RESUMO
Efferocytosis-mediated inflammatory reversal plays a crucial role in bone repairing process. However, in refractory bone defects, the macrophage continual efferocytosis may be suppressed due to the disrupted microenvironment homeostasis, particularly the loss of apoptotic signals and overactivation of intracellular oxidative stress. In this study, a polydopamine-coated short fiber matrix containing biomimetic "apoptotic signals" to reconstruct the microenvironment and reactivate macrophage continual efferocytosis for inflammatory reversal and bone defect repair is presented. The "apoptotic signals" (AM/CeO2) are prepared using CeO2 nanoenzymes with apoptotic neutrophil membrane coating for macrophage recognition and oxidative stress regulation. Additionally, a short fiber "biomimetic matrix" is utilized for loading AM/CeO2 signals via abundant adhesion sites involving π-π stacking and hydrogen bonding interactions. Ultimately, the implantable apoptosis-mimetic nanoenzyme/short-fiber matrixes (PFS@AM/CeO2), integrating apoptotic signals and biomimetic matrixes, are constructed to facilitate inflammatory reversal and reestablish the pro-efferocytosis microenvironment. In vitro and in vivo data indicate that the microenvironment biomimetic short fibers can activate macrophage continual efferocytosis, leading to the suppression of overactivated inflammation. The enhanced repair of rat femoral defect further demonstrates the osteogenic potential of the pro-efferocytosis strategy. It is believed that the regulation of macrophage efferocytosis through microenvironment biomimetic materials can provide a new perspective for tissue repair.
Assuntos
Apoptose , Materiais Biomiméticos , Cério , Inflamação , Macrófagos , Polímeros , Animais , Cério/química , Cério/farmacologia , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacologia , Inflamação/tratamento farmacológico , Ratos , Camundongos , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Polímeros/química , Polímeros/farmacologia , Apoptose/efeitos dos fármacos , Indóis/química , Indóis/farmacologia , Fagocitose/efeitos dos fármacos , Células RAW 264.7 , Regeneração Óssea/efeitos dos fármacos , Ativação de Macrófagos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Biomimética/métodos , Osteogênese/efeitos dos fármacos , Microambiente Celular/efeitos dos fármacos , EferocitoseRESUMO
Intraperitoneal sporadic tumor is a common and complicated syndrome in cancers, causing a high rate of death, and people find that intraperitoneal chemotherapy (IPC) can treat intraperitoneal sporadic tumors better than intravenous chemotherapy and surgery. However, the effectiveness and side effects of IPC are controversial, and the operation process of IPC is complicated. Herein, the injectable paclitaxel-loaded (PTX-loaded) electrospun short fibers are constructed through a series process of electrospinning, homogenizing, crosslinking, and subsequent polydopamine coating and folate acid (FA) modification. The evenly dispersed short fibers exhibited effective tumor cell killing and good injectable ability, which is convenient to use and greatly improved the complex operation procedure. Mussel-like protein poly-dopamine coating and FA modification endowed short fibers with the ability of targeted adhesion to tumors, and therefore the short fibers further acted as a kind of micro membrane that could release drugs to tumors at close range, maintaining local high drug concentration and prevent paclitaxel killing normal tissues. Thus, the target-adhesive injectable electrospun short fibers are expected to be the potential candidate for cancer treatment, especially the intraperitoneal sporadic tumors, which are hard to treat by surgery or intravenous chemotherapy.
Assuntos
Túnica Adventícia , Neoplasias , Humanos , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Proteínas , PerfusãoRESUMO
The lesion core is the area with the most serious injury and vigorous repair. Existing nanocarriers are difficult to break through the targeted delivery to the lesion core for precise treatment in the intracellular and extracellular microenvironment. Herein, a cellular membrane-engineered nanovesicle (CMEV) with a hierarchical structure is constructed using the double emulsion-extrusion method by integrating a neutrophil membrane, functional antibody, and gelled drug-loaded core as a three-stage booster to target the lesion core and deliver catestatin (CST), a small therapeutic peptide, for ischemic cardiomyopathy therapy. By coating the neutrophil membrane outside the shell, CMEV is endowed with the function of neutrophil-like migration to achieve the first stage of tissue targeting. Based on the specific anchoring to injured myocardium, a myosin light chain 3 (MLC3) antibody is embedded to fulfill the second stage of CMEV accumulation in the lesion core. The gelled core containing CST-sodium alginate (NaAlg) with a pH-responsive shell is prepared by ionic cross-linking to accomplish the third stage of precise CST administration. Triggered by the microenvironment, NaAlg electrostatically adheres to the lesion core for sustained release, enhancing the efficacy of CST in improving cardiomyocyte apoptosis, excessive fibrosis, macrophage polarization, and angiogenesis. Thus, the "three-stage booster" nanovesicle significantly ameliorates cardiac function and adverse remodeling to treat ischemic cardiomyopathy.
