RESUMEN
Peroxidase (POD)-like nanozymes have been found to act as nanoreactors for the generation of reactive oxygen species (ROS) to resolve drug resistance in the tumor microenvironment (TME). Amplifying cellular oxidative stress is considered to be a drug-free strategy to efficiently induce apoptosis in tumor cells. However, the limited content of intracellular hydrogen peroxide (H2O2) extremely restricts the performance of POD-like nanozymes to amplify cellular oxidative stress. Moreover, additional operational processes combined with exogenous reagents to achieve oxidative stress lead to a dilemma of extra cytotoxicity. Here, an integrated iron-porphyrin-MOF-based nanozyme composite named HA@GOx@PCN-224(Fe) (HGPF) was precisely designed and constructed. Generally, the POD-like nanozyme PCN-224(Fe) was used as a platform to immobilize glucose oxidase (GOx), and further embedded with hyaluronic acid (HA) to enable the targeting ability of tumor cells. When endocytosed by tumor cells, intracellular glucose was oxidized to H2O2 and gluconic acid catalyzed by immobilized GOx of HGPF. Afterwards, inspired by heme analogs, H2O2 was catalyzed by iron-porphyrin active sites of the HGPF nanozyme to generate hydroxyl radicals (ËOH). Under light irradiation, the iron-porphyrin of HGPF acted as a photosensitizer to facilely produce singlet oxygen (1O2). Such a synergistic generation of ROS strikingly amplified oxidative stress and induced severe apoptosis in tumor cells. HGPF was expected to integrate intracellular oxygen sources and overcome the dilemma of limited intracellular H2O2 content. Consequently, HGPF was constructed as an integrated nanoreactor to simultaneously achieve light-enhanced catalytic oxidation cascades, providing a promising strategy for a synergistic amplification of cellular oxidative stress.
Asunto(s)
Porfirinas , Porfirinas/farmacología , Especies Reactivas de Oxígeno , Peróxido de Hidrógeno , Estrés Oxidativo , Peroxidasa , Peroxidasas , Catálisis , Colorantes , Glucosa Oxidasa , Ácido HialurónicoRESUMEN
To minimize unwanted reactions with high concentrations of reduced glutathione (GSH) in the tumor microenvironment (TME) during chemodynamic therapy (CDT), a simple and effective strategy was developed to fabricate a TME stimuli-responsive theranostic nanomedicine (Fe-CD) for fluorescence imaging-guided GSH depletion and cancer therapy by combining fluorescent imaging carbon dots (CD) and Fe(III). Introducing Fe(III) into Fe-CD not only quenched the fluorescence of CD while reacting with and consuming intracellular GSH for fluorescence imaging of the depletion of GSH but also provided a source of metal ions to generate more abundant hydroxyl radicals (â¢OH) with hydrogen peroxide (H2O2) through the Fenton reaction to improve CDT. Fe-CD showed promising â¢OH generation under H2O2 to effectively degrade methylene blue in vitro and obviously activate the green fluorescence of the reactive oxygen species (ROS) probe in cells. Benefiting from the fluorescence enhancement in response to TME stimulation, Fe-CD greatly enhanced CDT cytotoxicity while monitoring successful GSH depletion by fluorescence imaging. Fe-CD has the potential to act as a theranostic nanomedicine for fluorescence imaging-guided GSH depletion to amplify CDT.
Asunto(s)
Nanopartículas , Neoplasias , Puntos Cuánticos , Carbono , Línea Celular Tumoral , Compuestos Férricos , Glutatión , Humanos , Peróxido de Hidrógeno , Imagen Óptica , Nanomedicina Teranóstica , Microambiente TumoralRESUMEN
In order to maximize the retention of the photodynamic therapy (PDT) efficacy, while avoiding the dilemma of hypoxia and high reducing substances in tumor tissue, fluoropolymers were synthesized in a simple and effective methods. Fluorous effect with good oxygen carrying capacity was endowed by the fluorine-containing section in fluoropolymers and the perfluorodecalin (PFD) together, the reaction site with GSH was provided by the disulfide bond, which enhanced PDT efficiency through the sequential "AND" logic gate design. Two kind of fluorine-containing nanocarriers (M-Ce6 and E-Ce6) were obtained by solvent evaporation or ultrasound emulsification with PFD, respectively. In vitro, both of them showed promising high ROS generation under photoirradiation. Benefiting by cavitation effects, E-Ce6 had a more significant statistical difference in cellular uptake. Furthermore, the cells incubating with E-Ce6 hardly were noticed that the hypoxia signal appeared under hypoxia, while reducing the intracellular GSH content by more than 15%. Through the sequential "AND" logic gate design, ROS production even under hypoxia and GSH conditions of E-Ce6 was also almost 1.5 times that of Ce6 under normoxia. Enhancing effect of E-Ce6 was 13.47 times and 6.85 times, while selectivity ratio reached 5.13 times and 4.81 times compared with Ce6 and M-Ce6. The two-pronged strategy showed a high potential for delivering the Ce6 to deep inside of cancer cells and killing it in the simulated tumor by PDT. These above results demonstrated the potential of E-Ce6, as oxygen self-sufficiency and GSH depletion nanocarriers for combined enhancement of photodynamic therapy.
