RESUMO
The insufficient abundance and weak activity of tumour-infiltrating lymphocytes (TILs) are two important reasons for the poor efficacy of PD-1 inhibitors in hepatocellular carcinoma (HCC) treatment. The combined administration of tanshinone IIA (TSA) and astragaloside IV (As) can up-regulate the abundance and activity of TILs by normalising tumour blood vessels and reducing the levels of immunosuppressive factors respectively. For enhancing the efficacy of PD-1 antibody, a magnetic metal-organic framework (MOF) with a homologous tumour cell membrane (Hm) coating (Hm@TSA/As-MOF) is established to co-deliver TSA&As into the HCC microenvironment. Hm@TSA/As-MOF is a spherical nanoparticle and has a high total drug-loading capacity of 16.13 wt%. The Hm coating and magnetic responsiveness of Hm@TSA/As-MOF provide a homologous-magnetic dual-targeting, which enable Hm@TSA/As-MOF to counteract the interference posed by ascites tumour cells and enhance the precision of targeting solid tumours. Hm coating also enable Hm@TSA/As-MOF to evade immune clearance by macrophages. The release of TSA&As from Hm@TSA/As-MOF can be accelerated by HCC microenvironment, thereby up-regulating the abundance and activity of TILs to synergistic PD-1 antibody against HCC. This study presents a nanoplatform to improve the efficacy of PD-1 inhibitors in HCC, providing a novel approach for anti-tumour immunotherapy in clinical practice.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Estruturas Metalorgânicas , Receptor de Morte Celular Programada 1 , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Carcinoma Hepatocelular/tratamento farmacológico , Animais , Camundongos , Humanos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Linhagem Celular Tumoral , Inibidores de Checkpoint Imunológico/farmacologia , Microambiente Tumoral/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Saponinas/farmacologia , Saponinas/química , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologiaRESUMO
Sustained retina drug delivery and rational drug combination are considered essential for enhancing the efficacy of therapy for wet age-related macular degeneration (wAMD) due to the conservative structure of the posterior ocular segment and the multi-factorial pathological mechanism. Designing a drug co-delivery system that can simultaneously achieve deep penetration and long-lasting retention in the vitreous is highly desired, yet remains a huge challenge. In this study, we fabricated Bor/RB-M@TRG as an intravitreal-injectable hydrogel depot for deep penetration into the posterior ocular segment and long-lasting distribution in the retinal pigment epithelium (RPE) layer. The Bor/RB-M@TRG consisted of borneol-decorated rhein and baicalein-coloaded microemulsions (Bor/RB-M, the therapy entity) and a temperature-responsive hydrogel matrix (the intravitreal depot). Bor/RB-M exhibited the strongest in vitro anti-angiogenic effects among all the groups studied, which is potentially associated with improved cellular uptake, as well as the synergism of rhein and baicalein, acting via anti-angiogenic and anti-oxidative stress pathways, respectively. Importantly, a single intravitreal (IVT) injection with Bor/RB-M@TRG displayed significant inhibition against the CNV of wAMD model mice, compared to all other groups. Particularly, coumarin-6-labeled Bor/RB-M@TRG (Bor/C6-M@TRG) could not only deeply penetrate into the retina but also stably accumulate in the RPE layer for at least 14 days. Our design integrates the advantages of borneol-decorated microemulsions and hydrogel depots, offering a promising new approach for clinically-translatable retinal drug delivery and synergistic anti-wAMD treatment.
Assuntos
Hidrogéis , Retina , Animais , Camundongos , AntraquinonasRESUMO
Cancer-associated fibroblasts (CAFs) deteriorate tumor microenvironment (TME) and hinder intra-tumoral drug delivery. Direct depleting CAFs exists unpredictable risks of tumor metastasis. Epithelial-mesenchymal transition (EMT) is a critical process of CAFs converted from hepatic stellate cells during hepatocellular tumorigenesis; however, until now the feasibility of reversing EMT to battle hepatocellular carcinoma has not been comprehensively explored. In this study, we report a CFH peptide (CFHKHKSPALSPVGGG)-decorated liposomal oxymatrine (CFH/OM-L) with a high affinity to Tenascin-C for targeted inactivating CAFs through reversing EMT, which is verified by the upregulation of E-cadherin and downregulation of vimentin, N-cadherin, and snail protein in vivo and in vitro. After the combination with icaritin-loaded lipid complex, CFH/OM-L obviously boosts the comprehensive anticancer efficacy in both 3D tumor spheroids and stromal-rich tumor xenograft nude mouse models. The combinational therapy not only effectively reversed the in vivo EMT process but also significantly lowered the collagen, creating favorable conditions for deep penetration of nanoparticles. More importantly, CFH/OM-L does not kill but inactivates CAFs, resulting in not only a low risk of tumor metastasis but also a reprogramming TME, such as M1 tumor-associated macrophages polarization and natural killer cells activation. Such strategy paves a moderate way to remold TME without depleting CAFs and provides a powerful tool to design strategies of combinational hepatocellular carcinoma therapy.
