RESUMO
Nanocarrier surface functionalization has been widely regarded as a promising approach for achieving precise and targeted drug delivery systems. In this work, the fabrication of functionalized-Ag-decorated Fe3O4@SiO2 (Fe3O4@SiO2-Ag) nanocarriers with folic acid (FA) and ß-cyclodextrin (BCD) exhibit a remarkable capacity for delivering two types of anticancer drugs, i.e., doxorubicin (DOX) and epirubicin (EPI), into cancer cells. The effective functionalization of Fe3O4@SiO2-Ag nanoparticles has been achieved through the use of cysteine (Cys) as an anchor for attaching FA and BCD via EDC-NHS coupling and Steglich esterification methods, respectively. The findings indicate that surface functionalization had no significant impact on the physicochemical characteristics of the nanoparticles. However, it notably affected DOX and EPI loading and release efficiency. The electrostatic conjugation of DOX/EPI onto the surface of Fe3O4@SiO2-Ag/Cys/FA and Fe3O4@SiO2-Ag/Cys/BCD exhibited maximum loading efficiency of 50-60% at concentration ratio of DOX/EPI to nanoparticles of 1:14. These nanocarriers also achieved an 40-47% DOX/EPI release over 36 days. Furthermore, the drug-loaded functionalized-nanocarrier showed cytotoxic effects on SK-MEL-2 cells, as demonstrated by an in vitro MTT assay. This suggests that the as-prepared functionalized-nanoparticles have promise as a carrier for the efficient anticancer drugs.
Assuntos
Antineoplásicos , Doxorrubicina , Portadores de Fármacos , Ácido Fólico , Dióxido de Silício , beta-Ciclodextrinas , Ácido Fólico/química , beta-Ciclodextrinas/química , Humanos , Doxorrubicina/farmacologia , Doxorrubicina/química , Doxorrubicina/administração & dosagem , Dióxido de Silício/química , Portadores de Fármacos/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/administração & dosagem , Epirubicina/farmacologia , Epirubicina/química , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacosRESUMO
Using targeted drug delivery systems has emerged as a promising approach to increase the efficacy of chemotherapy, particularly in combination with gene therapy. The overexpression of miR-21 plays a crucial role in colorectal cancer (CRC) progression, and targeted inhibition of miR-21 offers significant potential for enhancing CRC chemotherapy outcomes. In this study, a theranostic system based on mesoporous silica and superparamagnetic iron oxide nanoparticles (SPION@MSNs) was synthesized as a core-shell structure. After loading epirubicin (EPI) in the open pores of MSN, the plasmid expressing anti-miR-21 (pDNA) covered the outer surface with the help of a ZIF-8 (zeolitic imidazolate framework-8) film. Afterward, polyethylene glycol (PEG) and AS1411 aptamer were conjugated to the surface to improve the protective, biocompatibility, and targeting abilities of the nanocarrier. Moreover, the physicochemical characteristics as well as the loading capacity and release profile of EPI and pDNA were fully evaluated. The uptake of the nanoparticles by CRC and normal cell lines in addition to the anticancer effects related to targeted combinational therapy were investigated in vitro. Finally, in vivo tests were performed on BALB/c mice bearing colorectal tumors to evaluate the effectiveness of the targeted nanoparticles, their possible side effects, and also their application in fluorescence and magnetic imaging in vivo. The successful synthesis of SPION@MSN-EPI/pDNA-ZIF-8-PEG-Apt nanoparticles (â¼68 nm) and good loading efficiency and controlled release of EPI and pDNA were confirmed. Moreover, hemolysis and gel retardation assays demonstrated the biocompatibility and plasmid protection. Cellular uptake and expression of copGFP illustrated selective entry and transient transfection of targeted nanoparticles, consistent with the cytotoxicity results that indicated the synergistic effects of chemo-gene therapy. The results of animal studies proved the high antitumor efficiency of targeted nanoparticles with minimal tissue damage, which was in line with fluorescence and magnetic imaging results. The novel synthesized nanoparticles containing SPION@MSN-ZIF-8 were suitable for CRC theranostics, and the combined approach of chemo-gene therapy suppressed the tumor more effectively.
