RESUMEN
Considering the profound impact of structure on heterojunction catalysts, the rational design of emerging catalysts with optimized energy band structures is required for antitumor efficiency. Herein, we select titanium nitride (TiN) and Pt to develop a multifunctional Schottky heterojunction named Pt/H-TiN&SRF (PHTS) nanoparticles (NPs) with a narrowed bandgap to accomplish "four birds with one stone" involving enzyo/sono/photo three modals and additional ferroptosis. The in situ-grown Pt NPs acted as electron traps that can cause the energy band to bend upward and form a Schottky barrier, thereby facilitating the separation of electron/hole pairs in exogenous stimulation catalytic therapy. In addition, endogenous catalytic reactions based on peroxidase (POD)- and catalase (CAT)-mimicking activities can also be amplified, triggering intense oxidative stress, in which CAT-like activity decomposes endogenous H2O2 into O2 alleviating hypoxia and provides reactants for sonodynamic therapy. Moreover, PHTS NPs can elicit mild photothermal therapy with boosted photothermal properties as well as ferroptosis with loaded ferroptosis inducer sorafenib for effective tumor ablation and apoptosis-ferroptosis synergistic tumor inhibitory effect. In summary, this paper proposes an attractive design for antitumor strategies and highlights findings for heterojunction catalytic therapy with potential in tumor theranostics.
Asunto(s)
Antineoplásicos , Titanio , Animales , Ratones , Antineoplásicos/farmacología , Antineoplásicos/química , Humanos , Titanio/química , Titanio/farmacología , Ferroptosis/efectos de los fármacos , Apoptosis/efectos de los fármacos , Platino (Metal)/química , Platino (Metal)/farmacología , Sorafenib/farmacología , Sorafenib/química , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Terapia Fototérmica , Nanopartículas/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Ratones Endogámicos BALB CRESUMEN
Polydopamine nanoparticles (PDA NPs) are proposed as an anti-cancer tool against hepatocellular carcinoma through the combination of near-infrared (NIR)-mediated hyperthermia and loading with a chemotherapeutic drug, sorafenib (SRF). Cell membranes isolated from a liver cancer cell line (HepG2) have been exploited for the coating of the nanoparticles (thus obtaining CM-SRF-PDA NPs), to promote homotypic targeting toward cancer cells. The selective targeting ability and the combined photothermal and chemotherapeutic activity of the CM-SRF-PDA NPs following NIR irradiation have been evaluated on cell cultures in static and dynamic conditions, besides three-dimensional culture models. Eventually, the therapeutic effectiveness of the proposed approach has also been tested ex ovo on HepG2 spheroid-grafted quail embryos. This comprehensive investigation, supported by proteomic analysis, showed the effectiveness of the proposed nanoplatform and strongly suggests further pre-clinical testing in the treatment of liver cancer.
Asunto(s)
Antineoplásicos , Indoles , Neoplasias Hepáticas , Nanopartículas , Terapia Fototérmica , Polímeros , Indoles/química , Indoles/farmacología , Polímeros/química , Polímeros/farmacología , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/patología , Nanopartículas/química , Nanopartículas/uso terapéutico , Células Hep G2 , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Sorafenib/química , Sorafenib/farmacología , Sorafenib/uso terapéutico , Supervivencia Celular/efectos de los fármacosRESUMEN
Drug delivery is the process or method of delivering a pharmacological product to have therapeutic effects on humans or animals. The use of nanoparticles to deliver medications to cells is driving the present surge in interest in improving human health. Green nanodrug delivery methods are based on chemical processes that are acceptable for the environment or that use natural biomaterials such as plant extracts and microorganisms. In this study, zinc oxide-superparamagnetic iron oxide-silver nanocomposite was synthesized via green synthesis method using Fusarium oxysporum fungi mycelia then loaded with sorafenib drug. The synthesized nanocomposites were characterized by UV-visibile spectroscopy, FTIR, TEM and SEM techniques. Sorafenib is a cancer treatment and is also known by its brand name, Nexavar. Sorafenib is the only systemic medication available in the world to treat hepatocellular carcinoma. Sorafenib, like many other chemotherapeutics, has side effects that restrict its effectiveness, including toxicity, nausea, mucositis, hypertension, alopecia, and hand-foot skin reaction. In our study, 40 male albino rats were given a single dose of diethyl nitrosamine (DEN) 60 mg/kg b.wt., followed by carbon tetrachloride 2 ml/kg b.wt. twice a week for one month. The aim of our study is using the zinc oxide-superparamagnetic iron oxide-silver nanocomposite that was synthesized by Fusarium oxysporum fungi mycelia as nanocarrier for enhancement the sorafenib anticancer effect.