Assuntos
Fibroblastos Associados a Câncer , Carcinoma Hepatocelular , Neoplasias Hepáticas , Alcaloides , Animais , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/fisiologia , Fibroblastos/metabolismo , Humanos , Neoplasias Hepáticas/patologia , Camundongos , Peptídeos/metabolismo , Peptídeos/farmacologia , Quinolizinas , Microambiente TumoralRESUMO
Lung metastasis is a fatal and late-stage event for many solid tumors. Multiple lines of evidence have demonstrated that diallyl trisulfide (DATS), an active ingredient of garlic, possesses striking antimetastatic effects. However, the lack of highly efficient organ-compatible carriers restricts its application. In the present study, we showed that extracellular microparticles encapsulated with DATS (DATS-MPs) were capable of interfering with the prometastatic inflammatory microenvironment in local tissues. DATS-MPs were successfully prepared and exhibited typical characteristics of B16BL6-derived extracellular vesicles. The DATS-MPs preferentially fused with cancer cells and endogenous cells (mouse lung epithelial MLE-12 cells) from the metastatic organs in vitro. More interestingly, the systemically administered MPs predominantly accumulated in the lung tissue that serves as their main metastatic organ. The drug-loaded MPs exerted higher antimetastatic effects than DATS alone in both the spontaneous and the experimental metastasis models in mice (*p < 0.05). Additionally, we found that DATS-MPs inhibited tumor cell migration and interfered with the prometastatic inflammatory microenvironment via decreasing the release of S100A8/A9, serum amyloid A (SAA), and interleukin-6 (IL-6) and inhibiting the expression of fibronectin, MRP8, myeloperoxidase (MPO), and the toll-like receptor 4 (TLR4)-Myd88 in the lung tissues. Collectively, DATS-MPs appeared to enhance the antimetastatic efficiency of DATS in animal models under study.
Assuntos
Compostos Alílicos/farmacologia , Vesículas Extracelulares/metabolismo , Inflamação/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Melanoma/tratamento farmacológico , Sulfetos/farmacologia , Microambiente Tumoral/efeitos dos fármacos , Animais , Calgranulina A/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Fibronectinas/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Interleucina-6/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Melanoma/metabolismo , Melanoma/patologia , Camundongos , Peroxidase/metabolismo , Receptor 4 Toll-Like/metabolismoRESUMO
Tumor-targeted ligand modification and nanosized coloaded drug delivery systems are promising for cancer therapy. In this study, we showed that coix seed oil and tripterine coloaded microemulsions with a transferrin modification (Tf-CT-MEs) could improve the treatment of cervical cancer. Tf-CT-MEs exhibited good stability in serum and a notably synergistic antiproliferation effect. In the HeLa xenograft tumor-bearing mouse model, Tf-CT-MEs accumulated at tumor sites and penetrated deeply in tumor tissues. Tf-CT-MEs had superior anticancer efficacy in vivo, which greatly slowed the growth of tumors (***p < 0.001 vs saline). We also found that Tf-CT-MEs inhibited tumor cell proliferation, enhanced antiangiogenesis, and induced apoptosis by regulating bax/bcl-2 and the activating caspase-3 pathway. Tf-CT-MEs decreased by 27.7, 26.9, 61.2, and 42.5% of concentrations of TGF-ß1, CCL2, TNF-α, and IL-6 in serum, respectively. In addition, Tf-CT-MEs showed little toxicity in vital organs. These results were due to the improved drug delivery efficiency. Collectively, Tf-CT-MEs enhance tumor-targeting, facilitate deep penetration of drugs, and have promising potential as an efficient treatment for cervical cancer.