Asunto(s)
Fotoquimioterapia , Porfirinas , Línea Celular Tumoral , Flúor , Oxígeno , Fármacos Fotosensibilizantes/farmacologíaRESUMEN
BACKGROUND: Production of biodiesel from renewable sources such as inedible vegetable oils by enzymatic catalysis has been a hotspot but remains a challenge on the efficient use of an enzyme. COFs (Covalent Organic Frameworks) with large surface area and porosity can be applied as ideal support to avoid aggregation of lipase and methanol. However, the naturally low density limits its application. In this work, we reported a facile synthesis of core-shell magnetic COF composite (Fe3O4@COF-OMe) to immobilize RML (Rhizomucor miehei lipase), to achieve its utilization in biodiesel production. RESULT: This strategy gives extrinsic magnetic property, and the magnetic COFs is much heavier and could disperse in water medium well, facilitating the attachment with the enzyme. The resultant biocomposite exhibited an excellent capacity of RML due to its high surface area and fast response to the external magnetic field, as well as good chemical stability. The core-shell magnetic COF-OMe structure not only achieved highly efficient immobilization and recovery processes but also maintained the activity of lipase to a great extent. RML@Fe3O4@COF-OMe performed well in practical applications, while free lipase did not. The biocomposite successfully achieved the production of biodiesel from Jatropha curcas Oil with a yield of about 70% in the optimized conditions. CONCLUSION: Magnetic COFs (Fe3O4@COF-OMe) for RML immobilization greatly improved catalytic performance in template reaction and biodiesel preparation. The magneticity makes it easily recovered and separated from the system. This first successful attempt of COFs-based immobilized enzyme broadened the prospect of biodiesel production by COFs with some inspiration.
RESUMEN
Chemodynamic therapy (CDT) is a kind of method utilizing hydroxyl radicals (â¢OH) generated by Fenton or Fenton-like reactions in situ to kill tumor cells. Copper, a cofactor of many intracellular enzymes, which has good biocompatibility, is a transition metal with extremely high efficiency in the Fenton-like reaction. However, when the intracellular free copper exceeds the threshold, it will bring serious side effects. Hence, we used the chelation between glutathione (GSH) and copper ions to produce a nanocatalytic drug, which was named as Cu-GSSG NPs, to fix free copper. With the aid of hydrogen peroxide (H2O2) in vitro, Cu-GSSG NPs catalyzed it to â¢OH radicals, which could be confirmed by the electron spin resonance spectrum and the degradation experiment of methylene blue. Based on these results, we further studied the intracellular properties of Cu-GSSG NPs and found that Cu-GSSG NPs could react with the overexpressed H2O2 in tumor cells to produce â¢OH radicals effectively by the Fenton-like reaction to induce cell death. Therefore, Cu-GSSG NPs could be a kind of potential "green" nanocatalytic drug with good biocompatibility to achieve CDT.
