion block (SGB) at periinfarct zone in rabbits with myocardial infarction (MI). METHODS AND RESULTS: Sixty-four rabbits were randomly assigned to 2 groups: MI (n = 32), ligation of the anterior descending coronary and sham operation (SO) (n = 32), without coronary ligation. Both MI and SO groups were divided into 4 subgroups according to right or left SGB and corresponding control (n = 8, each). After 8 weeks, 90% of monophasic action potential duration (MAPD90) of epicardium, midmyocardium and endocardium, transmural dispersion of repolarization (TDR), effective refractory period (ERP), and ventricular fibrillation threshold (VFT) were measured at the infarct border zone (MI group) and corresponding zone (SO group) following SGB. For SGB, 0.5 mL of 0.25% bupivacaine was used. Compared with the corresponding control group, in both the MI and SO groups, left SGB (LSGB) prolonged the MAPD90 of the 3 layers, reduced TDR, and increased ERP and VFT (P < 0.05). However, right SGB (RSGB) shortened MAPD90, increased TDR, and reduced ERP and VFT (P < 0.05). CONCLUSION: The results of this study demonstrate that LSGB can increase the electrophysiological stability of ventricular myocardium.
Assuntos
Arritmias Cardíacas/prevenção & controle , Bloqueio Nervoso Autônomo , Técnicas Eletrofisiológicas Cardíacas , Ventrículos do Coração/fisiopatologia , Infarto do Miocárdio/fisiopatologia , Gânglio Estrelado/fisiopatologia , Função Ventricular , Potenciais de Ação , Anestésicos Locais , Animais , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/fisiopatologia , Bloqueio Nervoso Autônomo/métodos , Bupivacaína , Modelos Animais de Doenças , Endocárdio/patologia , Endocárdio/fisiopatologia , Feminino , Ventrículos do Coração/inervação , Ventrículos do Coração/patologia , Masculino , Infarto do Miocárdio/complicações , Infarto do Miocárdio/patologia , Miocárdio/patologia , Pericárdio/patologia , Pericárdio/fisiopatologia , Coelhos , Período Refratário Eletrofisiológico , Fatores de TempoRESUMO
Myocardial infarction (MI) leads to progressive left ventricular (LV) dilatation and is associated with interstitial fibrosis in the non-infarcted myocardium. The NF-κB signaling pathway plays an important role in ventricular remodeling after MI. Recent studies have indicated that the anti-malarial agent artemisinin can inhibit NF-κB activation, which may attenuate post-infarct myocardial remodeling. In this study, we investigated the effect of artemisinin on post-infarct myocardial remodeling using a rat model of MI. Adult male Sprague Dawley rats were divided into a sham group (n = 10) and MI groups that were treated either with oral gavage of artemisinin (75 mg/kg/day, n = 20) or vehicle (0.5% carboxymethyl cellulose, n = 20) three times a day for 4 weeks. Each treatment was started at 24 hours after ligation of the left anterior descending coronary artery. Four weeks after MI, the artemisinin-treated group showed a significantly improved survival rate compared with that of the vehicle-treated group (65% vs. 40%, P < 0.05). Although infarct size was similar in both groups, echocardiography showed significant improvements in cardiac function and left ventricular dimensions in the artemisinin-treated group. Moreover, the degree of myocardial fibrosis and elevated levels of fibrosis-related factors [transforming growth factor-ß1, collagen type I, matrix metalloproteinase (MMP)-2 and MMP-9] in the non-infarcted myocardium were remarkably ameliorated by artemisinin (all P < 0.05). Importantly, artemisinin inhibited the NF-κB pathway by blocking IKBα phosphorylation. In conclusion, artemisinin may attenuate post-infarct myocardial remodeling by down-regulating the NF-κB pathway.