Assuntos
Coix/química , Emulsões/farmacologia , Óleos de Plantas/farmacologia , Sementes/química , Transferrina/farmacologia , Triterpenos/farmacologia , Neoplasias do Colo do Útero/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Feminino , Células HeLa , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Triterpenos Pentacíclicos , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
The aim of this study is to demonstrate the enhanced therapeutic efficacy of anticancer drugs on drug-resistant breast cancer using multicomponent microemulsions (ECG-MEs) as an oral delivery system. The etoposide-loaded ECG-MEs were composed of coix seed oil and ginsenoside Rh2 (G-Rh2), both of which possess not only the synergistic antitumor effect with etoposide, but also have excipient-like properties. Orally administrated ECG-MEs were demonstrated to be able to accumulate at the tumor site following crossing the intestines as intact vehicles into the blood circulation. The spatiotemporal controlled release characteristics of ECG-MEs brought about the efficient P-gp inhibition by the initially released G-Rh2 and the increased intracellular accumulation of the sequentially released etoposide. The combination antitumor activity of etoposide, G-Rh2 and coix seed oil using ECG-MEs was verified on the xenograft drug-resistant breast tumor mouse models. In addition, the safety evaluation studies indicated that treatment with ECG-MEs did not cause any significant toxicity in vivo. These findings suggest that ECG-MEs as an oral formulation may offer a promising strategy to treat the drug-resistant breast cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Mamárias Experimentais/tratamento farmacológico , Nanoestruturas/química , Administração Oral , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/química , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Apoptose/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Células CACO-2 , Coix/química , Liberação Controlada de Fármacos , Sinergismo Farmacológico , Emulsões , Etoposídeo/administração & dosagem , Etoposídeo/química , Etoposídeo/farmacocinética , Etoposídeo/uso terapêutico , Excipientes , Feminino , Ginsenosídeos/administração & dosagem , Ginsenosídeos/química , Ginsenosídeos/farmacocinética , Ginsenosídeos/uso terapêutico , Humanos , Células MCF-7 , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos Endogâmicos ICR , Camundongos Nus , Óleos de Plantas/administração & dosagem , Óleos de Plantas/química , Óleos de Plantas/farmacocinética , Óleos de Plantas/uso terapêutico , Ratos Sprague-Dawley , Sementes/química , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Epimedium spp. is commonly used in Traditional Chinese Medicine. Epimedins A, B, and C are three major bioactive flavonoids found in Epimedium spp. that share similar chemical structures. In this study, the intestinal absorption mechanism of these three compounds was investigated using the Caco-2 cell monolayer model in both the apical-to-basolateral (A-B) and the basolateral-to-apical (B-A) direction. The absorption permeability (PAB) of epimedins A, B, and C were extremely low and increased as the concentration of the epimedins increased from 5 to 20 µM, but, at 40 µM, the PAB values were reduced. Meanwhile, the amount of transported compounds increased in a time-dependent manner. The PAB of epimedins A and C were significantly increased and efflux ratios decreased in the presence of verapamil (an inhibitor of P-glycoprotein) and dipyridamole (an inhibitor of breast cancer resistance protein) while, in the presence of MK571 (an inhibitor of multidrug resistance proteins), the absorption of epimedins A and C did not change significantly, indicating that P-gp and BCRP might be involved in the transport of epimedins A and C. The PAB of epimedin B significantly increased while its secretory permeability (PBA) significantly decreased in the presence of dipyridamole, indicating that BCRP might be involved in the transport of epimedin B. No obvious changes in the transport of epimedin B were observed in the presence of verapamil and MK571. In summary, our results clearly demonstrate, for the first time, that poor bioavailability of these three prenylated flavonoids is the result of poor intrinsic permeability and efflux by apical efflux transporters.
