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The co-delivery of photosensitizers with prodrugs sensitive to reactive oxygen species (ROS) for light-triggered ROS generation and cascaded prodrug activation has drawn tremendous attention. However, the absence of a feasible method to deliver the two components at a precise ratio has impaired the application potential. Herein, we report an efficient method to produce a nanosized platform for the delivery of an optimized ratio of the two components by the means of host-guest strategy for maximizing the combination therapy efficacy of cancer treatment. The key features of this host-guest strategy for the combination therapy are that the ratio between photosensitizer and ROS-sensitive prodrug can be easily tuned, near-infrared (NIR) irradiation can sensitize the photosensitizer and activate the paclitaxel prodrug for its release, and the accumulation process can be tracked by NIR imaging to maximize the efficacy of photodynamic and chemotherapy.
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Paclitaxel/farmacología , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/administración & dosificación , Fototerapia/métodos , Profármacos/farmacología , Especies Reactivas de Oxígeno/metabolismo , Neoplasias del Cuello Uterino/terapia , Animales , Antineoplásicos Fitogénicos/farmacología , Proliferación Celular , Terapia Combinada , Sistemas de Liberación de Medicamentos , Femenino , Humanos , Rayos Infrarrojos , Ratones , Ratones Desnudos , Profármacos/química , Células Tumorales Cultivadas , Neoplasias del Cuello Uterino/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Determination of molecular structural parameters of hydrophobic cholesterol-naphthalimide conjugates for water binding capabilities as well as their moisture-sensitive supramolecular self-assembly were revealed. Water binding was a key factor in leading trace water-induced crystallization against gelation in apolar solvent. Ordered water molecules entrapped in self-assembly arrays revealed by crystal structures behave as hydrogen-bonding linkers to facilitate three-dimensional growth into crystals rather than one-dimensional gel nanofibers. Water binding was also reflected on the supramolecular chirality inversion of vesicle self-assembly in aqueous media via heating-induced dehydration. Structural parameters that favor water binding were evaluated in detail, which could help rationally design organic building units for advancing soft materials, crystal engineering, and chiral recognition.
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[This corrects the article DOI: 10.7150/thno.21194.].
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A nanoscale therapeutic system with good biocompatibility was facilely fabricated by the coassembly of human serum albumin and glucose oxidase (GOD), where the former was pretreated with metal ions through a chelating agent or the chemotherapeutic prodrug oxaliplatin (Oxa(IV)). Among different chelating metal ions used, Mn2+ ion was selected to produce hydroxyl radical (â¢OH) efficiently through Fenton-like reaction, while GOD loaded in the system was able to generate a large amount of hydrogen peroxide for promoting efficient conversion into highly toxic â¢OH. In the meanwhile, the conversion of the Oxa(IV) prodrug into chemotherapeutic Oxa(II) was beneficial for the consumption of glutathione, thereby enhancing the chemodynamic therapy (CDT) efficacy. Based on the combined chemotherapy and CDT, the treatment with this system leads to superior antitumor outcome.
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Peróxido de Hidrógeno , Neoplasias , Albúminas , Línea Celular Tumoral , Glucosa Oxidasa/uso terapéutico , Glutatión , Humanos , Neoplasias/tratamiento farmacológicoRESUMEN
Hypoxia of solid tumor compromises the therapeutic outcome of photodynamic therapy (PDT) that relies on localized O2 molecules to produce highly cytotoxic singlet oxygen (1O2) species. Herein, we present a safe and versatile self-assembled PDT nanoagent, i.e., OxgeMCC-r single-atom enzyme (SAE), consisting of single-atom ruthenium as the active catalytic site anchored in a metal-organic framework Mn3[Co(CN)6]2 with encapsulated chlorin e6 (Ce6), which serves as a catalase-like nanozyme for oxygen generation. Coordination-driven self-assembly of organic linkers and metal ions in the presence of a biocompatible polymer generates a nanoscale network that adaptively encapsulates Ce6. The resulted OxgeMCC-r SAE possesses well-defined morphology, uniform size distribution and high loading capacity. When conducting the in situ O2 generation through the reaction between endogenous H2O2 and single-atom Ru species of OxgeMCC-r SAE, the hypoxia in tumor microenvironment is relieved. Our study demonstrates a promising self-assembled nanozyme with highly efficient single-atom catalytic sites for cancer treatment.