Asunto(s)
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Plata , Sorafenib , Óxido de Zinc , Animales , Sorafenib/farmacología , Sorafenib/química , Sorafenib/administración & dosificación , Óxido de Zinc/química , Óxido de Zinc/farmacología , Plata/química , Ratas , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/administración & dosificación , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Masculino , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Portadores de Fármacos/química , Fusarium/efectos de los fármacos , Nanopartículas de Magnetita/química , Nanocompuestos/química , Humanos , Nanopartículas Magnéticas de Óxido de Hierro/químicaRESUMEN
Cancer remains a leading cause of death worldwide, often resulting from uncontrolled growth in various organs. Protein kinase inhibitors represent an important class of targeted cancer therapies. Recently, the kinases BRAF and VEGFR-2 have shown synergistic effects on tumor progression. Seeking to develop dual BRAF/VEGFR-2 inhibitors, we synthesized 18 amino-benzothiazole derivatives with structural similarities to reported dual inhibitors. Four compounds-4a, 4f, 4l, and 4r-demonstrated remarkable cytotoxicity, with IC50 values ranging from 3.58 to 15.36 µM, against three cancer cell lines. Furthermore, these compounds showed IC50 values of 38.77-66.22 µM in the case of a normal cell line, which was significantly safer than the reference, sorafenib. Subsequent investigation revealed that compound 4f exhibited the capacity to inhibit the BRAF and VEGFR-2 enzymes, with IC50 values similar to sorafenib (0.071 and 0.194 µM, respectively). Moreover, compound 4f caused G2-M- and S-phase cycle arrest. Molecular modeling demonstrated binding patterns compatible with inhibition for both targets, where 4f exerted the critical interactions in the BRAF site and interacted in the VEGFR-2 site in a manner akin to sorafenib, demonstrating affinity similar to dabrafenib.
Asunto(s)
Antineoplásicos , Benzotiazoles , Proliferación Celular , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas , Proteínas Proto-Oncogénicas B-raf , Tiadiazoles , Receptor 2 de Factores de Crecimiento Endotelial Vascular , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Humanos , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/síntesis química , Benzotiazoles/química , Benzotiazoles/farmacología , Benzotiazoles/síntesis química , Tiadiazoles/química , Tiadiazoles/farmacología , Tiadiazoles/síntesis química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Diseño de Fármacos , Relación Estructura-Actividad , Sorafenib/farmacología , Sorafenib/química , Estructura Molecular , Simulación por Computador , Ensayos de Selección de Medicamentos AntitumoralesRESUMEN
Prostate cancer (PCa) with a high incidence worldwide is a serious threat to men's health. Despite the continuous development of treatment strategies for PCa in recent years, the long-term prognosis of patients is still poor. Hence, the discovery and development of novel, secure, and efficient therapeutic approaches hold significant clinical significance. Although sorafenib (SOR) displays potential as a therapeutic option for PCa, its clinical efficacy is hindered by drug resistance, limited water solubility, and rapid metabolism. Therefore, we proposed to prepare nanoparticles (named SOR@8P4 NPs) utilizing the phenylalanine-based poly(ester amide) polymer (8P4) as the drug carrier to enhance the solubility and drug stability of SOR and improve the therapeutic targeting and bioavailability. SOR@8P4 NPs had high stability and showed acid-responsive drug release at the acidic tumor microenvironment. Additionally, SOR@8P4 NPs demonstrated more remarkable anticancer, antimetastatic, and antiproliferative abilities in vitro, compared with those of free drugs. SOR@8P4 NPs showed high tumor targeting and significantly inhibited tumor growth in vivo. In summary, the drug delivery system of SOR@8P4 NPs provides new ideas for the clinical treatment of PCa.
Asunto(s)
Antineoplásicos , Nanopartículas , Neoplasias de la Próstata , Sorafenib , Masculino , Sorafenib/uso terapéutico , Sorafenib/farmacología , Sorafenib/química , Sorafenib/farmacocinética , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Nanopartículas/química , Nanopartículas/uso terapéutico , Humanos , Animales , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Poliésteres/química , Ratones , Portadores de Fármacos/química , Amidas/química , Amidas/uso terapéutico , Amidas/farmacología , Liberación de Fármacos , Proliferación Celular/efectos de los fármacos , Ratones Desnudos , Ratones Endogámicos BALB CRESUMEN
The existing kinase inhibitors for hepatocellular carcinoma (HCC) have conferred survival benefits but are hampered by adverse effects and drug resistance, necessitating the development of novel agents targeting distinct pathways. To discover potent new anti-HCC compounds, we leveraged scaffold hopping from Sorafenib and introduced morpholine/piperidine moieties to develop ureido-substituted 4-phenylthiazole analogs with optimized physicochemical properties and binding interactions. Notably, compound 27 exhibited potent cytotoxicity against HepG2 cells (IC50 = 0.62 ± 0.34 µM), significantly exceeding Sorafenib (IC50 = 1.62 ± 0.27 µM). Mechanistic investigations revealed that compound 27 potently inhibited HCC cell migration and colony formation, and it induced G2/M arrest and early-stage apoptosis. Kinase profiling revealed IGF1R as a key target, which compound 27 potently inhibited (76.84% at 10 µM). Molecular modeling substantiated compound 27's strong binding to IGF1R via multiple hydrogen bonds. Computational predictions indicate favorable drug-like properties for compound 27. These findings provide a promising drug candidate for the treatment of HCC patients.