Assuntos
Flavonoides/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Transporte Biológico/efeitos dos fármacos , Células CACO-2 , Permeabilidade da Membrana Celular , Sobrevivência Celular/efeitos dos fármacos , Dipiridamol/farmacologia , Flavonoides/farmacologia , Humanos , Absorção Intestinal , Propionatos/farmacologia , Quinolinas/farmacologia , Verapamil/farmacologiaRESUMO
Silver nanoparticles were synthesized from the extract of Fagopyri Dibotryis Rhizoma and the optimization of synthesis was studied. The absorbance of UV-visible spectroscopy was determined under the different influencing factors such as extracting time of Fagopyri Dibotryis Rhizoma powder, reation temperature of synthesis, volume of Fagopyri Dibotryis Rhizoma extract and concentration of AgNO3 to seek the optimization conditions. By means of FT-IR, TEM, DLS and XRD, the silver nanoparticles were characterized. The results showed that when the boiling time of Fagopyri Dibotryis Rhizoma powder was 5 min, resultant temperature was 25 degrees C, the volume ratio of 0.1 g x mL(-1) Fagopyri Dibotryis Rhizoma extract and 1 mmol x L(-1) AgNO3 was 1 to 10, and the reaction time was 3.5 h, the obtained silver nanoparticles had mean size about 27 nm and Zeta potential about -34.3 mV with good uniformity and dispersivity. Therefore, the green synthesis method of silver nanoparticles using extract of traditional Chinese medicine is stable and feasible.
Assuntos
Fagopyrum/química , Nanopartículas Metálicas/química , Extratos Vegetais/química , Rizoma/química , Prata/química , Luz , Nanopartículas Metálicas/ultraestrutura , Microscopia Eletrônica de Transmissão , Tamanho da Partícula , Espalhamento de Radiação , Nitrato de Prata/química , Espectroscopia de Infravermelho com Transformada de Fourier , Temperatura , Difração de Raios XRESUMO
Microsatellite-stable colorectal cancer (MSS-CRC) exhibits resistance to programmed cell death protein-1 (PD-1) therapy. Improving the infiltration and tumor recognition of cytotoxic T-lymphocytes (CTLs) is a promising strategy, but it encounters huge challenges from drug delivery and mechanisms aspects. Here, a zeolitic imidazolate framework (ZIF) coated with apoptotic body membranes derived from MSS-CRC cells is engineered for the co-delivery of ginsenoside Rg1 (Rg1) and atractylenolide-I (Att) to MSS-CRC, named as Ab@Rg1/Att-ZIF. This system is selectively engulfed by Ly-6C+ monocytes during blood circulation and utilizes a "hitchhiking" mechanism to migrate toward the core of MSS-CRC. Ab@Rg1/Att-ZIF undergoes rapid disassembly in the tumor, released Rg1 promotes the processing and transportation of tumor antigens in dendritic cells (DCs), enhancing their maturation. Meanwhile, Att enhances the activity of the 26S proteasome complex in tumor cells, leading to increased expression of major histocompatibility complex class-I (MHC-I). These coordinated actions enhance the infiltration and recognition of CTLs in the center of MSS-CRC, significantly improving the tumor inhibition of PD-1 treatment from ≈5% to ≈69%. This innovative design, involving inflammation-guided precise drug co-delivery and a rational combination, achieves synergistic engineering of the tumor microenvironment, providing a novel strategy for successful PD-1 treatment of MSS-CRC.
RESUMO
Sustainable retinal codelivery poses significant challenges technically, although it is imperative for synergistic treatment of wet age-related macular degeneration (wAMD). Here, a microemulsion-doped hydrogel (Bor/PT-M@TRG) is engineered as an intravitreal depot composing of temperature-responsive hydrogel (TRG) and borneol-decorated paeoniflorin (PF) & tetramethylpyrazine (TMP)-coloaded microemulsions (Bor/PT-M). Bor/PT-M@TRG, functioning as the "ammunition depot", resides in the vitreous and continuously releases Bor/PT-M as the therapeutic "bullet", enabling deep penetration into the retina for 21 days. A single intravitreal injection of Bor/PT-M@TRG yields substantial reductions in choroidal neovascularization (CNV, a hallmark feature of wAMD) progression and mitigates oxidative stress-induced damage in vivo. Combinational PF&TMP regulates the "reactive oxygen species/nuclear factor erythroid-2-related factor 2/heme oxygenase-1" pathway and blocks the "hypoxia inducible factor-1α/vascular endothelial growth factor" signaling in retina, synergistically cutting off the loop of CNV formation. Utilizing fluorescence resonance energy transfer and liquid chromatography-mass spectrometry techniques, they present compelling multifaceted evidence of sustainable retinal codelivery spanning formulations, ARPE-19 cells, in vivo eye balls, and ex vivo section/retina-choroid complex cell levels. Such codelivery approach is elucidated as the key driving force behind the exceptional therapeutic outcomes of Bor/PT-M@TRG. These findings highlight the significance of sustainable retinal drug codelivery and rational combination for effective treatment of wAMD.