Assuntos
Apoptose , Cardiomiopatias , Humanos , Membrana Celular , PeptídeosRESUMO
Acylphosphatase 1 (ACYP1), a protein located in the mammalian cell cytoplasm, has been shown to be associated with tumor initiation and progression by functioning as a metabolism-related gene. Here we explored the potential mechanisms by which ACYP1 regulates the development of HCC and participates in the resistance to lenvatinib. ACYP1 can promote the proliferation, invasion, and migration capacities of HCC cells in vitro and in vivo. RNA sequencing reveals that ACYP1 markedly enhances the expression of genes related to aerobic glycolysis, and LDHA is identified as the downstream gene of ACYP1. Overexpression of ACYP1 upregulates LDHA levels, which then increases the malignancy potential of HCC cells. GSEA data analysis reveals the enrichment of differentially expressed genes in the MYC pathway, indicating a positive correlation between MYC and ACYP1 levels. Mechanistically, ACYP1 exerts its tumor-promoting roles by regulating the Warburg effect through activating the MYC/LDHA axis. Mass spectrometry analysis and Co-IP assays confirm that ACYP1 can bind to HSP90. The regulation of c-Myc protein expression and stability by ACYP1 is HSP90 dependent. Importantly, lenvatinib resistance is associated with ACYP1, and targeting ACYP1 remarkably decreases lenvatinib resistance and inhibits progression of HCC tumors with high ACYP1 expression when combined with lenvatinib in vitro and in vivo. These results illustrate that ACYP1 has a direct regulatory role in glycolysis and drives lenvatinib resistance and HCC progression via the ACYP1/HSP90/MYC/LDHA axis. Targeting ACYP1 could synergize with lenvatinib to treat HCC more effectively.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Glicólise/genética , Regulação Neoplásica da Expressão Gênica , MamíferosRESUMO
Novel polymers applied in economic membrane technologies are a perennial hot topic in the fields of natural gas purification and O2 enrichment. Herein, novel hypercrosslinked polymers (HCPs) incorporating 6FDA-based polyimide (PI) MMMs were prepared via a casting method for enhancing transport of different gases (CO2, CH4, O2, and N2). Intact HCPs/PI MMMs could be obtained due to good compatibility between the HCPs and PI. Pure gas permeation experiments showed that compared with pure PI film, the addition of HCPs effectively promotes gas transport, increases gas permeability, and maintains ideal selectivity. The permeabilities of HCPs/PI MMMs toward CO2 and O2 were as high as 105.85 Barrer and 24.03 Barrer, respectively, and the ideal selectivities of CO2/CH4 and O2/N2 were 15.67 and 3.00, respectively. Molecular simulations further verified that adding HCPs was beneficial to gas transport. Thus, HCPs have potential utility in fabrication of MMMs for facilitating gas transport in the fields of natural gas purification and O2 enrichment.
RESUMO
Ganoderma lucidum is a traditional Chinese medicine with a variety of active compounds and possesses adequate lipid-lowering and anti-atherosclerotic effects. However, its main active components and potential mechanisms still remain unclear. Here, we evaluated the anti-hyperlipidemic effect of the adenosine extract from Ganoderma lucidum (AEGL) in high-fat-diet (HFD)-induced hyperlipidemic ApoE-/- mice and explored the underlying biological mechanism by multi-omics analysis. Treatment with AEGL for 8 weeks significantly decreased the serum levels of total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-c) by 45.59%, 41.22%, and 39.02%, respectively, as well as reduced liver TC and TG by 44.15% and 76.23%, compared with the HFD-only group. We also observed significant amelioration of hepatic steatosis without liver and kidney damage after AEGL treatment. Regulating the expression and acetylation/crotonylation of proteins involved in the PPAR signaling pathway may be one of the potential mechanisms involved in the observed lipid-lowering effects of AEGL.