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Nanopartículas/química , Fotoquimioterapia/métodos , Porfirinas/química , Oxígeno Singlete/química , Oxígeno Singlete/farmacología , Animales , Apoptosis/efectos de los fármacos , Materiales Biocompatibles , Catalasa/química , Catalasa/uso terapéutico , Línea Celular Tumoral , Clorofilidas , Células HEK293 , Células HeLa , Humanos , Peróxido de Hidrógeno/farmacología , Ratones , Nanopartículas/uso terapéutico , Nanotecnología , Neoplasias/tratamiento farmacológico , Fármacos Fotosensibilizantes/farmacología , Polímeros/farmacología , Especies Reactivas de Oxígeno/química , Especies Reactivas de Oxígeno/farmacología , Hipoxia Tumoral/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacosRESUMEN
Responsive delivery of anticancer proteins into cells is an emerging field in biological therapeutics. Currently, the delivery of proteins is highly compromised by multiple successive physiological barriers that reduce the therapeutic efficacy. Hence, there is a need to design a robust and sustainable nanocarrier to provide suitable protection of proteins and overcome the physiological barriers for better cellular accumulation. In this work, polyethylenimine (PEI) cross-linked by oxaliplatin(IV) prodrug (oxliPt(IV)) was used to fabricate a redox-responsive nanocomplex (PEI-oxliPt(IV)@RNBC/GOD) for the delivery of a reactive oxygen species-cleavable, reversibly caged RNase A protein (i.e., RNase A nitrophenylboronic conjugate, RNBC) and glucose oxidase (GOD) in order to realize efficient cancer treatment. The generation of hydrogen peroxide by GOD can uncage and restore the enzymatic activity of RNBC. On account of the responsiveness of the nanocomplex to highly reducing cellular environment, it would dissociate and release the protein and active oxaliplatin drug, causing cell death by both catalyzing RNA degradation and inhibiting DNA synthesis. As assessed by the RNA degradation assay, the activity of the encapsulated RNBC was recovered by the catalytic production of hydrogen peroxide from GOD and glucose substrate overexpressed in cancer cells. Monitoring of the changes in nanoparticle size confirmed that the nanocomplex could dissociate in the reducing environment, with the release of active oxaliplatin drug and protein. Confocal laser scanning microscopy (CLSM) and flow cytometry analysis revealed highly efficient accumulation of the nanocomplex as compared to free native proteins. In vitro cytotoxicity experiments using 4T1 cancer cells showed â¼80% cell killing efficacy, with highly efficient apoptosis induction. Assisted by the cationic polymeric carrier, it was evident from CLSM images that intracellular delivery of the therapeutic protein significantly depleted the RNA level. Thus, this work provides a promising platform for the delivery of therapeutic proteins and chemotherapeutic drugs for efficient cancer treatment.