Assuntos
Adenocarcinoma , Neoplasias do Colo , MicroRNAs , Nanopartículas , Animais , Camundongos , Epirubicina/farmacologia , Epirubicina/química , Neoplasias do Colo/tratamento farmacológico , Antagomirs , Medicina de Precisão , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/química , Polietilenoglicóis/química , Nanopartículas Magnéticas de Óxido de Ferro , Dióxido de Silício/químicaRESUMO
Unsatisfied tumor accumulation of chemotherapeutic drugs and a complicated immunosuppressive microenvironment diminish the immune response rate and the therapeutic effect. Surface modification of these drugs with target ligands can promote their cellular internalization, but the modified drugs may be subjected to unexpected immune recognition and clearance. Herein, a phenylboronic acid (PBA) group-shieldable dendritic nanomedicine that integrates an immunogenic cell death (ICD)-inducing agent (epirubicin, Epi) and an indoleamine 2,3-dioxgenase 1 (IDO1) inhibitor (NLG919) is reported for tumor chemo-immunotherapy. This NLG919-loaded Epi-conjugated PEGylated dendrimers bridged with boronate bonds (NLG919@Epi-DBP) maintains a stable nanostructure during circulation. Under a moderate acidic condition, the PBA group exposes to the sialic acid residue on the tumor cell membrane to enhance the internalization and penetration of NLG919@Epi-DBP. At pH 5.0, NLG919@Epi-DBP rapidly disassembles to release the incorporated Epi and NLG919. Epi triggers robust ICD of tumor cells that evokes strong immune response. In addition, inhibition of the IDO1 activity downregulates the metabolism of L-tryptophan to kynurenine, leading to a reduction in the recruitment of immunosuppressive cells and modulation of the tumor immune microenvironment. Collectively, this promising strategy has been demonstrated to evoke robust immune response as well as remodel the immunosuppressive microenvironment for an enhanced chemo-immunotherapeutic effect.
Assuntos
Nanomedicina , Neoplasias , Humanos , Epirubicina/química , Neoplasias/terapia , Triptofano/química , Triptofano/metabolismo , Triptofano/farmacologia , Imunoterapia , Microambiente Tumoral , Linhagem Celular TumoralRESUMO
OBJECTIVE: We evaluated the DNA nanocarriers synthesized by rolling circle amplification (RCA), composed of multiple repeats of AS1411 and FOXM1 aptamers for targeted epirubicin delivery to breast cancer cells. METHODS: Agarose gel electrophoresis and scanning electron microscopy were used to nanostructure characterizing. Drug loading and drug release were determined by fluorometry. Cytotoxicity comparison by MTT assay was applied among epirubicin, nanoparticle, and complex (nanoparticle carrying epirubicin) in L929 (normal murine fibroblast) and 4T1 (murine mammary carcinoma) cells. Cellular epirubicin internalization was assessed by flow cytometry and fluorescence imaging. In vivo studies in 4T1 tumor-bearing BALB/c mice were conducted by monitoring tumor volume, mouse weight, and mortality rate and measuring the accumulated epirubicin in organs. RESULTS: The negatively charged nanoparticles were under 200 nm and stable. Fifty microliters of 6 µM epirubicin was loaded in 50 µL nanoparticle. Epirubicin release at acidic pH was more. Complex compared with epirubicin, had more entry and cytotoxicity in target cells (p value ≤.01), higher therapeutic effect (p value ≤.001), and tumor drug accumulation. CONCLUSION: The poly-aptamer nanocarriers have the characteristics of being safe, stable, efficient epirubicin loading, pH-dependent drug release, and tumor-targeting ability in vitro and in vivo.
Assuntos
Nanopartículas , Neoplasias , Cricetinae , Animais , Camundongos , Epirubicina/química , Sistemas de Liberação de Medicamentos/métodos , Linhagem Celular Tumoral , Cricetulus , Células CHO , Antibióticos Antineoplásicos/farmacologia , Antibióticos Antineoplásicos/química , Nanopartículas/química , DNA , Neoplasias/tratamento farmacológicoRESUMO
Peptides, which are important components of the human body, appear in different chemistry applications. Perhaps the most important of these applications is the use of these structures in drug delivery systems due to their biocompatibility properties. Diphenylalanine (FF) peptide-based systems, which are part of the ß-amyloid polypeptide sequence and are known as the smallest dipeptide group, are particularly preferred due to their biocompatible nature, thermal stability, high ionic strength in water in new targeted drug systems. Epirubicin, the epimer of doxorubicin, is utilized in treating lung cancer. The side effects and the applied doses of epirubicin are being tried to be reduced. Therefore, in this study, epirubicin-loaded tert-butyloxycarbonyl protected diphenylalanine (Boc)-FF particles were synthesized and characterized and the effects of these peptides on cytotoxicity, genotoxicity, oxidative stress and apoptosis on non-small cell lung cancer cells (NSCLC) (A549) were evaluated. According to the results of the study, it was determined that epirubicin-loaded Boc-FF dipeptides significantly reduced the viability, oxidative stress, and increased DNA damage and apoptosis in the cells. The study suggests that epirubicin-loaded Boc-FF particles can be used as an alternative drug carrier for NSCLC treatment due to their physiological, chemical, and biological activity.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Nanopartículas , Humanos , Epirubicina/farmacologia , Epirubicina/química , Epirubicina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Neoplasias Pulmonares/tratamento farmacológico , Dipeptídeos/farmacologia , Apoptose , Nanopartículas/química , Dano ao DNA , Estresse OxidativoRESUMO