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Activated fibroblast-like synovial (FLS) cells are regarded as an important target for rheumatoid arthritis (RA) treatment via starvation therapy mediated by glucose oxidase (GOx). However, the hypoxic RA-FLS environment greatly reduces the oxidation process of glucose and leads to a poor therapeutic effect of the GOx-based starvation therapy. In this work, we designed a hollow mesoporous copper sulfide nanoparticles (CuS NPs)-based smart GOx/atovaquone (ATO) codelivery system (named as V-HAGC) targeting RA-FLS cells to realize a O2-economized dual energy inhibition strategy to solve the limitation of GOx-based starvation therapy. V-HAGC armed with dual multi-stimuli-responsive "doorkeepers" can guard drugs intelligently. Once under the stimulation of photothermal and acidic conditions at the targeted area, the dual intelligent responsive "doors" would orderly open to realize the controllable release of drugs. Besides, the efficacy of V-HAGC would be much improved by the additional chemodynamic therapy (CDT) and photothermal therapy (PTT) stimulated by CuS NPs. Meanwhile, the upregulated H2O2 and acid levels by starvation therapy would promote the Fenton-like reaction of CuS NPs under O2-economized dual energy inhibition, which could enhance the PTT and CDT efficacy as well. In vitro and in vivo evaluations revealed V-HAGC with much improved efficacy of this combination therapy for RA. In general, the smart V-HAGC based on the O2-economized dual energy inhibition strategy combined with enhanced CDT and PTT has the potential to be an alternative methodology in the treatment of RA.
Assuntos
Artrite Reumatoide , Nanopartículas , Neoplasias , Humanos , Cobre/farmacologia , Cobre/uso terapêutico , Terapia Fototérmica , Glucose Oxidase/uso terapêutico , Atovaquona/uso terapêutico , Peróxido de Hidrogênio , Nanopartículas/uso terapêutico , Sulfetos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Glucose , Nanotecnologia , Neoplasias/tratamento farmacológico , Linhagem Celular TumoralRESUMO
Aminoacyl transfer RNA (tRNA) synthetases (aaRSs) are attractive drug targets, and we present class I and II aaRSs as previously unrecognized targets for adenosine 5'-monophosphate-mimicking nucleoside sulfamates. The target enzyme catalyzes the formation of an inhibitory amino acid-sulfamate conjugate through a reaction-hijacking mechanism. We identified adenosine 5'-sulfamate as a broad-specificity compound that hijacks a range of aaRSs and ML901 as a specific reagent a specific reagent that hijacks a single aaRS in the malaria parasite Plasmodium falciparum, namely tyrosine RS (PfYRS). ML901 exerts whole-life-cycle-killing activity with low nanomolar potency and single-dose efficacy in a mouse model of malaria. X-ray crystallographic studies of plasmodium and human YRSs reveal differential flexibility of a loop over the catalytic site that underpins differential susceptibility to reaction hijacking by ML901.
Assuntos
Antimaláricos , Malária Falciparum , Terapia de Alvo Molecular , Plasmodium falciparum , Biossíntese de Proteínas , Proteínas de Protozoários , Tirosina-tRNA Ligase , Adenosina/análogos & derivados , Animais , Antimaláricos/química , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Cristalografia por Raios X , Humanos , Malária Falciparum/tratamento farmacológico , Malária Falciparum/parasitologia , Camundongos , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/enzimologia , Biossíntese de Proteínas/efeitos dos fármacos , Conformação Proteica , Proteínas de Protozoários/química , Proteínas de Protozoários/metabolismo , Ácidos Sulfônicos/química , Tirosina-tRNA Ligase/química , Tirosina-tRNA Ligase/metabolismoRESUMO
The Plasmodium falciparum proteasome is a potential antimalarial drug target. We have identified a series of amino-amide boronates that are potent and specific inhibitors of the P. falciparum 20S proteasome (Pf20S) ß5 active site and that exhibit fast-acting antimalarial activity. They selectively inhibit the growth of P. falciparum compared with a human cell line and exhibit high potency against field isolates of P. falciparum and Plasmodium vivax They have a low propensity for development of resistance and possess liver stage and transmission-blocking activity. Exemplar compounds, MPI-5 and MPI-13, show potent activity against P. falciparum infections in a SCID mouse model with an oral dosing regimen that is well tolerated. We show that MPI-5 binds more strongly to Pf20S than to human constitutive 20S (Hs20Sc). Comparison of the cryo-electron microscopy (EM) structures of Pf20S and Hs20Sc in complex with MPI-5 and Pf20S in complex with the clinically used anti-cancer agent, bortezomib, reveal differences in binding modes that help to explain the selectivity. Together, this work provides insights into the 20S proteasome in P. falciparum, underpinning the design of potent and selective antimalarial proteasome inhibitors.