Asunto(s)
Antineoplásicos , Apoptosis , Proliferación Celular , Inhibidores de Proteínas Quinasas , Receptor IGF Tipo 1 , Tiazoles , Humanos , Receptor IGF Tipo 1/antagonistas & inhibidores , Receptor IGF Tipo 1/metabolismo , Proliferación Celular/efectos de los fármacos , Células Hep G2 , Tiazoles/química , Tiazoles/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Apoptosis/efectos de los fármacos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/metabolismo , Movimiento Celular/efectos de los fármacos , Relación Estructura-Actividad , Simulación del Acoplamiento Molecular , Receptores de Somatomedina/antagonistas & inhibidores , Receptores de Somatomedina/metabolismo , Estructura Molecular , Línea Celular Tumoral , Sorafenib/farmacología , Sorafenib/química , Modelos MolecularesRESUMEN
Photodynamic therapy (PDT) using aggregation-induced emission photosensitizer (AIE-PS) holds tremendous potential but is limited by its inherent disadvantages and the high concentrations of reduced glutathione (GSH) in tumor cells that can neutralize ROS to weaken PDT. Herein, we designed a nanodelivery system (CM-HSADSP@[PS-Sor]) in which albumin was utilized as a carrier for hydrophobic drug AIE-PS and Sorafenib, cross-linkers with disulfide bonds were introduced to form a nanogel core, and then cancer cell membranes were wrapped on its surface to confer homologous tumor targeting ability. A two-way strategy was employed to disturb redox-homeostasis through blocking GSH synthesis by Sorafenib and consuming excess GSH via abundant disulfide bonds, thereby promoting the depletion of GSH, which in turn increased the ROS levels in cancer cells to amplify the efficacy of ferroptosis and PDT, achieving an efficient in vivo antibreast cancer effect. This study brings a new strategy for ROS-based cancer therapy and expands the application of an albumin-based drug delivery system.
Asunto(s)
Ferroptosis , Oxidación-Reducción , Fotoquimioterapia , Fármacos Fotosensibilizantes , Ferroptosis/efectos de los fármacos , Fotoquimioterapia/métodos , Humanos , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Fármacos Fotosensibilizantes/química , Animales , Especies Reactivas de Oxígeno/metabolismo , Ratones , Línea Celular Tumoral , Glutatión/metabolismo , Homeostasis/efectos de los fármacos , Nanopartículas/química , Nanopartículas/uso terapéutico , Neoplasias/tratamiento farmacológico , Ratones Endogámicos BALB C , Sistemas de Liberación de Medicamentos/métodos , Sorafenib/farmacología , Sorafenib/uso terapéutico , Sorafenib/químicaRESUMEN
Photodynamic therapy (PDT) and ferroptosis show significant potential in tumor treatment. However, their therapeutic efficacy is often hindered by the oxygen-deficient tumor microenvironment and the challenges associated with efficient intracellular drug delivery into tumor cells. Toward this end, this work synthesized perfluorocarbon (PFC)-modified Pluronic F127 (PFC-F127), and then exploits it as a carrier for codelivery of photosensitizer Chlorin e6 (Ce6) and the ferroptosis promoter sorafenib (Sor), yielding an oxygen self-supplying nanoplatform denoted as Ce6-Sor@PFC-F127. The PFCs on the surface of the micelle play a crucial role in efficiently solubilizing and delivering oxygen as well as increasing the hydrophobicity of the micelle surface, giving rise to enhanced endocytosis by cancer cells. The incorporation of an oxygen-carrying moiety into the micelles enhances the therapeutic impact of PDT and ferroptosis, leading to amplified endocytosis and cytotoxicity of tumor cells. Hypotonic saline technology was developed to enhance the cargo encapsulation efficiency. Notably, in a murine tumor model, Ce6-Sor@PFC-F127 effectively inhibited tumor growth through the combined use of oxygen-enhanced PDT and ferroptosis. Taken together, this work underscores the promising potential of Ce6-Sor@PFC-F127 as a multifunctional therapeutic nanoplatform for the codelivery of multiple cargos such as oxygen, photosensitizers, and ferroptosis inducers.