Assuntos
Pirazinas , Animais , Pirazinas/química , Pirazinas/administração & dosagem , Pirazinas/farmacologia , Pirazinas/farmacocinética , Retina/efeitos dos fármacos , Retina/metabolismo , Degeneração Macular/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Humanos , Neovascularização de Coroide/tratamento farmacológico , Neovascularização de Coroide/metabolismo , Neovascularização de Coroide/patologia , Camundongos , Hidrogéis/química , Hidrogéis/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Canfanos/química , Canfanos/farmacologia , Camundongos Endogâmicos C57BL , Espécies Reativas de Oxigênio/metabolismoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Coronary heart disease (CHD) is a chronic disease that seriously threatens people's health and even their lives. Currently, there is no ideal drug without side effects for the treatment of CHD. Trichosanthis Pericarpium (TP) has been used for several years in the treatment of diseases associated with CHD. However, there is still a need for systematic research to unravel the pharmacodynamic substances and possible mechanism of TP in the treatment of coronary heart. AIM OF THE STUDY: The purpose of current study was to explore the pharmacodynamic substances and potential mechanisms of TP in the treatment of CHD via integrating network pharmacology with plasma pharmacochemistry and experimental validation. MATERIALS AND METHODS: The effect of TP intervention in CHD was firstly assessed on high-fat diet combined with isoprenaline-induced CHD rats and H2O2-induced H9c2 cells, respectively. Then, the LC-MS was utilized to identify the absorbed components of TP in the plasma of CHD rats, and this was used to develop a network pharmacology prediction to obtain the possible active components and mechanisms of action. Molecular docking and immunohistochemistry were used to explore the interaction between TP and key targets. Subsequently, the efficacy of the active ingredients was investigated by in vitro cellular experiments, and their metabolic pathways in CHD rats were further analyzed. RESULTS: The effects of TP on amelioration of CHD were verified by in vivo and in vitro experiments. Plasma pharmacochemistry and network pharmacology screened six active components in plasma including apigenin, phenylalanine, quercetin, linoleic acid, luteolin, and tangeretin. The interaction of these compounds with potential key targets AKT1, IL-1ß, IL-6, TNF-α and VEGFA were preliminarily verified by molecular docking. And immunohistochemical results showed that TP reduced the expression of AKT1, IL-1ß, IL-6, TNF-α and VEGFA in CHD rat hearts. Then cellular experiments confirmed that apigenin, phenylalanine, quercetin, linoleic acid, luteolin, and tangeretin were able to reduce the ROS level in H2O2-induced HUVEC cells and promote the migration and tubule formation of HUVEC cells, indicating the pharmacodynamic effects of the active components. Meanwhile, the metabolites of TP in CHD rats suggested that the pharmacological effects of TP might be the result of the combined effects of the active ingredients and their metabolites. CONCLUSION: Our study found that TP intervention in CHD is characterized by multi-component and multi-target regulation. Apigenin, phenylalanine, linoleic acid, quercetin, luteolin, and tangeretin are the main active components of TP. TP could reduce inflammatory response and endothelial damage by regulating AKT1, IL-1ß, IL-6, TNF-α and VEGFA, reduce ROS level to alleviate the oxidative stress situation and improve heart disease by promoting angiogenesis to regulate endothelial function. This study also provides an experimental and scientific basis for the clinical application and rational development of TP.