Assuntos
Compostos de Boro/farmacologia , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/química , Inibidores de Proteassoma/farmacologia , Administração Oral , Animais , Compostos de Boro/administração & dosagem , Compostos de Boro/química , Domínio Catalítico , Humanos , Malária Falciparum/enzimologia , Malária Falciparum/parasitologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Modelos Moleculares , Plasmodium falciparum/enzimologia , Inibidores de Proteassoma/administração & dosagem , Inibidores de Proteassoma/químicaRESUMO
In this work, dimeric artesunate-phosphatidylcholine conjugate (dARTPC)-based liposomes encapsulated with irinotecan (Ir) were developed for anticancer combination therapy. First, dARTPC featured with unique amphipathic properties formed liposomes by classical thin-film methods. After that, Ir was encapsulated into dARTPC-based liposomes (Ir/dARTPC-LP) by the triethylammonium sucrose octasulfate gradient method. Physicochemical characterization indicated that Ir/dARTPC-LP had a mean size of around 140 nm and a negative ζ potential of approximately -30 mV. Most noticeably, liposomes displayed an encapsulation efficiency of greater than 98% with a controllable drug loading of 4-22%. The in vitro release of dihydroartemisinin (DHA) and Ir from Ir/dARTPC-LP was investigated by dialysis in different media. It was found that effective release of both DHA (65.42%) and Ir (77.28%) in a weakly acidic medium (pH 5.0) after 48 h was achieved in comparison to very slow release under a neutral environment (DHA 9.90% and Ir 8.72%), indicating the controllable release of both drugs. Confocal laser scanning microscopy confirmed the improved cellular internalization of Ir/dARTPC-LP. The cytotoxicity of Ir/dARTPC-LP was evaluated in the MCF-7, A549, and HepG2 cell lines. The results showed that Ir/dARTPC-LP had significant synergistic efficacy in the loss of cell growth. In vivo anticancer evaluation was performed using a 4T1 xenograft tumor model. Ir/dARTPC-LP had a high tumor inhibition rate of 62.7% without significant toxicity in comparison with the injection of Ir solution. Taken together, dARTPC encapsulated with Ir has great potential for anticancer combination therapy.
Assuntos
Artesunato/administração & dosagem , Sistemas de Liberação de Medicamentos , Irinotecano/administração & dosagem , Lipossomos/administração & dosagem , Animais , Protocolos de Quimioterapia Combinada Antineoplásica , Apoptose/efeitos dos fármacos , Artesunato/farmacocinética , Artesunato/uso terapêutico , Linhagem Celular Tumoral , Combinação de Medicamentos , Sistemas de Liberação de Medicamentos/métodos , Feminino , Irinotecano/farmacocinética , Irinotecano/uso terapêutico , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Neoplasias Experimentais/tratamento farmacológico , FosfatidilcolinasRESUMO
7-Ethyl-10-hydroxycamptothecin (SN38), a potent camptothecin derivative specifically targeting DNA topoisomerase I cleavage complexes, has shown great potential in the treatment of solid tumors. Because of its poor solubility and chemical and metabolic stability, the clinical application of SN38 is highly limited. To address these problems, a novel redox-responsive SN38 conjugate based liposomal formulation is developed in this report. First, SN38 was conjugated with lysophospholipid by using a cleavable disulfide bond linker. After that, the conjugate (SN38-SS-PC) was assembled into liposomes by thin film method. Dynamic lightscattering(DLS) characterization indicated that SN38-SS-PC liposomes possessed a narrow size distribution (172.8 ± 10.5 nm) and negative charged zeta potential (-8.9 ± 0.3 mV). The results of storage and physiological stabilities showed that SN38-SS-PC liposomes was stable under different conditions. More importantly, a reduction responsive release of parent drug SN38 was observed in the medium containing glutathione (GSH). In addition, SN38-SS-PC liposomes had a much more rapid cellular uptake behavior against cancer cells. The enhanced anti-cancer efficacy of SN38-SS-PC liposomes was further demonstrated by in vitro cytotoxicity assay against MCF-7 and A549 cells. Under in vivo evaluation in 4 T1 xenograft tumor model, SN38-SS-PC liposomes were observed to have lower systemic toxicity and higher tumor inhibition rate of 53.3% compared with the commercialized SN38 prodrug Irinotecan (Ir). In summary, SN38-SS-PC liposomes could be a promising redox responsive delivery system of SN38 for cancer therapy.
