RESUMEN
The development of a radioresponsive delivery platform has led to an innovative combination radioimmunotherapy strategy for treating tumors. However, controlling the release of immunomodulators by local radiotherapy in vivo remains a significant challenge in order to minimize off-target toxicity, reduce radiation-induced immunosuppression, and maximize synergistic radioimmunotherapy efficacy. In this study, we report the development of core-cross-linked diselenide nanoparticles (dSeNPs) as carriers for radioresponsive delivery of the toll-like receptors 7/8 agonist through systemic administration to achieve combined radioimmunotherapy of tumors. The dSeNPs were fabricated from a ring-opening reaction between 2,2'-diselenidebis(ethylamine) and the ethylene oxide group of an amphiphilic block copolymer. The diselenide bonds were naturally protected in the core of the self-assembled nanostructure, making the dSeNPs extremely stable in the physiological environment. However, they exhibited dose- and time-dependent radiosensitivity, meaning that X-ray irradiation could spatiotemporally control the release of R848 from the dSeNPs. In vivo results showed that local radioresponsive R848 release from dSeNPs greatly improved the synergistic efficacy of combined radioimmunotherapy via the programmed cooperative immune system activation process. This process included macrophage polarization, dendritic cell maturation, and cytotoxic T cell activation. Our findings suggest that core-cross-linked dSeNPs are a promising platform for combined radiotherapy due to their spatiotemporal controllability of radioresponsive drug release.
Asunto(s)
Antineoplásicos , Nanopartículas , Neoplasias , Humanos , Receptor Toll-Like 7/agonistas , Radioinmunoterapia , Neoplasias/tratamiento farmacológico , Adyuvantes Inmunológicos , Nanopartículas/químicaRESUMEN
Due to the complexity and particularity of cancer cell microenvironments, redox responsive drug delivery systems (DDSs) for cancer therapy have been extensively explored. Compared with widely reported cancer treatment systems based on disulfide bonds, diselenide bonds have better redox properties and greater anticancer efficiency. In this review, the significance and application of diselenide bonds in DDSs are summarized, and the stimulation sensitivity of diselenide bonds is comprehensively reported. The potential and prospects for the application of diselenide bonds in next-generation anticancer drug treatment systems are extensively discussed.
Asunto(s)
Antineoplásicos , Neoplasias , Humanos , Antineoplásicos/uso terapéutico , Oxidación-Reducción , Neoplasias/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Disulfuros , Portadores de Fármacos/química , Microambiente TumoralRESUMEN
Smart hydrogels are typical functional soft materials, but their functional and mechanical properties are compromised upon micro- or macro-mechanical damage. In contrast, hydrogels with self-healing properties overcome this limitation. Herein, a dual dynamic bind, cross-linked, self-healing protein hydrogel is prepared, based on Schiff base bonds and diselenide bonds. The Schiff base bond is a typical dynamic covalent bond and the diselenide bond is an emerging dynamic covalent bond with a visible light response, which gives the resulting hydrogel a dual response in visible light and a desirable self-healing ability. The diselenide-containing protein hydrogels were biocompatible due to the fact that their main component was protein. In addition, the hydrogels loaded with glucose oxidase (GOx) could be transformed into sols in glucose solution due to the sensitive response of the diselenide bonds to the generated hydrogen peroxide (H2O2) by enzymatic catalysis. This work demonstrated a diselenide-containing protein hydrogel that could efficiently self-heal up to nearly 100% without compromising their mechanical properties under visible light at room temperature.
RESUMEN
Two novel stimuli-responsive drug delivery systems (DDSs) were successfully created from bovine serum albumin- or myoglobin-gated upconversion nanoparticle-embedded mesoporous silica nanovehicles (UCNP@mSiO2) via diselenide (Se-Se)-containing linkages. More importantly, multiple roles of each scaffold of the nanovehicles were achieved. The controlled release of the encapsulated drug doxorubicin (DOX) within the mesopores was activated by triple stimuli (acidic pH, glutathione, or H2O2) of tumor microenvironments, owing to the conformation/surface charge changes in proteins or the reductive/oxidative cleavages of the Se-Se bonds. Upon release of DOX, the Förster resonance energy transfer between the UCNP cores and encapsulated DOX was eliminated, resulting in an increase in ratiometric upconversion luminescence for DOX release tracking in real time. The two protein-gated DDSs showed some differences in the drug release performances, relevant to structures and properties of the protein nanogates. The introduction of the Se-Se linkages not only increased the versatility of reductive/oxidative cleavages but also showed less cytotoxicity to all cell lines. The DOX-loaded protein-gated nanovehicles showed the inhibitory effect on tumor growth in tumor-bearing mice and negligible damage/toxicity to the normal tissues. The constructed nanovehicles in a spatiotemporally controlled manner have fascinating prospects in targeted drug delivery for cancer chemotherapy.