Treatment of epithelial ovarian cancer (EOC) is a challenge because it still leads to unsatisfactory clinical prognosis. This is due to the toxicity and poor targeting of chemotherapeutic agents, as well as metastasis of the tumor. In this study, we designed a targeted liposome with nanostructures to overcome these problems. In the liposomes, epirubicin and curcumin were encapsulated to achieve their synergistic antitumor efficacy, while Epi-1 was modified on the liposomal surface to target epithelial cell adhesion molecule (EpCAM). Epi-1, a macrocyclic peptide, exhibits active targeting for enhanced cellular uptake and potent cytotoxicity against tumor cells. The encapsulation of epirubicin and curcumin synergistically inhibited the formation of neovascularization and vasculogenic mimicry (VM) channels, thereby suppressing tumor metastasis on SKOV3 cells. The dual drug loaded Epi-1-liposomes also induced apoptosis and downregulated metastasis-related proteins for effective antitumor in vitro. In vivo studies showed that dual drug loaded Epi-1-liposomes prolonged circulation time in the blood and increased the selective accumulation of drug at the tumor site. H&E staining and immunohistochemistry with Ki-67 also showed that targeted liposomes elevated antitumor activity. Also, targeted liposomes downregulated angiogenesis-related proteins to inhibit angiogenesis and thus tumor metastasis. In conclusion, the production of dual drug loaded Epi-1-liposomes is an effective strategy for the treatment of EOC.
Assuntos
Curcumina , Neoplasias Ovarianas , Humanos , Feminino , Epirubicina/farmacologia , Epirubicina/química , Epirubicina/uso terapêutico , Lipossomos/química , Molécula de Adesão da Célula Epitelial , Curcumina/farmacologia , Carcinoma Epitelial do Ovário/tratamento farmacológico , Linhagem Celular Tumoral , Neoplasias Ovarianas/tratamento farmacológicoRESUMO
The anticancer efficacy of chemotherapeutic agents can be enhanced by the loading of DNA nanostructures, which is closely related to their interactions. This study achieved pH-responsive and targeted anthracycline delivery using i-motif and MUC1 aptamer co-modified DNA tetrahedron (MUC1-TD). The thermodynamic parameters for the binding of doxorubicin (DOX) and epirubicin (EPI) to MUC1-TD at pHs 7.4 and 5.0 were obtained. The smaller binding constant and the number of binding sites at pH 5.0 than at pH 7.4 indicated that acidic conditions favored the release of DOX and EPI loaded by MUC1-TD. The binding affinity of DOX was stronger than that of EPI at the same pH value due to their different chemical stereostructures. The intercalative binding mechanism was verified. In vitro release experiments revealed that acid pH and deoxyribonuclease I accelerated the release of DOX and EPI. The faster release rate of EPI than DOX was related to their binding affinity. In vitro cytotoxicity and cell uptake experiments revealed that the cytotoxicity of DOX and EPI loaded by MUC1-TD to MCF-7 cells was significantly higher than that to L02 cells. This work will provide theoretical guidance for the application of pH-responsive MUC1-TD nanocarriers in the field of pharmaceutics.
Assuntos
Antraciclinas , Antibióticos Antineoplásicos , Humanos , Antraciclinas/farmacologia , Doxorrubicina/farmacologia , Epirubicina/farmacologia , Epirubicina/química , DNA/química , Células MCF-7 , Concentração de Íons de Hidrogênio , Sistemas de Liberação de MedicamentosRESUMO
Bacterial infections can cause serious complications in cancer treatment and have been proven to weaken therapeutic benefits. Recently, antibacterial nanomaterials that serve as carriers for anticancer drug delivery have been attracting extensive interest due to their combined antimicrobial and anticancer activities. In this study, antibacterial metal-phenolic nanosheets (Cu-TA) were successfully prepared via the self-assembly of the metal-phenolic coordination complexes formed between copper ions and tannic acid, and the structure, morphology, and formation mechanism of Cu-TA nanosheets were explored. The antibacterial activity of Cu-TA nanosheets against both Gram-positive and Gram-negative bacteria was detected using the minimum inhibitory concentration (MIC), zone of inhibition and plate counting methods. The MIC values of both bacterial strains were about 0.4 mg mL-1, and the killing rates of Cu-TA samples were close to 100% at the concentration of 2 and 0.2 mg mL-1 after 12-hour incubation. Epirubicin hydrochloride (EPI) molecules were successfully loaded on the porous Cu-TA nanosheets mainly through the formation of the Cu-EPI chelate complex and strong electrostatic interactions. The Cu-EPI complex and Cu-TA nanosheets could be disassembled under acidic conditions or in the presence of high levels of glutathione (GSH) after uptake by cancer cells, which triggered the unique pH and GSH-responsive controlled release behaviors of EPI and copper ions. The MTT assay results revealed that the presence of bacteria in Hep G2 cells can greatly impair the cell death rate induced by free EPI, but the resultant EPI-loaded Cu-TA nanosheets can significantly enhance cell death both in the presence and absence of bacteria.