Assuntos
Antineoplásicos Fitogênicos , Camptotecina , Linhagem Celular Tumoral , Irinotecano , Lisofosfolipídeos , OxirreduçãoRESUMO
In this report, a novel irinotecan (IR) encapsulated redox-responsive liposome was developed. The redox-responsive liposomes were prepared based on disulfide phosphatidylcholine (SS-PC), DSPC, DSPE-PEG2000 and cholesterol by ethanol injection method. IR was actively loaded by triethylammonium sucrose octasulfate (TEA8-SOS) gradient method to generate IR/SS-PC liposomes (IR/SS-LP). The particle size of IR/SS-PC was characterized by using dynamic light scattering (DLS) and transmission electron microscopy (TEM). It was found that IR/SS-LP with 30 % content of SS-PC (IR/SS30-LP) had an average size of 125.5 ± 5.8 nm with a negative zeta potential of -19.5 ± 0.1. The encapsulation efficiency (EE) was further determined to be 98.1 ± 0.8 % and drug loading (DL) was 31.8 ± 0.1 %. The redox-responsiveness of IR/SS-LP was investigated by observing the change of particle size and morphology as well as the release behavior of IR triggered by glutathione (GSH). The data indicated GSH breaks the disulfide bonds in SS-PC and leads to the controlled release of IR. At 1 mM GSH, 60.2 % irinotecan was released from IR/SS30-LP within 24 h. Finally, the effects of IR/SS-LP in cell and animal experiments were evaluated in detail. The results showed that IR/SS30-LP had superior pharmacokinetic and antitumor efficacy compared to free irinotecan and traditional irinotecan liposome (ONIVYDE®-like). Taken together, IR/SS30-LP displayed redox-responsive release of IR, ultra-high loading and enhanced anti-tumor activity, which has great potential for clinical application as a new generation of IR liposomal formulation.
Assuntos
Lipossomos , Fosfatidilcolinas , Animais , Liberação Controlada de Fármacos , Irinotecano , OxirreduçãoRESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies with poor prognosis. There are many selectable treatments with good prognosis in Barcelona Clinic Liver Cancer- (BCLC-) 0, A, and B HCC patients, but the most crucial factor affecting survival is the high recurrence rate after treatments. Therefore, it is of great significance to predict the recurrence of BCLC-0, BCLC-A, and BCLC-B HCC patients. AIM: To develop a gene signature to enhance the prediction of recurrence among HCC patients. MATERIALS AND METHODS: The RNA expression data and clinical data of HCC patients were obtained from the Gene Expression Omnibus (GEO) database. Univariate Cox regression analysis and least absolute shrinkage and selection operator (LASSO) regression analysis were conducted to screen primarily prognostic biomarkers in GSE14520. Multivariate Cox regression analysis was introduced to verify the prognostic role of these genes. Ultimately, 5 genes were demonstrated to be related with the recurrence of HCC patients and a gene signature was established. GSE76427 was adopted to further verify the accuracy of gene signature. Subsequently, a nomogram based on gene signature was performed to predict recurrence. Gene functional enrichment analysis was conducted to investigate the potential biological processes and pathways. RESULTS: We identified a five-gene signature which performs a powerful predictive ability in HCC patients. In the training set of GSE14520, area under the curve (AUC) for the five-gene predictive signature of 1, 2, and 3 years were 0.813, 0.786, and 0.766. Then, the relative operating characteristic (ROC) curves of five-gene predictive signature were verified in the GSE14520 validation set, the whole GSE14520, and GSE76427, showed good performance. A nomogram comprising the five-gene signature was built so as to show a good accuracy for predicting recurrence-free survival of HCC patients. CONCLUSION: The novel five-gene signature showed potential feasibility of recurrence prediction for early-stage HCC.
