RESUMEN
Nanomedicines are extensively used in cancer therapy. Covalent organic frameworks (COFs) are crystalline organic porous materials with several benefits for cancer therapy, including porosity, design flexibility, functionalizability, and biocompatibility. This review examines the use of COFs in cancer therapy from the perspective of reticular chemistry and function-oriented materials design. First, the modification sites and functionalization methods of COFs are discussed, followed by their potential as multifunctional nanoplatforms for tumor targeting, imaging, and therapy by integrating functional components. Finally, some challenges in the clinical translation of COFs are presented with the hope of promoting the development of COF-based anticancer nanomedicines and bringing COFs closer to clinical trials.
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Estructuras Metalorgánicas , Neoplasias , Estructuras Metalorgánicas/uso terapéutico , Nanomedicina , Porosidad , Neoplasias/tratamiento farmacológicoRESUMEN
Multicomponent reactions (MCRs) combine at least three reactants to afford the desired product in a highly atom-economic way and are therefore viewed as efficient one-pot combinatorial synthesis tools allowing one to significantly boost molecular complexity and diversity. Nowadays, MCRs are no longer confined to organic synthesis and have found applications in materials chemistry. In particular, MCRs can be used to prepare covalent organic frameworks (COFs), which are crystalline porous materials assembled from organic monomers and exhibit a broad range of properties and applications. This synthetic approach retains the advantages of small-molecule MCRs, not only strengthening the skeletal robustness of COFs, but also providing additional driving forces for their crystallization, and has been used to prepare a series of robust COFs with diverse applications. The present perspective article provides the general background for MCRs, discusses the types of MCRs employed for COF synthesis to date, and addresses the related critical challenges and future perspectives to inspire the MCR-based design of new robust COFs and promote further progress in this emerging field.
RESUMEN
Covalent organic frameworks (COFs) are a class of organic crystalline porous materials discovered in the early 21st century that have become an attractive class of emerging materials due to their high crystallinity, intrinsic porosity, structural regularity, diverse functionality, design flexibility, and outstanding stability. However, many chemical and physical properties strongly depend on the presence of metal ions in materials for advanced applications, but metal-free COFs do not have these properties and are therefore excluded from such applications. Metalated COFs formed by combining COFs with metal ions, while retaining the advantages of COFs, have additional intriguing properties and applications, and have attracted considerable attention over the past decade. This review presents all aspects of metalated COFs, from synthetic strategies to various applications, in the hope of promoting the continued development of this young field.
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Estructuras Metalorgánicas , Iones , Estructuras Metalorgánicas/química , PorosidadRESUMEN
Chemodynamic therapy (CDT), which induces cell death by decomposing high levels of H2 O2 in tumor cells into highly toxic ·OH, is recognized as a promising antineoplastic approach. However, current CDT approaches are often restricted by the highly controlled and upregulated cellular antioxidant defense. To enhance ·OH-induced cellular damage by CDT, a covalent organic framework (COF)-based, ferrocene (Fc)- and glutathione peroxidase 4 (GPX4) inhibitor-loaded nanodrug, RSL3@COF-Fc (2b), is fabricated. The obtained 2b not only promotes in situ Fenton-like reactions to trigger ·OH production in cells, but also attenuates the repair mechanisms under oxidative stress via irreversible covalent GPX4 inhibition. As a result, these two approaches synergistically result in massive lipid peroxide accumulation, subsequent cell damage, and ultimately ferroptosis, while not being limited by intracellular glutathione. It is believed that this research provides a paradigm for enhancing reactive oxygen species-mediated oncotherapy through redox dyshomeostasis and may provide new insights for developing COF-based nanomedicine.
Asunto(s)
Antineoplásicos , Estructuras Metalorgánicas , Línea Celular Tumoral , Peróxido de Hidrógeno , Metalocenos , Oxidación-ReducciónRESUMEN
Heat shock protein 90 (Hsp90), as a member of the Hsp family and widely found in the gonads of humans and animals, plays an essential role in male reproduction and induces various changes in the process of reproduction. Hsp90 regulates the division of germ cells and participates in spermatogenesis, location of germ cells, formation of sperm microtubes, protection of sperm from oxidative stress, and inducement of acrosomal reaction. Studies showed significant changes in location and expression of Hsp90 in the sperm of oligospermia and asthenospermia patients. This paper presents an overview of Hsp90 in male reproduction and male infertility and a prospect of the treatment of male infertility.