Assuntos
Artemisininas/uso terapêutico , Regulação para Baixo , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/fisiopatologia , NF-kappa B/metabolismo , Transdução de Sinais , Remodelação Ventricular , Animais , Artemisininas/química , Artemisininas/farmacologia , Western Blotting , Cardiomegalia/complicações , Cardiomegalia/diagnóstico por imagem , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Colágeno Tipo I/metabolismo , Regulação para Baixo/efeitos dos fármacos , Fibrose , Hemodinâmica/efeitos dos fármacos , Proteínas I-kappa B/metabolismo , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Inibidor de NF-kappaB alfa , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Análise de Sobrevida , Fator de Crescimento Transformador beta1/metabolismo , Ultrassonografia , Remodelação Ventricular/efeitos dos fármacosRESUMO
Digestive system cancer is the most common cause of cancer death in the world. Although cancer treatment options are increasingly diversified, the mortality rate of malignant cancer of the digestive system remains high. Therefore, it is necessary to explore effective cancer treatment methods. Recently, biomimetic nanoparticle delivery systems based on natural cells that organically integrate the low immunogenicity, high biocompatibility, cancer targeting, and controllable, versatile functionality of smart nanocarrier design with natural cells have been expected to break through the bottleneck of tumor targeted therapy. In this review, we focus on the dynamic changes and complex cellular communications that occur in vivo in natural cells based vehicles. Recent studies on the development of advanced targeted drug delivery systems using the dynamic behaviors such as specific surface protein affinity, morphological changes, and phenotypic polarization of natural cells are summarized. In addition to drug delivery mediated by dynamic behavior, functional "delivery" based on the natural cell themselves is also involved. Aiming to make the best use of the functions of cells, providing clues for the development of advanced drug delivery platforms.
Assuntos
Materiais Biomiméticos , Neoplasias do Sistema Digestório , Nanopartículas , Humanos , Biomimética/métodos , Sistemas de Liberação de Medicamentos/métodos , Proteínas de MembranaRESUMO
Despite the remarkable success of immunotherapies over the past decade, their effectiveness against triple-negative breast cancer (TNBC) is limited to a small subset of patients, mainly due to the low immunogenicity and unfavorable tumor microenvironment. In this study, we successfully constructed a programmed site-specific delivery nanosystem for the combined delivery of transforming growth factor beta (TGF-ß) receptor inhibitor LY3200882 (LY) and PD-L1 siRNA (siPD-L1) to boost anti-tumor immunotherapy. As expected, LY in the outer layer of the nanosystem was released by stimulation of MMP2, and dramatically down-regulated the expression of extracellular matrix (ECM) in the tumor-associated fibroblasts (TAFs), and thus promoted the infiltration of effector T cells and penetration of nanomedicines. Simultaneously, the blockade of TGF-ß by LY also triggered immunogenic cell death (ICD) of tumor cells and induced the maturation of dendritic cells. Moreover, the programmed design provided the siPD-L1/protamine cationic inner core with easier access to tumor cells and TAFs after MMP2-stimulated breakup of the outer layer, down-regulating the expression of PD-L1 in both types of cells. Notably, the synergistic effect of LY and siPD-L1 remarkably enhanced the tumor antigen presentation and immunosuppressive microenvironment remodeling, thus efficiently inhibiting the TNBC growth, metastasis, and recurrence. Therefore, the programmed site-specific delivery nanosystem is a promising drug delivery platform for boosting anti-tumor immunotherapy efficacy for TNBC.