Assuntos
Carcinoma Hepatocelular/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/genética , Recidiva Local de Neoplasia/genética , Carcinoma Hepatocelular/patologia , Intervalo Livre de Doença , Feminino , Ontologia Genética , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Nomogramas , Prognóstico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Curva ROC , Reprodutibilidade dos Testes , Fatores de RiscoRESUMO
As an important DNA topoisomerase I inhibitor in oncotherapy, camptothecin (CPT) with traditional formulation only shows a limited clinical application mainly because of its poor solubility. In this study, a novel redox responsive nanoscaled delivery system was developed to overcome the inherent defect of CPT. Firstly, a CPT prodrug (CPT-LA) and two crosslinkable surfactants (SO-LA and MPEG-LA) was synthesized, all of which contained the same lipoic acid (LA) structure. In the preparation, highly core-crosslinked structure was formed by adding a thiol crosslinker, which can induce LA ring opening polymerization and disulfide crosslinking. The resulting CPT-LA core-crosslinked nanomicelles (CPT-LA CNM) were formulated with a highly crosslinked core and a PEG hydrophilic shell. Dynamic light scattering (DLS) characterization indicated that CPT-LA CNM possessed a narrow size distribution (184.6 ± 3.6 nm) and negatively charged zeta potential (-3.5 ± 1.2 mV). The storage and physiological stabilities showed that the size distribution of CPT-LA CNM was relatively stable in both conditions which were neutral PBS at 4 °C (1 week period) and PBS containing 10% serum at 37 °C (24 h period). Moreover, the effective CPT release behavior of CPT-LA CNM was confirmed in the reducing circumstances containing dithiothreitol (DTT). Under confocal laser scanning microscopy (CLSM), CPT-LA CNM demonstrated a rapid cellular uptake behavior against cancer cells when compared to CPT suspension. Finally, the enhanced anticancer efficacy of CPT-LA CNM was also detected by in vitro cytotoxicity and cell apoptosis assay. In summary, the core-crosslinked CPT-LA CNM could be a promising CPT delivery system because of high stability, effectively controlled release as well as improved anticancer activity.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Camptotecina/administração & dosagem , Portadores de Fármacos/administração & dosagem , Micelas , Pró-Fármacos/administração & dosagem , Tensoativos/administração & dosagem , Ácido Tióctico/administração & dosagem , Células A549 , Antineoplásicos Fitogênicos/química , Apoptose/efeitos dos fármacos , Camptotecina/química , Sobrevivência Celular/efeitos dos fármacos , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Eritrócitos/efeitos dos fármacos , Hemólise/efeitos dos fármacos , Células Hep G2 , Humanos , Células MCF-7 , Nanopartículas/administração & dosagem , Nanopartículas/química , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/química , Pró-Fármacos/química , Propanolaminas/administração & dosagem , Propanolaminas/química , Propilenoglicóis/administração & dosagem , Propilenoglicóis/química , Tensoativos/química , Ácido Tióctico/químicaRESUMO
The microtubule inhibitor paclitaxel (PTX) is used to treat a wide range of solid tumors. Due to the poor aqueous solubility of PTX, a continuous demand for safe, efficient PTX formulations with improved antitumor activity exists. Here, we report a novel form of redox-sensitive paclitaxel (PTX)-encapsulated liposomes based on the previously developed disulfide phosphatidylcholine (SS-PC). PTX-loaded stealth liposomes (PTX/SS-LP) composed of SS-PC, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-PEG2000 (DSPE-PEG2000), and cholesterol were prepared using the reverse-phase evaporation method. The characterization of the PTX/SS-LP liposomes using dynamic light scattering and transmission electron microscopy confirmed their uniform particle size and typical unilamellar vesicle structure with an average bilayer thickness of approximately 4 nm. Changes in the size and morphology as well as the rapid release of PTX triggered by the addition of dithiothreitol revealed the redox sensitivity of PTX/SS-LP. Finally, evaluations in MCF-7 and A549 cells in vitro and in BALB/c mice in vivo revealed the improved anticancer efficiency, biodistribution, and safety of PTX/SS-LP compared with those of Taxol and nonredox-sensitive PTX/LP. In conclusion, PTX/SS-LP displays a redox-responsive release of paclitaxel with improved antitumor activity and has great potential as a next-generation stealth liposomal PTX delivery system.