Asunto(s)
Antineoplásicos , Clorofilidas , Ensayos de Selección de Medicamentos Antitumorales , Ferroptosis , Fluorocarburos , Micelas , Oxígeno , Fotoquimioterapia , Fármacos Fotosensibilizantes , Ferroptosis/efectos de los fármacos , Fluorocarburos/química , Fluorocarburos/farmacología , Animales , Ratones , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/síntesis química , Humanos , Oxígeno/química , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Ensayo de Materiales , Tamaño de la Partícula , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Materiales Biocompatibles/síntesis química , Porfirinas/química , Porfirinas/farmacología , Supervivencia Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Ratones Endogámicos BALB C , Sorafenib/química , Sorafenib/farmacología , Sorafenib/administración & dosificación , Poloxámero/química , Línea Celular Tumoral , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/patología , Neoplasias Experimentales/metabolismo , Estructura MolecularRESUMEN
As a famous drug delivery system (DDS), mesoporous organosilica nanoparticles (MON) are degraded slowly in vivo and the degraded components are not useful for cell nutrition or cancer theranostics, and superparamagnetic iron oxide nanoparticles (SPION) are not mesoporous with low drug loading content (DLC). To overcome the problems of MON and SPION, we developed mesoporous SPIONs (MSPIONs) with an average diameter of 70 nm and pore size of 3.9 nm. Sorafenib (SFN) and/or brequinar (BQR) were loaded into the mesopores of MSPION, generating SFN@MSPION, BQR@MSPION and SFN/BQR@MSPION with high DLC of 11.5% (SFN), 10.1% (BQR) and 10.0% (SNF + BQR), demonstrating that our MSPION is a generic DDS. SFN/BQR@MSPION can be used for high performance ferroptosis therapy of tumors because: (1) the released Fe2+/3+ in tumor microenvironment (TME) can produce â¢OH via Fenton reaction; (2) the released SFN in TME can inhibit the cystine/glutamate reverse transporter, decrease the intracellular glutathione (GSH) and GSH peroxidase 4 levels, and thus enhance reactive oxygen species and lipid peroxide levels; (3) the released BQR in TME can further enhance the intracellular oxidative stress via dihydroorotate dehydrogenase inhibition. The ferroptosis therapeutic mechanism, efficacy and biosafety of MSPION-based DDS were verified on tumor cells and tumor-bearing mice.
Asunto(s)
Sistemas de Liberación de Medicamentos , Ferroptosis , Nanopartículas Magnéticas de Óxido de Hierro , Sorafenib , Ferroptosis/efectos de los fármacos , Animales , Nanopartículas Magnéticas de Óxido de Hierro/química , Ratones , Humanos , Sistemas de Liberación de Medicamentos/métodos , Sorafenib/farmacología , Sorafenib/química , Sorafenib/uso terapéutico , Línea Celular Tumoral , Microambiente Tumoral/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Porosidad , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Ratones Endogámicos BALB CRESUMEN
BACKGROUND: VEGFR-2 has emerged as a prominent positive regulator of cancer progression. AIM: Discovery of new anticancer agents and apoptotic inducers targeting VEGFR-2. METHODS: Design and synthesis of new thiazolidine-2,4-diones followed by extensive in vitro studies, including VEGFR-2 inhibition assay, MTT assay, apoptosis analysis, and cell migration assay. In silico investigations including docking, MD simulations, ADMET, toxicity, and DFT studies were performed. RESULTS: Compound 15 showed the strongest VEGFR-2 inhibitory activity with an IC50 value of 0.066 µM. Additionally, most of the synthesized compounds showed anti-proliferative activity against HepG2 and MCF-7 cancer cell lines at the micromolar range with IC50 values ranging from 0.04 to 4.71 µM, relative to sorafenib (IC50 = 2.24 ± 0.06 and 3.17 ± 0.01 µM against HepG2 and MCF-7, respectively). Also, compound 15 showed selectivity indices of 1.36 and 2.08 against HepG2 and MCF-7, respectively. Furthermore, compound 15 showed a significant apoptotic effect and arrested the cell cycle of MCF-7 cells at the S phase. Moreover, compound 15 had a significant inhibitory effect on the ability of MCF-7 cells to heal from. Docking studies revealed that the synthesized thiazolidine-2,4-diones have a binding pattern approaching sorafenib. MD simulations indicated the stability of compound 15 in the active pocket of VEGFR-2 for 200 ns. ADMET and toxicity studies indicated an acceptable pharmacokinetic profile. DFT studies confirmed the ability of compound 15 to interact with VEGFR-2. CONCLUSION: Compound 15 has promising anticancer activity targeting VEGFR-2 with significant activity as an apoptosis inducer.