Assuntos
Antibacterianos , Cobre , Antibacterianos/química , Bactérias , Cobre/química , Preparações de Ação Retardada/farmacologia , Epirubicina/química , Epirubicina/farmacologia , Bactérias Gram-Negativas , Bactérias Gram-Positivas , Metais/químicaRESUMO
3D-printed hydrogels are particularly advantageous as drug-delivery platforms but their loading with water-soluble active compounds remains a challenge requiring the development of innovative inks. Here, we propose a new 3D extrusion-based approach that, by exploiting the internal gelation of the alginate, avoids the post-printing crosslinking process and allows the loading of epirubicin-HCl (EPI). The critical combinations of alginate, calcium carbonate and d-glucono-δ-lactone (GDL) combined with the scaffold production parameters (extrusion time, temperature, and curing time) were evaluated and discussed. The internal gelation in tandem with 3D extrusion allowed the preparation of alginate hydrogels with a complex shape and good handling properties. The dispersion of epirubicin-HCl in the hydrogel matrix confirmed the potential of this self-crosslinking alginate-based ink for the preparation of 3D-printed drug-delivery platforms. Drug release from 3D-printed hydrogels was monitored, and the cytotoxic activity was tested against MCF-7 cells. Finally, the change in the expression pattern of anti-apoptotic, pro-apoptotic, and autophagy protein markers was monitored by liquid-chromatography tandem-mass-spectrometry after exposure of MCF-7 to the EPI-loaded hydrogels.
Assuntos
Alginatos , Portadores de Fármacos , Epirubicina , Hidrogéis , Impressão Tridimensional , Alginatos/química , Alginatos/farmacologia , Reagentes de Ligações Cruzadas/química , Portadores de Fármacos/síntese química , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Epirubicina/química , Epirubicina/farmacocinética , Epirubicina/farmacologia , Humanos , Hidrogéis/síntese química , Hidrogéis/química , Hidrogéis/farmacologia , Células MCF-7RESUMO
Mesoporous silica nanoparticles (MNs) emerged as new promising drug-delivery platforms capable to overcome resistance in bacteria. Dual loading of drugs on these nanocarriers, exploiting synergistic interactions between the nanoparticles and the drugs, could be considered as a way to increase the efficacy against resistant bacteria with a positive effect even at very low concentrations. Considering that patients with cancer are highly susceptible to almost any type of bacterial infections, in this work, nanocarriers mesoporous silica-based, MNs and MNs@EPI were synthetized and submitted to single and/or dual loading of antibiotics (ofloxacin - OFLO) and anticancer drugs (Doxorubicin - DOX; Epirubicin - EPI), and investigated regarding their antibacterial activity against Escherichia coli, Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), Enterococcus faecalis and Pseudomonas aeruginosa. Formulations containing ofloxacin such as MNs-OFLO, MNs-EPI + OFLO, MNs-DOX + OFLO and MNs@EPI + OFLO, present antibacterial activity in all bacterial strains tested. All these are more effective in E.coli with MIC and MBC values for MNs-OFLO, MNs-EPI + OFLO and MNs-DOX + OFLO of around 1 and 2 µgnanomaterial/mL, corresponding to ofloxacin concentrations of 0.03, 0.02 and 0.04 µg/mL, respectively. In the cocktail formulations the conjugation of epirubicin with ofloxacin presents a more effective antibacterial activity with more than 3-fold reduction of ofloxacin concentration when comparing to the single ofloxacin system. By far, the most effective synergistic effect was obtained for the system where epirubicin was functionalized at nanoparticles surface (MNs@EPI), where a 40-fold and 33-fold reductions of ofloxacin concentration were obtained, in P. aeruginosa in comparison to the MNs-OFLO and MNs-EPI + OFLO systems, respectively. These effects are shown in all bacterial strains tested, even in strains that have acquired resistance mechanisms, such as MRSA.