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Lipossomos/química , Neoplasias/tratamento farmacológico , Paclitaxel/administração & dosagem , Fosfatidilcolinas/química , Animais , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Colesterol/química , Ditiotreitol , Liberação Controlada de Fármacos , Difusão Dinâmica da Luz , Humanos , Lipossomos/farmacologia , Lipossomos/toxicidade , Lipossomos/ultraestrutura , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Eletrônica de Transmissão , Oxirredução/efeitos dos fármacos , Paclitaxel/química , Paclitaxel/farmacologia , Fosfatidilcolinas/síntese química , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Distribuição Tecidual , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Aim: A redox-triggered camptothecin (CPT) liposomal system was developed for an improved clinical potential in tumor therapy. Materials & methods: CPT-phosphorylcholine conjugates (CPT-SS-GPCs: CPT-SS-3-GPC and CPT-SS-11-GPC) were synthesized by conjugating CPT to glycerylphosphorylcholine via disulfide bond linker. CPT-SS-GPCs could be assembled into liposomes. Different in vitro and in vivo analyses were used to evaluate the anticancer activities of CPT-SS-GPCs. Results: CPT-SS-GPCs liposomes exhibited extremely high drug loading and uniform size of 150-200 nm. Moreover, the rapid release of parent CPT in reductive condition and high cellular uptake of CPT-SS-GPCs liposomes were observed. At last, in vitro and in vivo anticancer assay showed the enhanced efficacy of CPT-SS-GPCs liposomes. Conclusion: Redox-triggered CPT-SS-GPC liposomes have great potential in tumor therapy.
Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/uso terapêutico , Camptotecina/química , Camptotecina/uso terapêutico , Lipossomos/química , Fosfatidilcolinas/química , Animais , Apoptose/efeitos dos fármacos , Camptotecina/efeitos adversos , Sobrevivência Celular/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Eritrócitos/efeitos dos fármacos , Feminino , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Oxirredução/efeitos dos fármacos , Polímeros/químicaRESUMO
Liposomes are the most valuable nanocarriers in clinical use because of their biocompatibility, biodegradation, and effective encapsulation of hydrophilic or hydrophobic drugs. However, their applications are limited by the structure and functions of the most common phospholipids used as the main component of the liposomes. In this work, novel series of thioether phosphatidylcholines (S-PCs) and S-PC-based liposomes (S-LPs) were developed for reactive oxygen species (ROS)-responsive drug release. First of all, S-PCs with different chain lengths were synthesized by a combination of click reaction and heterogeneous esterification. Differential scanning calorimetry studies indicated that S-PCs had different phase transition temperatures depending on their chain lengths. Their critical aggregation concentrations were measured by the fluorescence probe technique indicating the self-assembly ability. After that, S-PC-based stealth liposomes (S-LPs) containing DSPE-PEG2000 and cholesterol were prepared via a classic thin-film method. Doxorubicin (DOX) as a model drug was loaded in the stealth liposomes (DOX/S-LPs) by using the ammonium sulfate gradient method with high encapsulation efficiency. DOX/S-LPs were characterized by dynamic light scattering (DLS), transmission electron microscope (TEM), and cryogenic TEM, confirming their spherical structure with the bilayer thickness of about 4 nm. The ROS sensitivity of S-PCs and S-LPs was carefully evaluated in the presence of H2O2 by means of mass spectrometry, DLS, TEM, and ultraviolet spectroscopy and release study. The results indicated the significant structural change of S-LPs after H2O2 treatment, which demonstrated that S-LPs possessed an efficient ROS-triggered disintegration because of thioether oxidation of S-PCs. Finally, in vitro and in vivo anticancer efficiency assays revealed the improved drug potency of DOX/S-LPs, which can be attributed to ROS-triggered destruction of S-LPs after the uptake by tumor cells followed by rapid release of DOX. All together, as alternatives of traditional phosphatidylcholines, S-PC-based stealth liposomes are promising ROS-responsive carriers for the controlled delivery of drugs.
Assuntos
Doxiciclina , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Fosfatidilcolinas , Espécies Reativas de Oxigênio/metabolismo , Sulfetos , Células A549 , Animais , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacologia , Doxiciclina/química , Doxiciclina/farmacologia , Feminino , Humanos , Lipossomos , Células MCF-7 , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fosfatidilcolinas/química , Fosfatidilcolinas/farmacologia , Sulfetos/química , Sulfetos/farmacologiaRESUMO
Phosphatidylcholine is the main component of liposomes and other phospholipid-based nanocarriers in drug delivery. However, the functions and applications of these nanocarriers are extremely limited by conventional phospholipids. Here we report novel disulfide phosphatidylcholines (SS-PCs) and SS-PC based liposomes (SS-LPs) used as alternatives to traditional phospholipids and liposomes.