Assuntos
Antineoplásicos , Neoplasias de Mama Triplo Negativas , Antineoplásicos/uso terapêutico , Antígeno B7-H1/genética , Linhagem Celular Tumoral , Humanos , Fatores Imunológicos/uso terapêutico , Imunoterapia , Metaloproteinase 2 da Matriz , RNA Interferente Pequeno/uso terapêutico , Fator de Crescimento Transformador beta/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Microambiente TumoralRESUMO
PURPOSE: The effective treatment of ulcerative colitis (UC) poses substantial challenges, and the aetiopathogenesis of UC is closely related to infectious, immunological and environmental factors. Currently, there is a considerable need for the development of orally bioavailable dosage forms that enable the effective delivery of therapeutic drugs to local diseased lesions in the gastrointestinal tract. METHODS: Berberine (BBR) and Atractylodes macrocephala Koidz (AM) volatile oil, derived from the Chinese herbs Coptis chinensis Franch and Atractylodes macrocephala Koidz, have anti-inflammatory and immunomodulatory activities. In this study, we prepared colon-targeted pellets loaded with BBR and stomach-targeted pellets loaded with AM volatile oil for the synergistic treatment of UC. The Box-Behnken design and ß-cyclodextrin inclusion technique were used to optimize the enteric coating formula and prepare volatile oil inclusion compounds. RESULTS: The two types of pellets were spherical and had satisfactory physical properties. The pharmacokinetic results showed that the AUC and MRT values of the dual-targeted (DPs) pellets were higher than those of the control pellets. In addition, in vivo animal imaging confirmed that the DPs could effectively deliver BBR to the colon. Moreover, compared with sulfasalazine and monotherapy, DPs exerted a more significant anti-inflammatory effect by inhibiting the expression of inflammatory factors including IL-1ß, IL-4, IL-6, TNF-α and MPO both in serum and tissues and enhancing immunity by decreasing the production of IgA and IgG. CONCLUSION: The DPs play a synergistic anti-UC effect by exerting systemic and local anti-inflammatory and provide an effective oral targeted preparation for the treatment of UC.
Assuntos
Berberina/farmacologia , Colite Ulcerativa/tratamento farmacológico , Óleos Voláteis/farmacologia , Administração Oral , Animais , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/farmacologia , Área Sob a Curva , Atractylodes/química , Berberina/isolamento & purificação , Berberina/farmacocinética , Química Farmacêutica , Colite Ulcerativa/fisiopatologia , Sistemas de Liberação de Medicamentos , Sinergismo Farmacológico , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Óleos Voláteis/isolamento & purificação , Óleos Voláteis/farmacocinética , Ratos , Ratos Sprague-Dawley , Distribuição TecidualRESUMO
Malignant melanoma is considered the most aggressive skin carcinoma with invasive growth patterns. Triptolide (TPL) possesses various biological and pharmacological activities involved in cancer treatment. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce cancer cell apoptosis by binding to DR5 highly expressed on cancer cells. Exosomes are natural nanomaterials with low immunogenicity, nontoxicity, and excellent biocompatibility and have been extensively used as emerging delivery vectors for diverse therapeutic cargos. Herein, a delivery system based on TRAIL-engineered exosomes (TRAIL-Exo) for loading TPL for targeted therapy against malignant melanoma is proposed and systematically investigated. Our results showed that TRAIL-Exo/TPL could improve tumor targetability, enhance cellular uptake, inhibit proliferation, invasion, and migration, and induce apoptosis of A375 cells through activating the extrinsic TRAIL pathway and the intrinsic mitochondrial pathway in vitro. Moreover, intravenous injection of TRAIL-Exo/TPL significantly suppressed tumor progression and reduced the toxicity of TPL in the melanoma nude mouse model. Together, our research presents a novel strategy for high-efficiency exosome-based drug-delivery nanocarriers and provides an alternative dimension for developing a promising approach with synergistic therapeutic efficacy and targeting capacity for melanoma treatment.
Assuntos
Antineoplásicos/uso terapêutico , Diterpenos/uso terapêutico , Portadores de Fármacos/química , Exossomos/química , Melanoma/tratamento farmacológico , Fenantrenos/uso terapêutico , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Diterpenos/química , Portadores de Fármacos/metabolismo , Liberação Controlada de Fármacos , Compostos de Epóxi/química , Compostos de Epóxi/uso terapêutico , Exossomos/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fenantrenos/química , Células RAW 264.7 , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos , Ligante Indutor de Apoptose Relacionado a TNF/química , Ligante Indutor de Apoptose Relacionado a TNF/metabolismoRESUMO
Nanotechnology provides synthetic carriers for cancer drug delivery that protect cargos from degradation, control drug release and increase local accumulation at tumors. However, these non-natural vehicles display poor tumor targeting and potential toxicity and are eliminated by the immune system. Recently, biomimetic nanocarriers have been widely developed based on the concept of 'mimicking nature.' Among them, cell-derived biomimetic vehicles have become the focus of bionics research because of their multiple natural functions, such as low immunogenicity, long circulation time and targeting ability. Cell membrane-coated carriers and extracellular vesicles are two widely used cell-based biomimetic materials. Here, this review summarizes the latest progress in the application of these two biomimetic carriers in targeted cancer therapy. Their properties and performance are compared, and their future challenges and development prospects are discussed.