Assuntos
Antibacterianos/farmacologia , Antibióticos Antineoplásicos/farmacologia , Infecções Bacterianas/tratamento farmacológico , Doxorrubicina/farmacologia , Epirubicina/farmacologia , Ofloxacino/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antibióticos Antineoplásicos/química , Relação Dose-Resposta a Droga , Doxorrubicina/química , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Enterococcus faecalis/efeitos dos fármacos , Epirubicina/química , Escherichia coli/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Nanopartículas/química , Ofloxacino/química , Tamanho da Partícula , Porosidade , Pseudomonas aeruginosa/efeitos dos fármacos , Dióxido de Silício/química , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade , Propriedades de SuperfícieRESUMO
Inhibition of autophagy has been accepted as a promising therapeutic strategy in cancer, but its clinical application is hindered by lack of effective and specific autophagy inhibitors. We previously identified cepharanthine (CEP) as a novel autophagy inhibitor, which inhibited autophagy/mitophagy through blockage of autophagosome-lysosome fusion in human breast cancer cells. In this study we investigated whether and how inhibition of autophagy/mitophagy by cepharanthine affected the efficacy of chemotherapeutic agent epirubicin in triple negative breast cancer (TNBC) cells in vitro and in vivo. In human breast cancer MDA-MB-231 and BT549 cells, application of CEP (2 µM) greatly enhanced cepharanthine-induced inhibition on cell viability and colony formation. CEP interacted with epirubicin synergistically to induce apoptosis in TNBC cells via the mitochondrial pathway. We demonstrated that co-administration of CEP and epirubicin induced mitochondrial fission in MDA-MB-231 cells, and the production of mitochondrial superoxide was correlated with mitochondrial fission and apoptosis induced by the combination. Moreover, we revealed that co-administration of CEP and epirubicin markedly increased the generation of mitochondrial superoxide, resulting in oxidation of the actin-remodeling protein cofilin, which promoted formation of an intramolecular disulfide bridge between Cys39 and Cys80 as well as Ser3 dephosphorylation, leading to mitochondria translocation of cofilin, thus causing mitochondrial fission and apoptosis. Finally, in mice bearing MDA-MB-231 cell xenografts, co-administration of CEP (12 mg/kg, ip, once every other day for 36 days) greatly enhanced the therapeutic efficacy of epirubicin (2 mg/kg) as compared with administration of either drug alone. Taken together, our results implicate that a combination of cepharanthine with chemotherapeutic agents could represent a novel therapeutic strategy for the treatment of breast cancer.
Assuntos
Fatores de Despolimerização de Actina/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Benzilisoquinolinas/farmacologia , Epirubicina/farmacologia , Dinâmica Mitocondrial/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Antineoplásicos/química , Benzilisoquinolinas/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Epirubicina/química , Humanos , Estrutura Molecular , Oxirredução , Relação Estrutura-Atividade , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Células Tumorais CultivadasRESUMO
Mitochondrial proteins, most of which are encoded in the nucleus and the rest of which are regulated by the mitochondrial genome, play pivotal roles in essential cellular functions. However, fluorescent probes that can be used for monitoring mitochondrial proteins have not yet been widely developed, thereby severely limiting the exploration of the functions of proteins in mitochondria. Towards this end, here we propose a near-infrared (NIR) fluorescence probe MPP to effectively illuminate the dynamic changes in mitochondrial proteins in live cells under oxidative stress, with excellent temporal and spatial resolution. Of particular importance, MPP extends the study of the pharmacology involved in apoptosis induced by anti-cancer drugs (hydroxycamptothecin (HCPT), epirubicin (Epi) and cyclophosphamide (CPA)) for the first time. Furthermore, employing a protein-activatable strategy, this probe could serve as an excellent phototherapeutic agent in photodynamic therapy (PDT). Finally, in vivo experiments suggest that this versatile probe can be used to image tumors in HeLa tumor-bearing mice for 24 h, which demonstrates that our probe could play a dual role as a robust phototherapeutic and imaging agent.