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Neoplasias , Oxaliplatino , Profármacos , Ribonucleasa Pancreática , Antineoplásicos , Línea Celular Tumoral , ADN de Neoplasias/biosíntesis , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/farmacocinética , Preparaciones de Acción Retardada/farmacología , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacología , Humanos , Peróxido de Hidrógeno/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Oxaliplatino/química , Oxaliplatino/farmacocinética , Oxaliplatino/farmacología , Oxidación-Reducción , Profármacos/química , Profármacos/farmacocinética , Profármacos/farmacología , Estabilidad del ARN/efectos de los fármacos , Ribonucleasa Pancreática/química , Ribonucleasa Pancreática/farmacocinética , Ribonucleasa Pancreática/farmacologíaRESUMEN
Nanomedicine has emerged as a promising strategy for effective cancer treatment. A useful approach is to develop carrier-free nanodrugs via a facile supramolecular self-assembly process. To achieve high therapeutic effect, integrating photodynamic therapy with chemotherapy has been sought after. In this work, we designed a nanocarrier (PEG-Por-CD: oxliPt(IV)-ada) assembled with oxaliplatin prodrug (oxliPt(IV)-ada) and porphyrin photosensitizer (PEG-Por-CD) through host-guest interaction to achieve stimulus-responsive combination therapy. Contributed by excellent spatial control of the binding ratio between host and guest molecules, porphyrin and oxaliplatin were separately modified with ß-cyclodextrin and adamantane to prepare the amphiphilic host-guest complex for subsequent self-assembly into therapeutic nanoparticles. The obtained PEG-Por-CD: oxliPt(IV)-ada nanoparticles exhibited good colloidal stability with an average hydrodynamic size of 164 nm while undergoing the disassembly under reductive environment to release active therapeutic species. Confocal imaging demonstrated the ability of PEG-Por-CD: oxliPt(IV)-ada to effectively accumulate in the cells and produce reactive oxygen species in vitro upon 630 nm light irradiation. As compared with the monotherapy, the PEG-Por-CD: oxliPt(IV)-ada nanoparticles exhibited 3-fold enhanced cytotoxicity and 2-fold increase in the apoptosis. In vivo experiments using 4T1 tumor-bearing mice confirmed that the nanoparticles were efficient in suppressing the tumor growth without eliciting systemic toxicity. The present self-delivery nanosystem constructed from the self-assembly approach not only allows precise control over the drug and photosensitizer loading ratio but also eliminates systemic toxicity concern of the drug carriers, providing a solution for further development of combinational cancer treatment.
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Sistemas de Liberación de Medicamentos , Nanopartículas/administración & dosificación , Neoplasias/terapia , Oxaliplatino/administración & dosificación , Apoptosis/efectos de los fármacos , Terapia Combinada , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/química , Liberación de Fármacos , Quimioterapia , Humanos , Células MCF-7 , Nanopartículas/química , Neoplasias/patología , Oxaliplatino/química , Fotoquimioterapia , Profármacos/administración & dosificación , Profármacos/química , Especies Reactivas de Oxígeno/química , Nanomedicina Teranóstica/tendenciasRESUMEN
Inorganic nanoparticles with tunable and diverse properties hold tremendous potential in the field of nanomedicine, while having non-negligible toxicity concerns in healthy tissues/organs that have resulted in their restricted clinical translation to date. In the past decade, the emergence of biodegradable or clearable inorganic nanoparticles has made it possible to completely solve this long-standing conundrum. A comprehensive understanding of the design of these inorganic nanoparticles with their metabolic performance in the body is of crucial importance to advance clinical trials and expand their biological applications in disease diagnosis. Here, a diverse variety of biodegradable or clearable inorganic nanoparticles regarding considerations of the size, morphology, surface chemistry, and doping strategy are highlighted. Their pharmacokinetics, pathways of metabolism in the body, and time required for excretion are discussed. Some inorganic materials intrinsically responsive to various conditions in the tumor microenvironment are also introduced. Finally, an overview of the encountered challenges is provided along with an outlook for applying these inorganic nanoparticles toward future clinical translations.