Assuntos
Doença das Coronárias , Medicamentos de Ervas Chinesas , Humanos , Animais , Ratos , Apigenina , Luteolina/farmacologia , Luteolina/uso terapêutico , Peróxido de Hidrogênio , Interleucina-6 , Ácido Linoleico , Simulação de Acoplamento Molecular , Farmacologia em Rede , Quercetina , Espécies Reativas de Oxigênio , Fator de Necrose Tumoral alfa , Doença das Coronárias/tratamento farmacológico , Interleucina-1beta , FenilalaninaRESUMO
The aim of this study was to compare the significance of the intestinal hydrolysis of prenylated flavonoids in Herba Epimedii by an intestinal enzyme and flora. Flavonoids were incubated at 37 °C with rat intestinal enzyme and intestinal flora. HPLC-UV was used to calculate the metabolic rates of the parent drug in the incubation and LC/MS/MS was used to determine the chemical structures of metabolites generated by different flavonoid glycosides. Rates of flavonoid metabolism by rat intestinal enzyme were quicker than those of intestinal flora. The sequence of intestinal flora metabolic rates was icariin>epimedin B>epimedin A>epimedin C>baohuoside I, whereas the order of intestinal enzyme metabolic rates was icariin>epimedin A>epimedin C>epimedin B>baohuoside I. Meanwhile, the LC/MS/MS graphs showed that icariin produced three products, epimedin A/B/C had four and baohuoside I yielded one product in incubations of both intestinal enzyme and flora, which were more than the results of HPLC-UV due to the fact LC/MS/MS has lower detectability and higher sensitivity. Moreover, the outcomes indicated that the rate of metabolization of flavonoids by intestinal enzyme were faster than those of intestinal flora, which was consistent with the HPLC-UV results. In conclusion, the metabolic pathways of the same components by intestinal flora and enzyme were the same. What's more, an intestinal enzyme such as lactase phlorizin hydrolase exhibited a more significant metabolic role in prenylated flavonoids of Herba Epimedi compared with intestinal flora.
Assuntos
Epimedium/química , Flavonoides/metabolismo , Mucosa Intestinal/metabolismo , Lactase-Florizina Hidrolase/metabolismo , Microbiota/fisiologia , Animais , Cromatografia Líquida de Alta Pressão , Flavonoides/química , Glicosídeos/metabolismo , Hidrólise , Intestinos/enzimologia , Intestinos/microbiologia , Masculino , Espectrometria de Massas , Redes e Vias Metabólicas , Estrutura Molecular , RatosRESUMO
Background: Berberine (BR) shows promise as a candidate for treating irritable bowel syndrome with diarrhea (IBS-D). However, the undesired physicochemical properties and poor oral absorption limit its clinical translation. A ketogenic diet (KD) can induce intestinal overexpression of cannabidiol (CB) receptors, which may offer a potential target for IBS-D-specific delivery of BR. Methods: The microemulsions loaded with BR and decorated with cannabidiol (CBD/BR-MEs) were developed through a one-step emulsion method. The pharmaceutical behaviors of the CBD/BR-MEs were measured using dynamic light scattering and high-performance liquid chromatography. The efficacy of the anti-IBS-D therapy was evaluated by assessing fecal water content, Bristol score, and AWR score. The intestinal permeability were assessed through immunofluorescent staining of CB1 and ZO-1, respectively. The signaling of CREB/BDNF/c-Fos was also studied along with immunofluorescent and immunohistochemical examination of brain sections. Results: The CBD/BR-MEs, which had a particle size of approximately 30 nm and a surface density of 2% (wt%) CBD, achieved greater than 80% (wt%) encapsulation efficiency of BR. The pharmacokinetics performance of CBD/BR-MEs was significantly improved in the KD-fed IBS-D rats than the standard diet-fed ones, which is highly related to intestinal expression of CB1 receptors. The treatment with CBD/BR-MEs and KD exhibited evident comprehensive advantages over the other groups in terms of anti-IBS-D efficacy. CBD/BR-MEs and KD synergistically decreased intestinal permeability. Moreover, the treatment with CBD/BR-MEs and KD not only blocked the CREB/BDNF/c-Fos signaling in the brain but also decreased the levels of neurotrophic factors, neurotransmitters, and inflammatory cytokines in the serum of IBS-D model rats. Conclusion: Such a design represents the first attempt at IBS-D-targeted drug delivery for improved oral absorption and efficacy through KD-induced target exposure, which holds promising potential for the treatment of IBS-D.