Assuntos
Compostos de Anilina/farmacologia , Antineoplásicos/farmacologia , Corantes Fluorescentes/farmacologia , Proteínas Mitocondriais/análise , Imagem Óptica , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Compostos de Anilina/síntese química , Compostos de Anilina/química , Antineoplásicos/síntese química , Antineoplásicos/química , Camptotecina/análogos & derivados , Camptotecina/química , Camptotecina/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ciclofosfamida/química , Ciclofosfamida/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Epirubicina/química , Epirubicina/farmacologia , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Humanos , Raios Infravermelhos , Estrutura Molecular , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/químicaRESUMO
The interactions of chemotherapeutic drugs with nanocage protein apoferritin (APO) are the key features in the effective encapsulation and release of highly toxic drugs in APO-based controlled drug delivery systems. The encapsulation enables mitigating the drugs' side effects, collateral damage to healthy cells, and adverse immune reactions. Herein, the interactions of anthracycline drugs with APO were studied to assess the effect of drug lipophilicity on their encapsulation excess n and in vitro activity. Anthracycline drugs, including doxorubicin (DOX), epirubicin (EPI), daunorubicin (DAU), and idarubicin (IDA), with lipophilicity P from 0.8 to 15, were investigated. We have found that in addition to hydrogen-bonded supramolecular ensemble formation with n = 24, there are two other competing contributions that enable increasing n under strong polar interactions (APO(DOX)) or under strong hydrophobic interactions (APO(IDA) of the highest efficacy). The encapsulation/release processes were investigated using UV-Vis, fluorescence, circular dichroism, and FTIR spectroscopies. The in vitro cytotoxicity/growth inhibition tests and flow cytometry corroborate high apoptotic activity of APO(drugs) against targeted MDA-MB-231 adenocarcinoma and HeLa cells, and low activity against healthy MCF10A cells, demonstrating targeting ability of nanodrugs. A model for molecular interactions between anthracyclines and APO nanocarriers was developed, and the relationships derived compared with experimental results.
Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Apoferritinas/química , Daunorrubicina/administração & dosagem , Preparações de Ação Retardada/química , Doxorrubicina/administração & dosagem , Epirubicina/administração & dosagem , Antraciclinas/administração & dosagem , Antraciclinas/química , Antraciclinas/farmacologia , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Daunorrubicina/química , Daunorrubicina/farmacologia , Doxorrubicina/química , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos , Epirubicina/química , Epirubicina/farmacologia , Células HeLa , Humanos , Interações Hidrofóbicas e Hidrofílicas , Nanoestruturas/química , Neoplasias/tratamento farmacológicoRESUMO
Epirubicin (EPI) is one of the standard anticancer drugs that apply for various cancers treatment. However, the accumulation of EPI in the human body can be highly toxic, and it causes inevitable harm to organs. As a result, the evaluation of low concentrations of this drug in body samples requires sensitive, rapid, and accurate analysis methods. The fluorescence method is an efficient way in comparison of the traditional methods such as liquid chromatography, capillary electrophoresis, and electrochemical methods. Herein, we synthesized a novel fluorescence nanosensor named CMC-CdTe/ZnS based on using quantum dots (QDs). The structure of the prepared nanosensor is confirmed by different analysis methods such as FT-IR, TGA, and TEM. Besides that, the fluorescence intensity response of CMC-CdTe/ZnS QDs in the presence of Epirubicin drug is investigated. Based on obtained results, not only this nanosensor developed, but also the fluorescence quenching was explained by the typical Stern-Volmer equation. The best linear quenching equation for entitled nanosensor in the presence of Epirubicin is F0/F = 0.0346Q + 1.08 (R2 = 0.99), and the detection limit of Epirubicin is around 0.04 × 10-6 mol/L at 25 °C. All of the results display that this method could be reliable and suitable approach for determination of Epirubicin in commercial samples as well.
Assuntos
Antineoplásicos/análise , Compostos de Cádmio/química , Epirubicina/análise , Nanotecnologia/instrumentação , Pontos Quânticos/química , Sulfetos/química , Telúrio/química , Compostos de Zinco/química , Antineoplásicos/química , Epirubicina/química , Limite de DetecçãoRESUMO
Recent developments on self-propelled microdroplets, moving controllably in response to an external stimulus like chemical, electrical, or magnetic field, have opened a new horizon for smart drug delivery investigations. On the other hand, the new achievements in 3D printing technology has provided a promising option for the fabrication of microfluidic devices, which is an unrivalled platform for in-vitro drug delivery studies. By synergizing the features of chemotaxis, 3D printing, and microfluidic techniques a new approach was introduced to deliver the drug to targeted sites with a well-controlled method and a reasonable speed. A self-propelled ionic liquid ([P6,6,6,14][Cl]) microdroplet, as the drug carrier, was utilised for the targeted delivery of epirubicin anticancer drug within an integrated drug delivery microfluidic system. The asymmetric diffusion of [P6,6,6,14]+ ion from the microdroplet into an aqueous solution with chloride gradient concentration (created under an external electrical field) caused the microdroplet to move. The spatial and temporal position of the moving microdroplet could be controlled by changing the magnitude and polarity of the external electrical field. A piece of hollow-fiber, fixed next to the anode, was filled with phosphate buffer (as the receptor) and used to remove the drug from the carrier. The receptor solution was then taken and injected into a HPLC system for quantification of the released drug. After one-at-a-time optimization of the channel geometry and electrolyte concentration, the experimental variables affecting the drug loading including contact time, pH, and volume of carrier were optimized via a central composite design (CCD) approach.