Assuntos
Materiais Biomiméticos/farmacologia , Biomimética/métodos , Membrana Celular/metabolismo , Portadores de Fármacos/farmacologia , Vesículas Extracelulares/metabolismo , Materiais Biomiméticos/farmacocinética , Química Farmacêutica , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Humanos , Nanopartículas/química , Neoplasias/tratamento farmacológicoRESUMO
Metastatic breast cancer is a major cause of cancer-related mortality worldwide. The tumor-specific penetration and triggered drug release for "full-line" inhibition of pre-metastatic initiation are of essential importance in improving mortality rates. Here, a crosslinked, redox-sensitive amphiphilic conjugate (cHLC) was constructed with a combination of features, including hyaluronic acid (HA)-mediated tumor active targeting, lipoic acid (LA) core-crosslinking based bio-stability and reducibility, and lipid raft anchoring-promoted HA-mediated endocytosis through cholesterol (CHO) modification for the penetrated co-delivery of paclitaxel (PTX) and the multi-targeted anti-metastatic agent, silibinin (SB). Resultantly, the nanodrug (cHLC/(PTX + SB)) demonstrated enhanced tumor cytoplasm-selective rapid drug delivery in a 4T1 model both in vitro and in vivo. The released SB efficiently sensitized cells to PTX treatment and inhibited the whole process of pre-metastatic initiation including epithelial-to-mesenchymal transition (EMT), local and blood vessel invasion. The exquisite design of this delivery system provides a deep insight into enhancing focus accessibility of multi-targeted drugs for an efficient inhibition of tumor metastasis.
Assuntos
Ácido Hialurônico , Neoplasias , Colesterol , Preparações de Ação Retardada , Humanos , Micelas , OxirreduçãoRESUMO
BACKGROUND: Combination of the prodrug technique with an albumin nano drug-loaded system is a novel promising approach for cancer treatment. However, the long-lasting and far-reaching challenge for the treatment of cancers lies in how to construct the albumin nanometer drug delivery system with lead compounds and their derivatives. METHODS: In this study, we reported the preparation of injectable albumin nanoparticles (NPs) with a high and quantitative drug loading system based on the NabTM technology of paclitaxel palmitate (PTX-PA). RESULTS: Our experimental study on drug tissue distribution in vivo demonstrated that the paclitaxel palmitate albumin nanoparticles (Nab-PTX-PA) remained in the tumor for a longer time post-injection. Compared with saline and paclitaxel albumin nanoparticles (Abraxane®), intravenous injection of Nab-PTX-PA not only reduced the toxicity of the drug in normal organs, and increased the body weight of the animals but maintained sustained release of paclitaxel (PTX) in the tumor, thereby displaying an excellent antitumor activity. Blood routine analysis showed that Nab-PTX-PA had fewer adverse effects or less toxicity to the normal organs, and it inhibited tumor cell proliferation more effectively as compared with commercial paclitaxel albumin nanoparticles. CONCLUSIONS: This carrier strategy for small molecule drugs is based on naturally evolved interactions between long-chain fatty acids (LCFAs) and Human Serum Albumin (HSA), demonstrated here for PTX. Nab-PTX-PA shows higher antitumor efficacy in vivo in breast cancer models. On the whole, this novel injectable Nab-PTX-PA has great potential as an effective drug delivery system in the treatment of breast cancer.