Assuntos
Dissulfetos/química , Portadores de Fármacos/química , Lipossomos/química , Fosfatidilcolinas/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Dissulfetos/síntese química , Dissulfetos/metabolismo , Doxorrubicina/química , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Portadores de Fármacos/síntese química , Portadores de Fármacos/metabolismo , Humanos , Lipossomos/síntese química , Lipossomos/metabolismo , Camundongos , Oxirredução , Fosfatidilcolinas/síntese química , Fosfatidilcolinas/metabolismoRESUMO
In this report, a novel redox-responsive liposomes based on disulfide derivative paclitaxel-ss-lysophosphatidylcholine prodrug (PTX-ss-PC) with high PTX loading was developed for triggering drug release. First of all, PTX-ss-PC was synthesized by a facile esterification and verified by MS, 1H NMR and HPLC. After that, PTX-ss-PC derived liposomes (PTX-ss-PC liposomes) containing EPC:Chol:mPEG2000-DSPE components were prepared by the conventional film method. Moreover, physicochemical characterizations of the PTX-ss-PC liposomes were carried out by using transmission electron microscope (TEM), dynamic light scattering (DLS) and release test. It was demonstrated that the PTX-ss-PC liposomes possessed average diameter of 234.9â¯nm and zeta potential of -29.1â¯mV with highest PTX loading 7.97%. The PTX-ss-PC liposomes dissociated rapidly in a reduction medium, as confirmed by their triggered aggregation/disruption and rapid release of PTX in the presence of glutathione (GSH). Finally, in vitro cytotoxicity of the liposomes was checked against MCF-7 and A549 cells. It was found that the PTX-ss-PC liposomes exhibited favorable GSH-mediated anti-proliferative activity in comparison with the nonresponsive counterpart. Taken together, the novel PTX-ss-PC based liposomes possess improved loading capacity, reduction triggered release of PTX and efficient anti-proliferative activity, which should be valuable for further preclinical evaluation.
Assuntos
Antineoplásicos Fitogênicos/química , Lisofosfatidilcolinas/química , Paclitaxel/química , Antineoplásicos Fitogênicos/administração & dosagem , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Glutationa/química , Humanos , Lipossomos , Lisofosfatidilcolinas/administração & dosagem , Oxirredução , Paclitaxel/administração & dosagemRESUMO
Liposomes have emerged as a fascinating nanocarriers for the delivery of cancer therapeutics. However, their efficacy for cancer therapy is reduced partially because of the serum-instability and incomplete drug release. In this study, a novel disulfide cross-linked liposomes (CLs) assembled from dimeric lipoic acid-derived glycerophosphorylcholine (di-LA-PC) conjugate was developed. The conjugate was synthesized by a facial esterification of lipoic acid (LA) and glycerophosphorylcholine (GPC) and characterized by MS, 1H NMR and 13C NMR. Featuring the enhanced serum-stability and intracellular drug release determined by in vitro stability and GSH-responsive behavior, CLs prepared with dried thin film technique following 10â¯% dithiothreitol (DTT) cross-linking can attain effective delivery of anticancer candidates. Notably, CLs stably encapsulated doxorubicin (Dox) in their vesicular structures and showed a remarkable thiol-sensitive release of payload upon cellular uptake by cancer cells, compared to that of uncross-linked liposomes (uCLs) or Doxil-like liposome (DLLs). The cell viability and apoptosis of Dox-loaded CLs worked the pronounced cytotoxic effects to MCF-7 cells with an IC50 value of 10.8⯵g Dox equiv./mL comparable to free Dox and 2.8-fold higher than DLLs. More importantly, it is demonstrated that the nanoscale characteristics of Dox-loaded CLs could prevent the proliferation of adriamycin-resistant MCF-7/ADR cell line, highlighting their potential in reversal of drug resistance. Furthermore, the preliminary in vivo test (nâ¯=â¯3) showed that disulfide cross-linked liposomal formulation of Dox (Dox-CLs) improved the therapeutic efficacy compared to free Dox and DLLs in a human breast carcinoma xenograft mouse model. Therefore, the current thiol-responsive cross-linked liposome may provide a robust drug delivery platform for cancer therapy.