Assuntos
Sistemas de Liberação de Medicamentos/métodos , Epirubicina , Dispositivos Lab-On-A-Chip , Quimiotaxia , Cromatografia Líquida de Alta Pressão , Epirubicina/análise , Epirubicina/química , Epirubicina/farmacocinética , Desenho de Equipamento , Líquidos Iônicos/química , Impressão TridimensionalRESUMO
Drug repurposing is an alternative avenue for identifying new drugs to treat tuberculosis (TB). Despite the broad-range of anti-tubercular drugs, the emergence of multi-drug-resistant and extensively drug-resistant strains of Mycobacterium tuberculosis (Mtb) H37Rv, as well as the significant death toll globally, necessitates the development of new and effective drugs to treat TB. In this study, we have employed a drug repurposing approach to address this drug resistance problem by screening the drugbank database to identify novel inhibitors of the Mtb target enzyme, DNA gyrase. The compounds were screened against the ATPase domain of the gyrase B subunit (MtbGyrB47), and the docking results showed that echinacoside, doxorubicin, epirubicin, and idarubicin possess high binding affinities against MtbGyrB47. Comprehensive assessment using fluorescence spectroscopy, surface plasmon resonance spectroscopy (SPR), and circular dichroism (CD) titration studies revealed echinacoside as a potent binder of MtbGyrB47. Furthermore, ATPase, and DNA supercoiling assays exhibited an IC50 values of 2.1-4.7â µM for echinacoside, doxorubicin, epirubicin, and idarubicin. Among these compounds, the least MIC90 of 6.3 and 12â µM were observed for epirubicin and echinacoside, respectively, against Mtb. Our findings indicate that echinacoside and epirubicin targets mycobacterial DNA gyrase, inhibit its catalytic cycle, and retard mycobacterium growth. Further, these compounds exhibit potential scaffolds for optimizing novel anti-mycobacterial agents that can act on drug-resistant strains.
Assuntos
Antituberculosos/farmacologia , DNA Girase/metabolismo , Mycobacterium tuberculosis/enzimologia , Adenosina Trifosfatases/metabolismo , Antituberculosos/química , Dicroísmo Circular , Doxorrubicina/química , Doxorrubicina/farmacologia , Desenho de Fármacos , Reposicionamento de Medicamentos/métodos , Epirubicina/química , Epirubicina/farmacologia , Glicosídeos/química , Glicosídeos/farmacologia , Idarubicina/química , Idarubicina/farmacologia , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Relação Estrutura-Atividade , Ressonância de Plasmônio de Superfície , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase II/farmacologiaRESUMO
Anthracycline anticancer drugs show multiple strategies of action on gene functioning by regulation of telomerase enzyme by apoptotic factors, e.g. ceramide level, p53 activity, bcl-2 protein levels, besides inhibiting DNA/RNA synthesis and topoisomerase-II action. We report binding of epirubicin with G-quadruplex (G4) DNA, [d-(TTAGGGT)]4, comprising human telomeric DNA sequence TTAGGG, using 1H and 31P NMR spectroscopy. Diffusion ordered spectroscopy, sequence selective changes in chemical shift (~0.33 ppm) and line broadening in DNA signals suggest formation of a well-defined complex. Presence of sequential nuclear Overhauser enhancements at all base quartet steps and absence of large downfield shifts in 31P resonances preclude intercalative mode of interaction. Restrained molecular dynamics simulations using AMBER force field incorporating intermolecular drug to DNA interproton distances, involving ring D protons of epirubicin depict external binding close to T1-T2-A3 and G6pT7 sites. Binding induced thermal stabilization of G4 DNA (~36 °C), obtained from imino protons and differential scanning calorimetry, is likely to come in the way of telomerase association with telomeres. The findings pave the way for drug-designing with modifications at ring D and daunosamine sugar.
Assuntos
Antineoplásicos/farmacologia , Epirubicina/farmacologia , Quadruplex G/efeitos dos fármacos , Telômero/genética , Antineoplásicos/química , Antineoplásicos/metabolismo , Sequência de Bases , Epirubicina/química , Epirubicina/metabolismo , Humanos , Simulação de Dinâmica Molecular , Conformação de Ácido Nucleico , Desnaturação de Ácido Nucleico , Espectroscopia de Prótons por Ressonância Magnética , Temperatura de TransiçãoRESUMO
Combination therapy using chemically distinct drugs has appeared as one of the promising strategies to improve anticancer treatment efficiency. In the present investigation, poly-(lactic-co-glycolic) acid (PLGA) nanoparticles electrostatically conjugated with polyethylenimine (PEI)-based co-delivery system for epirubicin and paclitaxel (PLGA-PEI-EPI-PTX NPs) has been developed. The PLGA-PEI-EPI-PTX NPs exhibited a monodispersed size distribution with an average size of 240.93 ± 12.70 nm as measured through DLS and 70.8-145 nm using AFM. The zeta potential of 41.95 ± 0.65 mV from -17.45 ± 2.15 mV further confirmed the colloidal stability and PEI modification on PLGA nanoparticles. Encapsulation and loading efficiency along with in vitro release of drug for nanoparticles were done spectrophotometrically. The FTIR analysis of PLGA-PEI-EPI-PTX NPs revealed the involvement of amide moiety between polymer PLGA and PEI. The effect of nanoparticles on the cell migration was also corroborated through wound healing assay. The MTT assay demonstrated that PLGA-PEI-EPI-PTX NPs exhibited considerable anticancer potential as compared to the naïve drugs. Further, p53 protein expression analysed through western blot showed enhanced expression. This study suggests that combination therapy using PLGA-PEI-EPI-PTX NPs represent a potential approach and could offer clinical benefits in the future for lung cancer patients.