Assuntos
Paclitaxel Ligado a Albumina/farmacologia , Antineoplásicos/farmacologia , Paclitaxel Ligado a Albumina/administração & dosagem , Paclitaxel Ligado a Albumina/efeitos adversos , Paclitaxel Ligado a Albumina/farmacocinética , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Proliferação de Células , Química Farmacêutica , Portadores de Fármacos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Feminino , Camundongos , Camundongos Endogâmicos ICR , Nanopartículas , Tamanho da Partícula , Distribuição Aleatória , Propriedades de SuperfícieRESUMO
BACKGROUND: Skin pharmacokinetics is an indispensable indication for studying the drug fate after administration of transdermal drug delivery systems (TDDS). However, the heterogeneity and complex skin structured with stratum corneum, viable epidermis, dermis, and subcutaneous tissue inevitably leads the drug diffusion coefficient (Kp) to vary depending on the skin depth, which seriously limits the development of TDDS pharmacokinetics in full thickness skin. METHODS: A multilayer geometry skin model was established and the Kp of drug in SC, viable epidermis, and dermis was obtained using the technologies of molecular dynamics simulation, in vitro permeation experiments, and in vivo microdialysis, respectively. Besides, finite element analysis (FEA) based on drug Kps in different skin layers was applied to simulate the paeonol nanoemulsion (PAE-NEs) percutaneous dynamic penetration process in two and three dimensions. In addition, PAE-NEs skin pharmacokinetics profile obtained by the simulation was verified by in vivo experiment. RESULTS: Coarse-grained modeling of molecular dynamic simulation was successfully established and the Kp of PAE in SC was 2.00×10-6 cm2/h. The Kp of PAE-NE in viable epidermis and in dermis detected using penetration test and microdialysis probe technology, was 1.58×10-5 cm2/h and 3.20×10-5 cm2/h, respectively. In addition, the results of verification indicated that PAE-NEs skin pharmacokinetics profile obtained by the simulation was consistent with that by in vivo experiment. DISCUSSION: This study demonstrated that the FEA combined with the established multilayer geometry skin model could accurately predict the skin pharmacokinetics of TDDS.
Assuntos
Administração Cutânea , Sistemas de Liberação de Medicamentos/métodos , Emulsões/farmacocinética , Epiderme/efeitos dos fármacos , Nanoestruturas/administração & dosagem , Acetofenonas/administração & dosagem , Acetofenonas/farmacocinética , Animais , Emulsões/administração & dosagem , Células Epidérmicas/efeitos dos fármacos , Análise de Elementos Finitos , Masculino , Microdiálise , Modelos Biológicos , Ratos Sprague-Dawley , Pele/efeitos dos fármacos , Absorção Cutânea/efeitos dos fármacosRESUMO
Bone-metastasis prostate cancer (BMPCa)-targeting gene therapy is gaining increasing concern in recent years. The peptide T7-modified polypeptide nanoparticles for delivery DNA (CRD-PEG-T7/pPMEPA1) was prepared as our previous study. However, the feasibility of CRD-PEG-T7/pPMEPA1 for BMPCa treatment, the mechanisms underlying cellular uptake, anti-BMPCa effect, and administration safety requires further research. LNCaP cells treated with endocytosis inhibitors and excessive T7 under different culture condition were carried out to investigate the mechanisms of cellular uptake of the CRD-PEG-T7-pPMEPA1. A transwell assay was applied to evaluate the cell migration ability. Besides, the tumor volume and survival rates of the PCa xenograft mice model were recorded to estimate the anti-tumor effect. In addition, the weight profiles of the PCa tumor-bearing mice, the blood chemistry, and the HE analysis of visceral organs and tumor was conducted to investigate the administration safety of CRD-PEG-T7/pPMEPA1. The results showed that PCa cellular uptake was decreased after treating with excessive free T7, endocytosis inhibitors and lower incubation temperature. Besides, CRD-PEG-T7/pPMEPA1 could inhibit the LNCaP cells chemotaxis and tumor growth. In addition, the survival duration of the PCa tumor-bearing mice treating with CRD-PEG-T7/pPMEPA1 was significantly prolonged with any systemic toxicity or damage to the organs. In conclusion, this research proposes a promising stratagem for treatment BMPCa by providing the biocompatible and effective carrier for delivery DNA therapeutic agents.