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Proteínas de Choque Térmico , Humanos , MasculinoRESUMEN
As newly emerged crystalline porous materials, covalent organic frameworks (COFs) possess fascinating structures and some specific features such as modularity, crystallinity, porosity, stability, versatility, and biocompatibility. Besides adsorption/separation, sensing, catalysis, and energy applications, COFs have recently shown a promise in biomedical applications. This contribution provides an overview of the recent developments of COF-based medicines in cancer therapeutics, including drug delivery, photodynamic therapy (PDT), photothermal therapy (PTT), and combined therapy. Furthermore, the major challenges and developing trends in this field are also discussed. These recent developments are summarized and discussed to help encourage further contributions in this emerging and promising field.
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Estructuras Metalorgánicas , Neoplasias/tratamiento farmacológico , Fotoquimioterapia/métodos , Adsorción , Catálisis , Humanos , PorosidadRESUMEN
Ca2+ , a ubiquitous but nuanced modulator of cellular physiology, is meticulously controlled intracellularly. However, intracellular Ca2+ regulation, such as mitochondrial Ca2+ buffering capacity, can be disrupted by 1 O2 . Thus, the intracellular Ca2+ overload, which is recognized as one of the important cell pro-death factors, can be logically achieved by the synergism of 1 O2 with exogenous Ca2+ delivery. Reported herein is a nanoscale covalent organic framework (NCOF)-based nanoagent, namely CaCO3 @COF-BODIPY-2I@GAG (4), which is embedded with CaCO3 nanoparticle (NP) and surface-decorated with BODIPY-2I as photosensitizer (PS) and glycosaminoglycan (GAG) targeting agent for CD44 receptors on digestive tract tumor cells. Under illumination, the light-triggered 1 O2 not only kills the tumor cells directly, but also leads to their mitochondrial dysfunction and Ca2+ overload. An enhanced antitumor efficiency is achieved via photodynamic therapy (PDT) and Ca2+ overload synergistic therapy.
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Antineoplásicos/uso terapéutico , Compuestos de Boro/química , Carbonato de Calcio/química , Neoplasias/tratamiento farmacológico , Animales , Señalización del Calcio , Línea Celular Tumoral , Sinergismo Farmacológico , Glicosilación , Humanos , Ratones , Microscopía Electrónica de Rastreo , Microscopía Electrónica de Transmisión , Fotoquimioterapia , Análisis Espectral/métodos , Difracción de Rayos X , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
We report herein a new ZIF-90-based PDT agent which was synthesized by in situ assembly of imidazole-2-carboxaldehyde (IcaH), Zn(NO3)2, and heavy atom iodine-attached Bodipy. The obtained 2I-BodipyPhNO2@ZIF-90 (1) host-guest photosensitive system featured low cytotoxicity, good biocompatibility, pH-driven selective cancer cell uptake and release, mitochondria targeting, and highly efficient pH-triggered 1O2 generation. Therefore, it can be used as a high-performing PDT agent to selectively kill tumor cells. In comparison to free 2I-BodipyPhNO2, 1 exhibits a much higher antitumor efficacy and selectivity, which was confirmed by in vitro cell experiments.