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Materiales Biocompatibles/química , Materiales Biocompatibles/metabolismo , Nanopartículas/química , Nanopartículas/metabolismo , Animales , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/metabolismo , Preparaciones de Acción Retardada/farmacocinética , Humanos , Terapia Molecular Dirigida/métodosRESUMEN
Tumor hypoxia compromises the therapeutic efficiency of photodynamic therapy (PDT) as the local oxygen concentration plays an important role in the generation of cytotoxic singlet oxygen (1 O2 ). Herein, a versatile mesoporous nanoenzyme (NE) derived from metal-organic frameworks (MOFs) is presented for in situ generation of endogenous O2 to enhance the PDT efficacy under bioimaging guidance. The mesoporous NE is constructed by first coating a manganese-based MOFs with mesoporous silica, followed by a facile annealing process under the ambient atmosphere. After removing the mesoporous silica shell and post-modifying with polydopamine and poly(ethylene glycol) for improving the biocompatibility, the obtained mesoporous NE is loaded with chlorin e6 (Ce6), a commonly used photosensitizer in PDT, with a high loading capacity. Upon the O2 generation through the catalytic reaction between the catalytic amount NE and the endogenous H2 O2 , the hypoxic tumor microenvironment is relieved. Thus, Ce6-loaded NE serves as a H2 O2 -activated oxygen supplier to increase the local O2 concentration for significantly enhanced antitumor PDT efficacy in vitro and in vivo. In addition, the NE also shows T2 -weighted magnetic resonance imaging ability for its in vivo tracking. This work presents an interesting biomedical use of MOF-derived mesoporous NE as a multifunctional theranostic agent in cancer therapy.
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Estructuras Metalorgánicas/química , Nanoestructuras/química , Oxígeno/metabolismo , Fármacos Fotosensibilizantes/administración & dosificación , Porfirinas/administración & dosificación , Hipoxia Tumoral , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Clorofilidas , Cobalto/química , Humanos , Peróxido de Hidrógeno/metabolismo , Indoles/química , Manganeso/química , Ratones , Óxidos/química , Fotoquimioterapia/métodos , Polietilenglicoles/química , Polímeros/química , Porosidad , Dióxido de Silicio/química , Microambiente TumoralRESUMEN
Photodynamic therapy (PDT) as a treatment method has many advantages such as minimal invasiveness, repeatable dosage, and low systemic toxicity. Issues with conventional PDT agents include the limited availability of endogenous oxygen and difficulty in accumulation at the tumor site, which has hindered the successful treatment of tumors. Herein, we developed catalase-encapsulated hyaluronic-acid-based nanoparticles loaded with adamantane-modified photosensitizer for enhanced PDT of solid tumors. Chlorin e6 (Ce6) as the photosensitizer was modified with adamantane to yield adamantane-modified Ce6 (aCe6). The obtained nanosystem (HA-CAT@aCe6) could target overly expressed CD44 receptors on cancer cells, supplying oxygen by converting endogenous hydrogen peroxide (H2O2) to oxygen, and improving PDT efficacy upon light irradiation. HA-CAT@aCe6 nanoparticles showed high colloidal stability and monodispersity in aqueous solution. The uptake and targeting property of HA-CAT@aCe6 were demonstrated by confocal microscopy and flow cytometry in the MDA-MB-231 cell line possessing overly expressed CD44 receptors. The encapsulated catalase was able to decompose the endogenous H2O2 to generate O2 in situ for relieving hypoxia in cells incubated under hypoxic conditions. Cell viability assays indicated that HA-CAT@aCe6 possessed minimal cytotoxicity in the dark, while presenting high cellular toxicity under 660 nm light irradiation at normoxic conditions. As a result of the catalase capability in relieving hypoxia, HA-CAT@aCe6 also exhibited high cellular cytotoxicity under hypoxic condition. In vivo experiments revealed selective tumor accumulation of HA-CAT@aCe6 in MDA-MB-231 tumor bearing nude mice. Significant tumor regression was observed after intravenous injection of HA-CAT@aCe6 under light irradiation in comparison to the control system without loading catalase. Thus, HA-CAT@aCe6 demonstrated a great potential in overcoming hypoxia for targeted PDT.