Asunto(s)
Antineoplásicos , Cobre , Células A549 , Línea Celular Tumoral , Glutatión , Humanos , Peróxido de HidrógenoRESUMEN
To maximize the utilization and response to the high oxidative stress environment of tumor sites while avoiding the dilemma of enhancing reactive oxygen species (ROS) response in a single way, mitochondrial targeting combined with fluorescent self-reporting polymeric nanocarriers (1K-TPP and 2K-TPP) with grafted structures were synthesized via a chemoenzymatic method in a high yield to simultaneously enhance the drug delivery of endogenous ROS responses. 1K-TPP and 2K-TPP loaded doxorubicin (DOX) at a high content over 12% and formed homogeneous spherical micelles. In vitro, both of them showed promising high sensitivity (detection limit below 200 nM H2O2), fast response, and ratiometric fluorescent self-reporting properties (fluorescent enhancement more than 200 times) to ROS and excellent stability under physiological conditions, while achieving a rapid release of the DOX in response to 1 mM H2O2. Cell co-localization experiments exhibited that they had favorable mitochondrial targeting, and mitochondrial isolation experiments also confirmed that the TPP-modified 1K-TPP selectively accumulated nearly three times in mitochondria than that in total cells. The internalization of 1K-TPP and 2K-TPP into cancer cells was greatly improved by nearly 200% compared to that of unmodified control (1K-OH and 2K-OH) and also explored a unique energy-dependent endocytosis. Furthermore, stimulation of endogenous ROS enhanced the green fluorescence intensity (up to 51.4%) of the linked probe so as to destroy the internal structure of the nanocarriers, achieving self-reporting of the drug's intracellular release and tracking of the intracellular location of nanocarriers. The cytotoxicity of DOX-loaded 1K-TPP and 2K-TPP in tumor cells with a higher ROS content showed statistical superiority to that of 1K-OH and 2K-OH, benefiting from the extremely good endogenous ROS response sensitivity leading to the differential selective release of drugs. These results demonstrate the potential of 1K-TPP and 2K-TPP, especially for 1K-TPP, as mitochondria-targeted, fluorescent self-reporting nanocarriers for combined enhancement of endogenous ROS responsiveness.
Asunto(s)
Antibióticos Antineoplásicos/farmacología , Doxorrubicina/farmacología , Sistemas de Liberación de Medicamentos , Fluorescencia , Mitocondrias/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Antibióticos Antineoplásicos/química , Línea Celular , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/química , Portadores de Fármacos/química , Ensayos de Selección de Medicamentos Antitumorales , Células HeLa , Humanos , Mitocondrias/metabolismo , Estructura Molecular , Nanopartículas/química , Tamaño de la Partícula , Polímeros/síntesis química , Polímeros/química , Propiedades de SuperficieRESUMEN
A facile strategy to construct dual-drug delivery nanoparticles (TL-CPT NPs), which possessed higher loading content of CPT and TPP-LND. Notably, TL-CPT NPs showed promising ultrarapid pH/GSH response to release more than 86% of loaded TPP-LND or 93% of loaded CPT in just 2 h. The results showed that the nanoparticles hierarchically delivered CPT and TPP-LND to targeted different organelles without mutual influence benefiting the ultrarapid pH/GSH response to drug release, and further significantly and synergistically induced cell apoptosis and improved chemotherapeutic efficiency in cancer cells.
RESUMEN
Dual stimuli-responsive camptothecin polymeric prodrugs (CPT Prodrugs) with grafted structures were designed via chemoenzymatic methods and combined with doxorubicin (DOX) for synergistic drug delivery to improve anticancer efficiency. The CPT Prodrugs loaded DOX with a high efficiency through the cooperative contribution of several interaction forces. The produced amphiphilic polymeric prodrugs loaded with DOX, referred to as DOX@CPT Prodrugs, formed homogeneous spherical micelles of appropriate sizes (sub-50 nm). The DOX@CPT Prodrug micelles showed excellent stability in release experiments under in vitro physiological conditions and maintained over 80% drug loading after 4 weeks when stored at 4 °C. Under weakly acidic pH and reduced glutathione (GSH) conditions, the DOX@CPT Prodrugs with high disulfide and tertiary amine content achieved synergistic release of the two loaded drugs and biodegraded into low-molecular-weight compounds. The cell experiments confirmed that the internalization of DOX@CPT Prodrugs into cancer cells was greatly improved by nearly 30% compared with that of free drugs. Furthermore, the synergistic drug delivery system exhibited superior anticancer efficiency with highly improved cell selectivity ratios (up to 127.0%) and greatly enhanced synergistic effects (up to 23.9%) benefiting from good long-term stability, better internalization by cells and sensitive pH and GSH dual-responsivity. In addition, the DOX@CPT Prodrugs with suitable sizes and good water solubility also exhibited a greater penetrability in the case of simulating solid tumors than the free drugs. These results demonstrate the potential of DOX@CPT Prodrugs as biodegradable, dual-responsive combination therapy nanocarriers for synergistic anticancer treatment.