Assuntos
Berberina , Canabidiol , Dieta Cetogênica , Síndrome do Intestino Irritável , Ratos , Animais , Síndrome do Intestino Irritável/tratamento farmacológico , Síndrome do Intestino Irritável/metabolismo , Berberina/farmacologia , Berberina/uso terapêutico , Canabidiol/farmacologia , Canabidiol/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo , Diarreia/tratamento farmacológicoRESUMO
BACKGROUND: Conventional dissolving microneedles (DMNs) face significant challenges in anti-melanoma therapy due to the lack of active thrust to achieve efficient transdermal drug delivery and intra-tumoral penetration. METHODS: In this study, the effervescent cannabidiol solid dispersion-doped dissolving microneedles (Ef/CBD-SD@DMNs) composed of the combined effervescent components (CaCO3 & NaHCO3) and CBD-based solid dispersion (CBD-SD) were facilely fabricated by the "one-step micro-molding" method for boosted transdermal and tumoral delivery of cannabidiol (CBD). RESULTS: Upon pressing into the skin, Ef/CBD-SD@DMNs rapidly produce CO2 bubbles through proton elimination, significantly enhancing the skin permeation and tumoral penetration of CBD. Once reaching the tumors, Ef/CBD-SD@DMNs can activate transient receptor potential vanilloid 1 (TRPV1) to increase Ca2+ influx and inhibit the downstream NFATc1-ATF3 signal to induce cell apoptosis. Additionally, Ef/CBD-SD@DMNs raise intra-tumoral pH environment to trigger the engineering of the tumor microenvironment (TME), including the M1 polarization of tumor-associated macrophages (TAMs) and increase of T cells infiltration. The introduction of Ca2+ can not only amplify the effervescent effect but also provide sufficient Ca2+ with CBD to potentiate the anti-melanoma efficacy. Such a "one stone, two birds" strategy combines the advantages of effervescent effects on transdermal delivery and TME regulation, creating favorable therapeutic conditions for CBD to obtain stronger inhibition of melanoma growth in vitro and in vivo. CONCLUSIONS: This study holds promising potential in the transdermal delivery of CBD for melanoma therapy and offers a facile tool for transdermal therapies of skin tumors.
RESUMO
Programmed cell death protein 1 (PD-1) inhibitors are the most common immune-checkpoint inhibitors and considered promising drugs for hepatocellular carcinoma (HCC). However, in clinical settings, they have a low objective response rate (15%-20%) for patients with HCC; this is because of the insufficient level and activity of tumor-infiltrating T lymphocytes (TILs). The combined administration of oxymatrine (Om) and astragaloside IV (As) can increase the levels of TILs by inhibiting the activation of cancer-associated fibroblasts (CAFs) and improve the activity of TILs by enhancing their mitochondrial function. In the present study, we constructed a magnetic metal-organic framework (MOF)-based nanoplatform with platelet membrane (Pm) coating (PmMN@Om&As) to simultaneously deliver Om and As into the HCC microenvironment. We observed that PmMN@Om&As exhibited a high total drug-loading capacity (33.77 wt %) and good immune escape. Furthermore, it can target HCC tissues in a magnetic field and exert long-lasting effects. The HCC microenvironment accelerated the disintegration of PmMN@Om&As and the release of Om&As, thereby increasing the level and activity of TILs by regulating CAFs and the mitochondrial function of TILs. In addition, the carrier could synergize with Om&As by enhancing the oxygen consumption rate and proton efflux rate of TILs, thereby upregulating the mitochondrial function of TILs. Combination therapy with PmMN@Om&As and α-PD-1 resulted in a tumor suppression rate of 84.15% and prolonged the survival time of mice. Our study provides a promising approach to improving the antitumor effect of immunotherapy in HCC.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Estruturas Metalorgânicas , Humanos , Animais , Camundongos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Inibidores de Checkpoint Imunológico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Receptor de Morte Celular Programada 1 , Estruturas Metalorgânicas/farmacologia , Fenômenos Magnéticos , Microambiente Tumoral , Linfócitos T CD8-PositivosRESUMO
M1 polarization of tumor-associated macrophages (TAMs) is a promising approach to breaking through therapeutic barriers imposed by the immunosuppressive tumor microenvironment (TME). As a clinically-used immunopotentiator for cancer patients after chemotherapies; however, the immunomodulatory mechanism and potential of polyporus polysaccharide (PPS) remains unclear. Here, we present mannose-decorated PPS-loaded superparamagnetic iron-based nanocomposites (Man/PPS-SPIONs) for synergistic M1 polarization of TAMs and consequent combinational anti-breast cancer therapy. Once internalized by M2-like TAMs, PPS released from Man/PPS-SPIONs induces the M1 polarization via IFN-γ secretion and downstream NF-κB pathway activating. The SPIONs within the nanocomposites mediate a Fenton reaction, producing OH· and activating the subsequent NF-κB/MAPK pathway, further facilitating the M1 polarization. The Man/PPS-SPIONs thereby establish a positive feedback loop of M1 polarization driven by the "IFN-γ-Fenton-NF-κB/MAPK" multi-pathway, leading to a series of anti-tumoral immunologic responses in the TME and holding promising potential in combinational anticancer therapies. Our study offers a new strategy to amplify TME engineering by combinational natural carbohydrate polymers and iron-based materials.