Asunto(s)
Antineoplásicos/uso terapéutico , Doxorrubicina/uso terapéutico , Portadores de Fármacos/química , Nanopartículas del Metal/química , Neoplasias/tratamiento farmacológico , Animales , Antineoplásicos/química , Bovinos , Doxorrubicina/química , Portadores de Fármacos/metabolismo , Liberación de Fármacos , Erbio/química , Femenino , Fluoruros/química , Glutatión/metabolismo , Células HeLa , Humanos , Peróxido de Hidrógeno/metabolismo , Concentración de Iones de Hidrógeno , Ratones Endogámicos C57BL , Mioglobina/química , Mioglobina/metabolismo , Porosidad , Albúmina Sérica Bovina/química , Albúmina Sérica Bovina/metabolismo , Dióxido de Silicio/química , Ensayos Antitumor por Modelo de Xenoinjerto , Iterbio/química , Itrio/químicaRESUMEN
Chemotherapy causes off-target toxicity and is often ineffective against solid tumors. Targeted and on-demand release of chemotherapeutics remains a challenge. Here, cancer-cell-membrane-coated mesoporous organosilica nanoparticles (MONs) containing X-ray- and reactive oxygen species (ROS)-responsive diselenide bonds for controlled release of doxorubicin (DOX) at tumor sites are developed. DOX-loaded MONs coated with 4T1 breast cancer cell membranes (CM@MON@DOX) show greater accumulation at tumor sites and prolonged blood circulation time versus an uncoated control in mice bearing 4T1 orthotopic mammary tumors. Under low-dose X-ray radiation, the DOX-loaded MONs exhibit carrier degradation-controlled release via cleavage of diselenide bonds, resulting in DOX-mediated immunogenic cell death at the tumor site. Combination with a PD-L1 checkpoint blockade further enhances inhibition of tumor growth and metastasis with low systemic toxicity. Together, the findings show the promise of these biomimetic, radiation-responsive diselenide-bond-bridged MONs in chemo-immunotherapy.
Asunto(s)
Materiales Biomiméticos/química , Portadores de Fármacos/química , Inmunoterapia/métodos , Nanopartículas/química , Selenio/química , Dióxido de Silicio/química , Animales , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/radioterapia , Línea Celular Tumoral , Doxorrubicina/química , Doxorrubicina/uso terapéutico , Humanos , Ratones , Porosidad , Rayos XRESUMEN
Plasticity of thermoset polymers has been realized by introducing exchangeable bonds, and the plasticity is mostly triggered via heat or UV light. Visible light is a relatively mild trigger that has not been used to induce plasticity in polymer materials. Herein, thermoset polyurethanes (PUs) containing diselenide bonds are fabricated that possess visible light-induced plasticity along with shape memory behavior. A series of PUs with different diselenide bond contents were tested and their shape memory properties and plasticity varied. With a higher diselenide bond content, both shape memory and light-induced plasticity are achieved. By combining these two properties, reshaping the permanent shapes of the PUs is easier. Compared with heat or UV light, visible light has the advantage of spatial control. For instance, a pattern of visible light was introduced by a commercial projector to demonstrate facile reshaping of the materials. Because visible light can be introduced via various methods, PUs with visible light-induced plasticity have great potential applications.
RESUMEN
An injectable dual redox responsive diselenide-containing poly(ethylene glycol) (PEG) hydrogel was successfully developed by combining the conceptions of injectable hydrogels and dual redox responsive diselenides. In the first step, four-armed PEG was modified with N-hydroxysuccinimide (NHS)-activated esters and thereafter, crosslinked by selenocystamine crosslinkers to form injectable hydrogels via the rapid reaction between NHS-activated esters and amino groups. The cross-sectional morphology, mechanical properties, and crosslinking modes of hydrogels were well characterized via scanning electron microscope (SEM), rheological measurements, and Fourier transform infrared spectra, respectively. In addition, the oxidation- and reduction-responsive degradation behaviors of hydrogels were observed and analyzed. The model drug, rhodamine B, was encapsulated in the hydrogel. The drug-loaded hydrogel exhibited a dual redox responsive release profile, which was consistent with the degradation experiments. The results of all experiments indicated that the formulated injectable dual redox responsive diselenide-containing PEG hydrogel can have potential applications in various biomedical fields such as drug delivery and stimuli-responsive drug release. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2451-2460, 2017.