Asunto(s)
Antineoplásicos , Apoptosis , Proliferación Celular , Diseño de Fármacos , Simulación del Acoplamiento Molecular , Tiazolidinedionas , Receptor 2 de Factores de Crecimiento Endotelial Vascular , Humanos , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Tiazolidinedionas/farmacología , Tiazolidinedionas/química , Tiazolidinedionas/síntesis química , Células MCF-7 , Células Hep G2 , Proliferación Celular/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Ensayos de Selección de Medicamentos Antitumorales , Sorafenib/farmacología , Sorafenib/química , Simulación de Dinámica Molecular , Movimiento Celular/efectos de los fármacosRESUMEN
Therapeutic approaches for triple-negative breast cancer (TNBC) have been continuously advancing, but inadequate control over release behavior, insufficient tumor selectivity, and limited drug availability continue to impede therapeutic outcomes in nanodrug systems. In this study, we propose a general hydrophobic antineoplastic delivery system, termed spatiotemporally-controlled hydrophobic antineoplastic delivery system (SCHADS) for enhanced TNBC treatment. The key feature of SCHADS is the formation of metastable photosensitive-antineoplastic complexes (PACs) through the self-assembly of hydrophobic drugs driven by photosensitive molecules. With the further decoration of tumor-targeting peptides coupled with the EPR effect, the PACs tend to accumulate in the tumor site tremendously, promoting drug delivery efficiency. Meanwhile, the disassembly behavior of the metastable PACs could be driven by light on demand to achieve in situ drug release, thus promoting chemotherapeutics availability. Furthermore, the abundant ROS generated by the photosensitizer could effectively kill tumor cells, ultimately realizing an effective combination of photodynamic and chemotherapeutic therapy. As an exemplary presentation, chlorin e6 has been chosen to drive the formation of PACs with the system xc- inhibitor sorafenib. Compared with pure drug treatment, the PACs with the above-described preponderances exhibit superior therapeutic effects both in vitro and in vivo and circumvent the side effects due to off-target. By manipulating the laser irradiation, the PACs-treated cell death mechanism could be dynamically regulated, thus providing the potential to remedy intrinsic/acquired resistance of tumor. Collectively, this SCHADS achieves spatio-temporal control of the drug that greatly enhances the availability of anticarcinogen and realizes synergistic antitumor effect in TNBC treatment, even ultimately being extended to the treatment of other types of tumors.
Asunto(s)
Antineoplásicos , Sistemas de Liberación de Medicamentos , Interacciones Hidrofóbicas e Hidrofílicas , Fármacos Fotosensibilizantes , Porfirinas , Neoplasias de la Mama Triple Negativas , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Fármacos Fotosensibilizantes/administración & dosificación , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Femenino , Animales , Humanos , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Porfirinas/administración & dosificación , Porfirinas/química , Clorofilidas , Ratones Desnudos , Ratones Endogámicos BALB C , Fotoquimioterapia/métodos , Sorafenib/administración & dosificación , Sorafenib/farmacología , Sorafenib/química , Liberación de FármacosRESUMEN
In the course of antitumor therapy, the complex tumor microenvironment and drug-mediated changes in cell signaling and biological processes lead to drug resistance. The effect of sorafenib is greatly limited by the specific tumor microenvironment induced by antiangiogenic therapy and ferroptosis resistance induced by the upregulation of nuclear factor erythroid-2 related factor 2 (NRF2). In this study, a pH responsive and amphiphilic hyperbranched polyglycerol, HDP, is synthesized based on a co-graft click chemistry pathway. This nano-scale carrier provides excellent drug-loading capacity, storing stability and pH responsibility, and effectively co-delivery of sorafenib and siRNA. Sorafenib and siNRF2 plays a greatly synergistic effect in inducing reactive oxygen species (ROS), iron overloading, depleting glutathione (GSH), and promoting lipid peroxidation. Importantly, verified in two different animal experiments, HDP-ss (HDP loaded with both siNRF2 and sorafenib) presents a superior anti-tumor effect, by achieving a tumor inhibition rate of ≈94%. Thus, HDP can serve as an excellent targeted delivery nanocarrier with good biocompatibility in antitumor therapy, and combined application of siNRF2 effectively improves the antitumor effect of sorafenib by overcoming NRF2-mediated ferroptosis resistance. Taken together, this study provides a novel therapeutic strategy to combat the drug resistance in antiangiogenic therapy and ferroptosis.