RESUMO
Myocardial ischaemia-reperfusion injury (MI/RI) induces injury against cardiomyocytes and triggers myocardial infarction. Previously, we demonstrated that tetramethylprazine (TMP) was a promising therapeutic agent for attenuating MI/RI. However, poor absorption and low homing efficiency are two main obstacles to the further application of TMP. In this study, a platelet membrane-cloaking TMP-loaded microemulsion (P/TMP-MEs) capable of promoting in vivo absorption and decreasing non-targeted accumulation was fabricated for the improved MI/RI therapy. The average particle size and zeta potential of P/TMP-MEs were 35.9 ± 2.5 nm and -29.4 ± 3.1 mV, respectively. 35.4 ± 2.4 wt% TMP was released from P/TMP-MEs after 48 h of incubation with rat plasma. The coating of the platelet membrane significantly decreased the internalisation of P/TMP-MEs by THP-1 macrophage-like cells compared with the non-platelet modified TMP-loaded microemulsion (TMP-MEs). Besides, P/TMP-MEs did not activate the complement system. After treatment with P/TMP-MEs, the dehydrogenase (LDH) level of the cardiomyocytes was significantly lower than other controls. Rats single-administrated with P/TMP-MEs exhibited the area under the plasma concentration-time curve (AUC) at 463796.7 ± 53614.3 ng/mL/h, and â¼400 ng/mL TMP could still be detected from the plasma after 24 h of administration, exhibiting a prolonged blood circulation time as the platelet membrane coating. More importantly, in the MI/RI therapy in vivo, the creatine kinase (CK) and LDH of the rats treated with P/TMP-MEs were remarkably decreased compared with the free TMP and TMP-MEs groups. The combinational strategy of platelet membrane coating and microemulsion assembly endows TMP with a better prospect for MI/RI therapy.
Assuntos
Infarto do Miocárdio , Traumatismo por Reperfusão Miocárdica , Animais , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Miócitos Cardíacos , Tamanho da Partícula , Ratos , Ratos Sprague-DawleyRESUMO
Combinational icaritin (IC) and coix seed oil (CSO) holds promising potential in the treatment of hepatocellular carcinoma. However, traditional cocktail therapy is facing difficulties to optimize the synergistic antitumor efficacy due to the asynchronous pharmacokinetics. Therefore, we developed an icaritin-loaded microemulsion based on coix seed oil (IC-MEs) for improved pharmacokinetics and enhanced antitumor efficacy. The preparation technology of IC-MEs was optimized by the Box-Behnken design and the pharmaceutical properties were characterized in detail. IC-MEs show synergistic antiproliferation against HepG2 cells compared with monotherapy. The mechanism is associated with stronger apoptosis induction via enhancing caspases-3 activity. IC-MEs significantly improve the bioavailability of IC due to the encapsulation of coix oil-based microemulsion and also obtain the desired liver accumulation and elimination. More importantly, IC-MEs exhibit the overwhelming antitumor ability among all of the treatments on the HepG2 xenograft-bearing mice. This study verifies the feasibility of using coix oil-based microemulsion to improve the antitumor effect of water-insoluble components.
Assuntos
Coix , Neoplasias Hepáticas , Humanos , Animais , Camundongos , Flavonoides/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Óleos de Plantas/farmacologiaRESUMO
Amphiphilic chitosan derivatives have attracted wide attention as drug carriers due to their physicochemical properties. However, obtaining a desired amphiphilic chitosan derivative by tuning the various functional groups was complex and time-consuming. Therefore, a facile and common synthesis strategy would be promising. In this study, a modular strategy based on strain-promoted azide-alkyne cycloaddition (SPAAC) click reaction was designed and applied in synthesizing deoxycholic acid- or octanoic acid-modified N-azido propionyl-N,O-sulfate chitosan through tuning the hydrophobic groups. Additionally, chitosan derivatives with the same substitute groups were prepared via amide coupling as controls. We demonstrated that these derivates via the two strategies showed no obvious difference in physicochemical properties, drug loading ability and biosafety, indicating the feasibility of modular strategy. Notably, the modular strategy exhibited advantages including high reactivity, flexibility and reproducibility. We believe that this modular strategy could provide varied chitosan derivatives in an easy and high-efficiency way for improving multifunctional drug carriers.