Assuntos
Antineoplásicos/química , Portadores de Fármacos/química , Epirubicina/química , Nanopartículas/química , Paclitaxel/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Epirubicina/metabolismo , Epirubicina/farmacologia , Humanos , Concentração de Íons de Hidrogênio , Cinética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Paclitaxel/metabolismo , Paclitaxel/farmacologiaRESUMO
Mesoporous silica nanoparticles with a superparamagnetic iron oxide core were prepared in this work, in order to obtain multifunctional platforms with adequate features for cancer theranostics. Three different core-shell nanocomplexes were obtained: IO-OAm/mSiO2, IO-APTES/mSiO2 and IO/SiO2/mSiO2. In the case of IO-OAm/mSiO2 and IO-APTES/mSiO2, iron oxide (IO) was obtained by thermal decomposition, having in this case a coating of oleylamine (OAm) that was in the second formulation exchanged by (3-aminopropyl)triethoxysilane ligand (APTES). Regarding the IO/SiO2/mSiO2 formulation, iron oxide was synthesized by microemulsion. The mesoporous silica shell (mSiO2) on the IO nanoparticles was obtained by sol-gel and the final materials were dried by supercritical fluids drying. VSM confirmed the superparamagnetic behaviour of the nanoparticles, leading to MS of 4.0, 1.8 and 10.2 emu·g-1, for IO-OAm/mSiO2, IO-APTES/mSiO2 and IO/SiO2/mSiO2, respectively. NMR relaxometry has shown the potential of these nanoparticles to be used as T2 contrast agents, with r2 values as high as 63.93 s-1·mM-1 Fe. The three types of nanoparticles exhibited loading contents of epirubicin of ~3% and drug release percentages of 19% for IO-OAm/mSiO2, 24% for IO-APTES/mSiO2 and 31% for IO/SiO2/mSiO2. The cytotoxicity of drug-loaded and non-loaded most promising nanoparticles was assessed, showing high potential of these platforms for application as anticancer drug carriers.
Assuntos
Antibióticos Antineoplásicos/farmacologia , Epirubicina/farmacologia , Nanopartículas de Magnetita/química , Antibióticos Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Epirubicina/química , Células Hep G2 , Humanos , Tamanho da Partícula , Porosidade , Medicina de Precisão , Dióxido de Silício/químicaRESUMO
In our study, we describe the outcomes of the intercalation of different anthracycline antibiotics in double-stranded DNA at the nanoscale and single molecule level. Atomic force microscopy analysis revealed that intercalation results in significant elongation and thinning of dsDNA molecules. Additionally, using optical tweezers, we have shown that intercalation decreases the stiffness of DNA molecules, that results in greater susceptibility of dsDNA to break. Using DNA molecules with different GC/AT ratios, we checked whether anthracycline antibiotics show preference for GC-rich or AT-rich DNA fragments. We found that elongation, decrease in height and decrease in stiffness of dsDNA molecules was highest in GC-rich dsDNA, suggesting the preference of anthracycline antibiotics for GC pairs and GC-rich regions of DNA. This is important because such regions of genomes are enriched in DNA regulatory elements. By using three different anthracycline antibiotics, namely doxorubicin (DOX), epirubicin (EPI) and daunorubicin (DAU), we could compare their detrimental effects on DNA. Despite their analogical structure, anthracyclines differ in their effects on DNA molecules and GC-rich region preference. DOX had the strongest overall effect on the DNA topology, causing the largest elongation and decrease in height. On the other hand, EPI has the lowest preference for GC-rich dsDNA. Moreover, we demonstrated that the nanoscale perturbations in dsDNA topology are reflected by changes in the microscale properties of the cell, as even short exposition to doxorubicin resulted in an increase in nuclei stiffness, which can be due to aberration of the chromatin organization, upon intercalation of doxorubicin molecules.