Asunto(s)
Carcinoma Hepatocelular , Ferroptosis , Neoplasias Hepáticas , Factor 2 Relacionado con NF-E2 , Sorafenib , Sorafenib/farmacología , Sorafenib/química , Ferroptosis/efectos de los fármacos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/metabolismo , Humanos , Animales , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Portadores de Fármacos/química , Especies Reactivas de Oxígeno/metabolismo , Nanopartículas/química , Línea Celular Tumoral , Ratones , Glutatión/metabolismoRESUMEN
In addition to early detection, early diagnosis, and early surgery, it is of great significance to use new strategies for the treatment of hepatocellular carcinoma (HCC). Studies showed that the combination of sorafenib (SFN) and triptolide (TPL) could reduce the clinical dose of SFN and maintain good anti-HCC effect. But the solubility of SFN and TPL in water is low and both drugs have certain toxicity. Therefore, we constructed a biomimetic nanosystem based on cancer cell-platelet (PLT) hybrid membrane camouflage to co-deliver SFN and TPL taking advantage of PLT membrane with long circulation functions and tumor cell membrane with homologous targeting. The biomimetic nanosystem, SFN and TPL loaded cancer cell-PLT hybrid membrane-camouflaged liquid crystalline lipid nanoparticles ((SFN + TPL)@CPLCNPs), could simultaneously load SFN and TPL at the molar ratio of SFN to TPL close to 10:1. (SFN + TPL)@CPLCNPs achieved long circulation function and tumor targeting at the same time, promoting tumor cell apoptosis, inhibiting tumor growth, and achieving a better "synergy and attenuation effect", which provided new ideas for the treatment of HCC.
Asunto(s)
Carcinoma Hepatocelular/metabolismo , Diterpenos , Liposomas , Neoplasias Hepáticas/metabolismo , Nanopartículas , Fenantrenos , Sorafenib , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Materiales Biomiméticos/química , Plaquetas/química , Línea Celular Tumoral , Membrana Celular/química , Diterpenos/química , Diterpenos/farmacocinética , Diterpenos/farmacología , Compuestos Epoxi/química , Compuestos Epoxi/farmacocinética , Compuestos Epoxi/farmacología , Humanos , Liposomas/química , Liposomas/farmacocinética , Liposomas/toxicidad , Masculino , Ratones , Ratones Endogámicos BALB C , Nanomedicina , Nanopartículas/química , Nanopartículas/toxicidad , Fenantrenos/química , Fenantrenos/farmacocinética , Fenantrenos/farmacología , Células RAW 264.7 , Sorafenib/química , Sorafenib/farmacocinética , Sorafenib/farmacologíaRESUMEN
Sorafenib is a multikinase inhibitor widely used in cancer therapy with an antitumour effect related to biological processes as proliferation, migration or invasion, among others. Initially designed as a Raf inhibitor, Sorafenib was later shown to also block key molecules in tumour progression such as VEGFR and PDGFR. In addition, sorafenib has been connected with key signalling pathways in cancer such as EGFR/EGF. However, no definitive clue about the molecular mechanism linking sorafenib and EGF signalling pathway has been established so far. Our data in HeLa, U2OS, A549 and HEK293T cells, based on in silico, chemical and genetic approaches demonstrate that the MEK5/ERK5 signalling pathway is a novel target of sorafenib. In addition, our data show how sorafenib is able to block MEK5-dependent phosphorylation of ERK5 in the Ser218/Tyr220, affecting the transcriptional activation associated with ERK5. Moreover, we demonstrate that some of the effects of this kinase inhibitor onto EGF biological responses, such as progression through cell cycle or migration, are mediated through the effect exerted onto ERK5 signalling pathway. Therefore, our observations describe a novel target of sorafenib, the ERK5 signalling pathway, and establish new mechanistic insights for the antitumour effect of this multikinase inhibitor.