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Neoplasias de la Mama/tratamiento farmacológico , Catalasa/química , Ácido Hialurónico/química , Nanocápsulas/química , Fármacos Fotosensibilizantes/administración & dosificación , Porfirinas/administración & dosificación , Adamantano/análogos & derivados , Animales , Línea Celular Tumoral , Clorofilidas , Femenino , Humanos , Ratones Desnudos , Fotoquimioterapia , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/uso terapéutico , Porfirinas/química , Porfirinas/uso terapéuticoRESUMEN
Uncontrolled cancer cell proliferation, insufficient blood flow, and inadequate endogenous oxygen lead to hypoxia in tumor tissues. Herein, a unique type of hypoxia-responsive human serum albumin (HSA)-based nanosystem (HCHOA) is reported, prepared by cross-linking the hypoxia-sensitive azobenzene group between photosensitizer chlorin e6 (Ce6)-conjugated HSA (HC) and oxaliplatin prodrug-conjugated HSA (HO). The HCHOA nanosystem is stable under normal oxygen partial pressure with a size of 100-150 nm. When exposed to the hypoxic tumor microenvironment, the nanosystem can quickly dissociate into ultrasmall HC and HO therapeutic nanoparticles with a diameter smaller than 10 nm, significantly enabling their enhanced intratumoral penetration. After the dissociation, the quenched fluorescence of Ce6 in the produced HC nanoparticles can be recovered for bioimaging. At the same time, the production of singlet oxygen is increased because of the enhancement in the photoactivity of the photosensitizer. On account of these improvements, combined photodynamic therapy and chemotherapy is realized to display superior antitumor efficacy in vivo. Based on this simple strategy, it is possible to achieve the dissociation of hypoxic-responsive nanosystem to enhance the tumor penetration and therapeutic effect.
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Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Nanopartículas/química , Albúmina Sérica Humana/química , Albúmina Sérica Humana/metabolismo , Hipoxia Tumoral , Animales , Línea Celular Tumoral , Clorofilidas , Humanos , Ratones , Oxaliplatino/química , Oxaliplatino/metabolismo , Oxaliplatino/farmacología , Porfirinas/química , Porfirinas/farmacología , Profármacos/metabolismo , Hipoxia Tumoral/efectos de los fármacosRESUMEN
A redox-responsive supramolecular nanocarrier was constructed from the self-assembly of spermine modified cyclodextrin and oxaliplatin prodrug. The nanocarrier could preferentially accumulate in polyamine transporter over-expressing HCT116 cells, releasing drugs under a reducing intracellular environment to maximize anticancer treatment.
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Antineoplásicos/uso terapéutico , Neoplasias del Colon/tratamiento farmacológico , Ciclodextrinas/uso terapéutico , Compuestos Organoplatinos/farmacología , Profármacos/uso terapéutico , Espermina/química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Neoplasias del Colon/patología , Ciclodextrinas/química , Relación Dosis-Respuesta a Droga , Portadores de Fármacos/química , Ensayos de Selección de Medicamentos Antitumorales , Células HCT116 , Humanos , Sustancias Macromoleculares/síntesis química , Sustancias Macromoleculares/química , Estructura Molecular , Nanopartículas/química , Compuestos Organoplatinos/química , Compuestos Organoplatinos/uso terapéutico , Oxaliplatino , Tamaño de la Partícula , Profármacos/química , Espermina/síntesis química , Relación Estructura-Actividad , Propiedades de SuperficieRESUMEN
Construction of integrated self-assembly with ordered structures from two or more organic building blocks is currently a challenge, since it suffers from intrinsic systematic complexity and diverse competitive pathways. Here, it is reported that aromatic amino acid building units can be incorporated into two- or three-component coassembly driven primarily by hydrogen bonding interactions without the assistance of metal-ligand and macrocycle-based host-guest interactions. The key strategy is to employ a C3 -symmetric molecule with alternative hydrogen bonding donor/acceptor sites that are able to bind either carboxylic acid or pyridine appended building units. Aromatic amino acids, C3 -symmetric compound, and bipyridine unit constitute a unique ternary mutual binding system, where three coassembly pathways including two pairwise formations and one ternary combination are unveiled, giving rise to two- and three-component self-assemblies with ordered structures, respectively. The pathway complexity lies in the structural parameter of aromatic amino acids, which can be programmable by controlling substituents at the α-position of amino acids.