Asunto(s)
Hidrogeles/química , Inyecciones , Compuestos de Organoselenio/química , Polietilenglicoles/química , Reactivos de Enlaces Cruzados/química , Liberación de Fármacos , Hidrogeles/síntesis química , Microscopía Electrónica de Rastreo , Oxidación-Reducción , Polietilenglicoles/síntesis química , Espectroscopía de Protones por Resonancia Magnética , Reología , Rodaminas/farmacología , Espectroscopía Infrarroja por Transformada de Fourier , Succinimidas/químicaRESUMEN
Undesired physiological instability of nanocarriers and premature drug leakage during blood circulation result in compromised therapeutic efficacy and severe side effects, which have significantly impeded the development of nanomedicine. Facile crosslinking of drug-loaded nanocarriers while keeping the potency of site-specific degradation and drug release has emerged as a viable strategy to overcome these drawbacks. Additionally, combination therapy has already shown advantages in inhibiting advanced tumors and life extension than single drug therapy. Herein, three kinds of diselenide-rich polymers were fabricated with distinct hydrophobic side chains. The component effect was interrogated to screen out PEG-b-PBSe diblock copolymer due to its favorable self-assembly controllability and high drug loading of camptothecin (CPT) and doxorubicin (DOX) that had synergistic antitumor property. Facile visible light-induced diselenide metathesis and regeneration was employed to crosslink nanocarriers for the first time. The dual drug-loaded crosslinked micelles (CPT/DOX-CCM) were stable in physiological conditions with minimal drug leakage, possessing extended blood circulation, whereas hand-in-hand dual drug release was significantly accelerated in tumor's redox microenvironments. In vitro cytotoxicity evaluation and in vivo tumor suppression with low dosage drugs further demonstrated the favorable potency of the redox-responsive nanoplatform in tumor combination chemotherapy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Supervivencia Celular/efectos de los fármacos , Preparaciones de Acción Retardada/administración & dosificación , Nanocápsulas/administración & dosificación , Neoplasias Experimentales/tratamiento farmacológico , Compuestos de Selenio/administración & dosificación , Camptotecina/administración & dosificación , Camptotecina/química , Reactivos de Enlaces Cruzados/química , Reactivos de Enlaces Cruzados/efectos de la radiación , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/efectos de la radiación , Doxorrubicina/administración & dosificación , Doxorrubicina/química , Estabilidad de Medicamentos , Humanos , Luz , Células MCF-7 , Nanocápsulas/química , Nanocápsulas/efectos de la radiación , Neoplasias Experimentales/patología , Oxidación-Reducción/efectos de la radiación , Compuestos de Selenio/química , Resultado del TratamientoRESUMEN
BACKGROUND: Despite selenium's toxicity in plants at higher levels, crops supply most of the essential dietary selenium in humans. In plants, inorganic selenium can be assimilated into selenocysteine, which can replace cysteine in proteins. Selenium toxicity in plants has been attributed to the formation of non-specific selenoproteins. However, this paradigm can be challenged now that there is increasingly abundant evidence suggesting that selenium-induced oxidative stress also contributes to toxicity in plants. SCOPE: This Botanical Briefing summarizes the evidence indicating that selenium toxicity in plants is attributable to both the accumulation of non-specific selenoproteins and selenium-induced oxidative stress. Evidence is also presented to substantiate the claim that inadvertent selenocysteine replacement probably impairs or misfolds proteins, which supports the malformed selenoprotein hypothesis. The possible physiological ramifications of selenoproteins and selenium-induced oxidative stress are discussed. CONCLUSIONS: Malformed selenoproteins and oxidative stress are two distinct types of stress that drive selenium toxicity in plants and could impact cellular processes in plants that have yet to be thoroughly explored. Although challenging, deciphering whether the extent of selenium toxicity in plants is imparted by selenoproteins or oxidative stress could be helpful in the development of crops with fortified levels of selenium.