Asunto(s)
Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Proteína Quinasa 7 Activada por Mitógenos/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Sorafenib/farmacología , Biomarcadores de Tumor , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular , Susceptibilidad a Enfermedades , Factor de Crecimiento Epidérmico/metabolismo , Citometría de Flujo , Humanos , Proteína Quinasa 7 Activada por Mitógenos/química , Terapia Molecular Dirigida , Inhibidores de Proteínas Quinasas/química , Transducción de Señal/efectos de los fármacos , Sorafenib/química , Relación Estructura-ActividadRESUMEN
There are current attempts to find a safe substitute or adjuvant for Sorafenib (Sorf), the standard treatment for advanced hepatocellular carcinoma (HCC), as it triggers very harsh side effects and drug-resistance. The therapeutic properties of Bee Venom (BV) and its active component, Melittin (Mel), make them suitable candidates as potential anti-cancer agents per-se or as adjuvants for cancer chemotherapy. Hence, this study aimed to evaluate the combining effect of BV and Mel with Sorf on HepG2 cells and to investigate their molecular mechanisms of action. Docking between Mel and different tumor-markers was performed. The cytotoxicity of BV, Mel and Sorf on HepG2 and THLE-2 cells was conducted. Combinations of BV/Sorf and Mel/Sorf were performed in non-constant ratios on HepG2. Expression of major cancer-related genes and oxidative stress status was evaluated and the cell cycle was analyzed. The computational analysis showed that Mel can bind to and inhibit XIAP, Bcl2, MDM2, CDK2 and MMP12. Single treatments of BV, Mel and Sorf on HepG2 showed lower IC50than on THLE-2. All combinations revealed a synergistic effect at a combination index (CI) < 1. Significant upregulation (p < 0.05) of p53, Bax, Cas3, Cas7 and PTEN and significant downregulation (p < 0.05) of Bcl-2, Cyclin-D1, Rac1, Nf-κB, HIF-1a, VEGF and MMP9 were observed. The oxidative stress markers including MDA, SOD, CAT and GPx showed insignificant changes, while the cell cycle was arrested at G2/M phase. In conclusion, BV and Mel have a synergistic anticancer effect with Sorf on HepG2 that may represent a new enhancing strategy for HCC treatment.
Asunto(s)
Antineoplásicos/farmacología , Venenos de Abeja/farmacología , Meliteno/farmacología , Sorafenib/farmacología , Antineoplásicos/química , Venenos de Abeja/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células Hep G2 , Humanos , Peroxidación de Lípido/efectos de los fármacos , Meliteno/química , Simulación del Acoplamiento Molecular , Estructura Molecular , Sorafenib/química , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Sorafenib is recommended as the primary therapeutic drug for patients with hepatocellular carcinoma. To discover a new compound that avoids low response rates and toxic side effects that occur in sorafenib therapy, we designed and synthesized new hybrid compounds of sorafenib and 2,4,5-trimethylpyridin-3-ols. Compound 6 was selected as the best of 24 hybrids that inhibit each of the four Raf kinases. The anti-proliferative activity of 6 in HepG2, Hep3B, and Huh7 cell lines was slightly lower than that of sorafenib. However, in H6c7 and CCD841 normal epithelial cell lines, the cytotoxicity of 6 was much lower than that of sorafenib. In addition, similar to sorafenib, compound 6 inhibited spheroid forming ability of Hep3B cells in vitro and tumour growth in a xenograft tumour model of the chick chorioallantoic membrane implanted with Huh7 cells. Compound 6 may be a promising candidate targeting hepatocellular carcinoma with low toxic side effects on normal cells.
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Antineoplásicos/farmacología , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Pirimidinas/química , Sorafenib/química , Animales , Antineoplásicos/química , Línea Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Embrión de Pollo , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Sorafenib (Sor) is an oral multi-kinase inhibitor, but its water solubility is very low. To improve its solubility, sorafenib hydrochloride hydrate, sorafenib hydrobromide and sorafenib hydrobromide hydrate were prepared in the mixed solvent of the corresponding acid solution, and tetrahydrofuran (THF). The crystal structures of sorafenib hydrochloride trihydrate (Sor·HCl.3H2O), 4-(4-{3-[4-chloro-3-(trifluoro-methyl)phenyl]ureido}phenoxy)-2-(N-methylcarbamoyl) pyridinium hydrochloride trihydrate, C21H17ClF3N4O3+·Cl-.3H2O (I), sorafenib hydrochloride monohydrate (Sor·HCl.H2O), C21H17ClF3N4O3+·Cl-.H2O (II), its solvated form (sorafenib hydrochloride monohydrate monotetrahydrofuran (Sor·HCl.H2O.THF), C21H17ClF3N4O3+·Cl-.H2O.C4H8O (III)), sorafenib hydrobromide (Sor·HBr), 4-(4-{3-[4-chloro-3-(trifluoro-methyl)phenyl]ureido}phenoxy)-2-(N-methylcarbamoyl) pyridinium hydrobromide, C21H17ClF3N4O3+·Br- (IV) and sorafenib hydrobromide monohydrate (Sor·HBr.H2O), C21H17ClF3N4O3+·Br-.H2O (V) were analysed. Their hydrogen bond systems and topologies were investigated. The results showed the distinct roles of water molecules in stabilizing their crystal structures. Moreover, (II) and (V) were isomorphous crystal structures with the same space group P21/n, and similar unit cell dimensions. The predicted morphologies of these forms based on the BFDH model matched well with experimental morphologies. The energy frameworks showed that (I), and (IV) might have better tabletability than (II) and (V). Moreover, the solubility and dissolution rate data exhibited an improvement in the solubility of these salts compared with the free drug.