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Aminoácidos Aromáticos/química , Ácidos Carboxílicos/química , Enlace de Hidrógeno , Ligandos , Piridinas/químicaRESUMEN
Ultralong room temperature phosphorescence (URTP) emitted from pure amorphous organic molecules is very rare. Although a few crystalline organic molecules could realize URTP with long lifetimes (>100 ms), practical applications of these crystalline organic phosphors are still challenging because the formation and maintenance of high-quality crystals are very difficult and complicated. Herein, we present a rational design for minimizing the vibrational dissipation of pure amorphous organic molecules to achieve URTP. By using this strategy, a series of URTP films with long lifetimes and high phosphorescent quantum yields (up to 0.75 s and 11.23%, respectively) were obtained from amorphous organic phosphors without visible fluorescence and phosphorescence under ambient conditions. On the basis of the unique features of URTP films, a new green screen printing technology without using any ink was developed toward confidential information encryption and decryption. This work presents a breakthrough strategy in applying amorphous organic materials for URTP.
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Purpose: In this study, we report the design, development and evaluation of a hollow drug delivery nanoplatform for cancer therapy in vitro and in vivo. This composite nanosystem was prepared by modifying hollow mesoporous silica nanoparticles (HMSNs) with transferrin (Tf) targeting moieties via redox-liable linkage, and was capable of delivering therapeutic cargos (doxorubicin) specifically to the tumor site and subsequently releasing them in an on-demand manner. Moreover, the Tf corona could simultaneously reduce the inflammatory response after intravenous administration in vivo. Methods: Nanostructural morphology of the drug delivery system was observed by scanning electron microscope and transmission electron microscope. The preparation process was monitored primarily using Fourier-transform infrared spectroscopy, dynamic light scattering, nitrogen adsorption/desorption isotherm, and thermogravimetric analysis. The release profile in solution was monitored by fluorescence spectroscopy. In vitro drug delivery efficacy was evaluated on MDA-MB-231 breast cancer cell line using confocal laser scanning microscopy, MTT assay and flow cytometry. In vitro inflammatory response was evaluated on RAW264.7 macrophage cells. In vivo therapeutic experiments were carried out using in situ mouse breast cancer models. Results: The experimental results evidently demonstrate that the developed nanocarrier could effectively deliver anticancer drugs to the tumor site in a targeted manner and release them in response to the elevated glutathione level inside tumor cells, resulting in improved anticancer efficacy both in vitro and in vivo. Moreover, the Tf conjugation significantly ameliorated the inflammatory reaction triggered by the administration of the nanocarrier. Conclusions: This manuscript demonstrated that the Tf-conjugated HMSNs could enhance the delivery efficiency of anticancer drugs, while simultaneously alleviating the adverse side effects. The current study presents a promising integrated delivery system toward effective and safe cancer treatment.
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Inflamación/tratamiento farmacológico , Nanopartículas/administración & dosificación , Nanopartículas/química , Oxidación-Reducción/efectos de los fármacos , Transferrina/administración & dosificación , Transferrina/química , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Línea Celular Tumoral , Doxorrubicina/administración & dosificación , Doxorrubicina/química , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos/métodos , Ratones , Porosidad , Células RAW 264.7 , Dióxido de Silicio/químicaRESUMEN
Silver nanoprisms (AgNPrs) exhibit localized surface plasmon resonance (LSPR) in the near infrared (NIR) region of the electromagnetic spectrum. LSPR-driven electric field enhancement around AgNPr edges has been investigated in various studies. A coating of dielectric materials such as silica on the surface of the AgNPrs is employed to extend the application of these nanoparticles under biocompatible conditions and to increase the thermal stability. Upon interactions with optical excitation (pulsed laser excitation), the AgNPrs undergo light intensity field enhancement (LIFE) at the corners. In the cases of hybrid hetero-structures of AgNPrs with silica coatings (AgNPr@SiO2), LIFE leads to nano-structural deformations. In this study, we demonstrate that, depending on the intensity of the light excitation, the medium properties and the geometrical sharpness of the corners of the prisms, LIFE could induce localized damage or abrasion at the edges of the immediate dielectric contact, which in this case was the silica coating. A theoretical study was conducted to establish the influence of the finite radius of curvature (ROC) of the corners on the plasmonic interactions to generate LIFE during optical excitation. Experiments were performed on AgNPr@SiO2 using nanosecond pulsed laser excitation at 900 nm and electron microscopic analysis of the nanostructures revealed the localized edge abrasion of the silica at the prism corners. To further study the effect of the direct plasmonic excitation during LIFE, pulsed laser excitation on ultra-thin graphene oxide (GO) wrapped AgNPr@SiO2 (GO-AgNPr@SiO2) was conducted. Due to the GO wrapping and subsequent changes in light absorption, the extent of the LIFE at the corners diminishes, which leads to structural stability and preservation of the hetero-structure morphology.
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The integration of chemotherapy and photodynamic therapy (PDT) in a single delivery system is highly desirable for enhancing anticancer therapeutic efficacy. Herein, two cyclometalated Ir(III) complex-constructed micelles FIr-1 and FIr-2 were demonstrated for glutathione (GSH) activated targeted chemotherapy and PDT. The cyclometalated Ir(III) complexes were prepared by conjugating phosphorescent Ir(III) compounds with chemotherapeutic drug camptothecin (CPT) through GSH responsive disulfide bond linkages, and the Ir(III) complexes were then assembled with amphiphilic surfactant pluronic F127 via noncovalent encapsulation to afford micelles. The surfaces of the micelles were further decorated with folic acid as a targeting group. The micelles showed intense fluorescence that renders them with excellent real-time imaging capability. The release of free anticancer drug CPT from the micelles was realized through GSH-activated disulfide bond cleavage in tumor cells. In addition, the micelles were capable of generating singlet oxygen used for PDT upon visible light irradiation. On account of having folic acid targeting ligand, the micelles displayed greater cellular accumulation in folate receptor (FR) overexpressed HeLa cells than FR low-expressed MCF-7 cells, leading to selective cancer cell killing effect. As compared with solo therapeutic systems, the micelles with targeted combinational chemotherapy and PDT presented superior potency and efficacy in killing tumor cells at a low dosage. On the basis of these findings, the multifunctional micelles could serve as a versatile theranostic nanoplatform for cancer cell targeted imaging and combinational therapy.