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Antineoplásicos/química , Enlace de Hidrógeno , Inhibidores de Proteínas Quinasas/química , Sorafenib/química , Antineoplásicos/farmacología , Cristalografía por Rayos X , Cristales Líquidos/química , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/farmacología , Solubilidad , Sorafenib/farmacología , Análisis EspectralRESUMEN
The dissolution rate is the rate-limiting step for Biopharmaceutics Classification System (BCS) class II drugs to enhance their in vivo pharmacokinetic behaviors. There are some factors affecting the dissolution rate, such as polymorphism, particle size, and crystal habit. In this study, to improve the dissolution rate and enhance the in vivo pharmacokinetics of sorafenib tosylate (Sor-Tos), a BCS class II drug, two crystal habits of Sor-Tos were prepared. A plate-shaped crystal habit (ST-A) and a needle-shaped crystal habit (ST-B) were harvested by recrystallization from acetone (ACN) and n-butanol (BuOH), respectively. The surface chemistry of the two crystal habits was determined by powder X-ray diffraction (PXRD) data, molecular modeling, and face indexation analysis, and confirmed by X-ray photoelectron spectroscopy (XPS) data. The results showed that ST-B had a larger hydrophilic surface than ST-A, and subsequently a higher dissolution rate and a substantial enhancement of the in vivo pharmacokinetic performance of ST-B.
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Solubilidad/efectos de los fármacos , Sorafenib/química , Acetona/química , Biofarmacia/métodos , Química Farmacéutica/métodos , Cristalización/métodos , Interacciones Hidrofóbicas e Hidrofílicas , Tamaño de la Partícula , Polvos/química , Difracción de Rayos X/métodosRESUMEN
With the developments of nanodrugs, some drugs have combined with nanoparticles (NPs) to reduce their side-effects and increase their therapeutic activities. Here, a novel nanodrug platinum nanoparticle-sorafenib (PtNP-SOR) was proposed for the first time. By means of molecular dynamics simulation, the stability and biocompatibility of PtNP-SOR were investigated. Then, the interaction mechanism between PtNP-SOR and vascular endothelial growth factor receptor 2 (VEGFR2) was explored and compared with that of the peptide 2a coated PtNPs. The results showed that PtNP-SOR could bind to VEGFR2 more stably, which was driven by the Coulombic and strong dispersion interaction between PtNP-SOR and VEGFR2. According to their contributions obtained from the decomposition of binding free energies, the key residues in VEGFR2 were identified to form the specific space, which increased the affinity with PtNP-SOR. This study provided useful insights to the design of PtNP-drugs as well as important theoretical proofs to the interaction between PtNP-SOR and VEGFR2 at a molecular level, which can be of large help during the development and optimization of novel nanodrugs.
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Nanopartículas del Metal/química , Platino (Metal)/química , Sorafenib/química , Sorafenib/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Estabilidad de Medicamentos , Humanos , Simulación del Acoplamiento Molecular/métodos , Simulación de Dinámica Molecular , Proteínas de Neurofilamentos/metabolismo , Fragmentos de Péptidos/metabolismoRESUMEN
A series of 1,2,3-triazole-containing Sorafenib analogues, in which the aryl urea moiety of Sorafenib (1) was replaced with a 1,2,3-triazole ring linking a substituted phenoxy fragment, were prepared successfully via Huisgen 1,3-dipolar cycloaddition and nucleophilic aromatic substitution. The studies of cytotoxicity towards human hepatocellular carcinoma (HCC) cell lines, HepG2 and Huh7, indicated that p-tert-butylphenoxy analogue 2m showed significant inhibitory activity against Huh7 with IC50 = 5.67 ± 0.57 µM. More importantly, 2m showed low cytotoxicity against human embryonal lung fibroblast cell line, MRC-5, with IC50 > 100 µM, suggesting its highly selective cytotoxic activity (SI > 17.6) towards Huh7 which is much superior to that of Sorafenib (SI = 6.73). The molecular docking studies revealed that the analogue 2m bound B-RAF near the binding position of Sorafenib, while it interacted VEGFR2 efficiently at the same binding position of Sorafenib. However, 2m exhibited moderate inhibitory activity toward B-RAF, implying that its anti-Huh7 effect might not strictly relate to inhibition of B-RAF. Wound healing and BrdU cell proliferation assays confirmed anti-cell migration and anti-cell proliferative activities towards Huh7. With its inhibitory efficiency and high safety profile, 2m has been identified as a promising candidate for the treatment of HCC.