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Iridio/química , Línea Celular Tumoral , Glutatión , Humanos , Micelas , FotoquimioterapiaRESUMEN
Developing multifunctional hybrid nanosystems for controlled drug delivery is a challenging task. In this work, we prepared hierarchical core-shell nanoparticles (ZnO-DOX@ZIF-8) composed of mesoporous ZnO core and microporous ZIF-8 shell, in which the core serves as the drug storage reservoir for the loading of anticancer drug doxorubicin (DOX) and the shell could be used to prevent premature release of loaded drug at physiological environment. The mesoporous ZnO nanoparticles were first prepared, followed by DOX drug loading. Such ZnO nanoparticles were then employed as the zinc source to react with 2-methylimidazole for the formation of ZnO-DOX@ZIF-8 core-shell nanoparticles. The core-shell nanoparticles exhibit good dispersibility and stability as well as pH-responsive drug release property. While only up to 20% of loaded DOX was released in the buffer of pH 7.4, over 80% of DOX was released in the buffer of pH 5.5 because of the decomposition of the ZIF-8 shell as well as the dissolution of the ZnO core under acidic conditions. The confocal microscopy studies show that the core-shell nanoparticles could be efficiently internalized by cancer cells, and the loaded DOX in the nanoparticles could be successfully released under acidic intracellular environment. The in vitro cytotoxicity measurements demonstrate that the core-shell nanoparticles free of drug exhibit a significant cytotoxicity when the concentration was above 25 µg/mL on account of the production of reactive oxygen species. The reactive oxygen species are only generated in acidic condition, which could combine with DOX for a synergistic cancer treatment with satisfactory therapeutic efficacy. On the other hand, the nanoparticles were stable and nontoxic in physiological environment. Thus, the ZnO-DOX@ZIF-8 core-shell nanoparticles are a promising pH-responsive drug delivery system for the cancer therapy.
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The construction of prodrugs has been a popular strategy to overcome the limitations of chemotherapeutic drugs. However, complicated synthesis procedures and laborious purification steps make the fabrication of amphiphilic prodrugs rather difficult. By harnessing the concept of host-guest interaction, we designed and prepared a supra-amphiphile consisting of a dendritic cyclodextrin host and an adamantane/naphthalimide-modified camptothecin guest through glutathione-responsive disulfide linkage. This host-guest complex could self-assemble in aqueous solution to give nanosized vesicles. When the disulfide bond in adamantane/naphthalimide-modified camptothecin was cleaved by glutathione, the fluorescence of the freed adamantane/naphthalimide unit showed a significant red shift with enhanced intensity. Such glutathione-responsive fluorescence change allows for intracellular imaging and simultaneous monitoring of drug release in real time. On account of abundant positively charged amine groups on the supramolecular vesicle surface, siRNA (siPlK1) could be efficiently loaded on the vesicle. The gel retardation and fluorescence experiments proved that the siPlK1 was successfully bonded to the supramolecular vesicle. The vesicle with dendritic cyclodextrin ring exhibited negligible cytotoxicity even at high concentrations, avoiding the shortcoming of cytotoxicity from commonly used gene vectors. In vitro studies demonstrated that the loaded siRNA was transported into cancer cells to improve cancer therapeutic efficacy. Thus, we developed a prodrug-based supramolecular amphiphile via the host-guest interaction with better therapeutic performance than free camptothecin. The assembled system was utilized as a drug/gene vector to achieve combinational gene therapy and chemotherapy with a synergistic effect, providing an alternative strategy to deliver both prodrug and therapeutic gene.
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Profármacos/química , Camptotecina , Liberación de Fármacos , ARN Interferente Pequeño , Nanomedicina TeranósticaRESUMEN
Probing the supramolecular chirality of assemblies and controlling their handedness are closely related to the origin of chirality at the supramolecular level and the development of smart materials with desired handedness. However, it remains unclear how achiral residues covalently bonded to chiral amino acids can function in the chirality inversion of supramolecular assemblies. Herein, we report macroscopic chirality and dynamic manipulation of chiroptical activity of hydrogels self-assembled from phenylalanine derivatives, together with the inversion of their handedness achieved solely by exchanging achiral substituents between oligo(ethylene glycol) and carboxylic acid groups. This helicity inversion is mainly induced by distinct stacking mode of the self-assembled building blocks, as collectively confirmed by scanning electron microscopy, circular dichroism, crystallography, and molecular dynamics calculations. Through this straightforward approach, we were able to invert the handedness of helical assemblies by merely exchanging achiral substituents at the terminal of chiral gelators. This work not only presents a feasible strategy to achieve the handedness inversion of helical nanostructures for better understanding of chiral self-assembly process in supramolecular chemistry but also facilities the development of smart materials with controllable handedness in materials science.