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Antineoplásicos/farmacología , Compuestos de Boro/farmacología , Estructuras Metalorgánicas/farmacología , Nanopartículas/química , Fármacos Fotosensibilizantes/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/efectos de la radiación , Antineoplásicos/toxicidad , Apoptosis/efectos de los fármacos , Compuestos de Boro/síntesis química , Compuestos de Boro/efectos de la radiación , Compuestos de Boro/toxicidad , Línea Celular Tumoral , Estabilidad de Medicamentos , Humanos , Concentración de Iones de Hidrógeno , Estructuras Metalorgánicas/síntesis química , Estructuras Metalorgánicas/efectos de la radiación , Estructuras Metalorgánicas/toxicidad , Mitocondrias/metabolismo , Nanopartículas/efectos de la radiación , Nanopartículas/toxicidad , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/efectos de la radiación , Fármacos Fotosensibilizantes/toxicidad , Oxígeno Singlete/metabolismoRESUMEN
Herein, we report an iodine-attached Zn(II)-porphyrinic dicarboxylic building block (ZnDTPP-I2-2H, 1) that can be introduced into UiO-66 NMOF via one-pot synthetic approach to generate a new ZnDTPP-I2 doped UiO-66 type nano metal-organic framework (NMOF) of ZnDTPP-I2âUiO-66 (2). Compared to its homologous iodine-free NMOF of ZnDTPPâUiO-66 (4), ZnDTPP-I2âUiO-66 (2) with heavy iodine atoms is a more effective nanosized photosensitizer for singlet oxygen generation under physiological conditions. As expected, 2 displayed a high photodynamic therapy efficacy for treatment of liver cancer cells in vitro.
Asunto(s)
Estructuras Metalorgánicas/farmacología , Metaloporfirinas/farmacología , Fotoquimioterapia , Fármacos Fotosensibilizantes/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/efectos de la radiación , Estabilidad de Medicamentos , Células Hep G2 , Humanos , Luz , Luminiscencia , Estructuras Metalorgánicas/síntesis química , Estructuras Metalorgánicas/química , Estructuras Metalorgánicas/efectos de la radiación , Metaloporfirinas/síntesis química , Metaloporfirinas/química , Metaloporfirinas/efectos de la radiación , Nanopartículas/química , Nanopartículas/efectos de la radiación , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/efectos de la radiación , Oxígeno Singlete/química , Zinc/química , Circonio/químicaRESUMEN
Metal-free radiosensitizers, particularly iodine, have shown promise in enhancing radiotherapy due to their suitable X-ray absorption capacities and negligible biotoxicities. However, conventional iodine compounds have very short circulating half-lives and are not retained in tumors very well, which significantly limits their applications. Covalent organic frameworks (COFs) are highly biocompatible crystalline organic porous materials that are flourishing in nanomedicine but have not been developed for radiosensitization applications. Herein, we report the room-temperature synthesis of an iodide-containing cationic COF by the three-component one-pot reaction. The obtained TDI-COF can be a tumor radiosensitizer for enhanced radiotherapy by radiation-induced DNA double-strand breakage and lipid peroxidation and inhibits colorectal tumor growth by inducing ferroptosis. Our results highlight the excellent potential of metal-free COFs as radiotherapy sensitizers.
RESUMEN
Herein, we report the first reactive oxygen species (ROS)-responsive dithioketal-linked covalent organic framework (COF) for synergetic chemotherapy and photodynamic therapy (PDT) of cancer. The singlet oxygen (1O2)-responsive COF dissociation and DC_AC50 drug release complement and reinforce each other to allow an efficient combination of PDT and chemotherapy.
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Estructuras Metalorgánicas , Fotoquimioterapia , Línea Celular Tumoral , Terapia Combinada , Oxígeno , Fármacos Fotosensibilizantes , Especies Reactivas de Oxígeno , Oxígeno Singlete/químicaRESUMEN
Stimulus-responsive biodegradable nanocarriers with tumor-selective targeted drug delivery are critical for cancer therapy. Herein, we report for the first time a redox-responsive disulfide-linked porphyrin covalent organic framework (COF) that can be nanocrystallized by glutathione (GSH)-triggered biodegradation. After loading 5-fluorouracil (5-Fu), the generated nanoscale COF-based multifunctional nanoagent can be further effectively dissociated by endogenous GSH in tumor cells, releasing 5-Fu efficiently to achieve selective chemotherapy on tumor cells. Together with the GSH depletion-enhanced photodynamic therapy (PDT), an ideal synergistic tumor therapy for MCF-7 breast cancer via ferroptosis is achieved. In this research, the therapeutic efficacy was significantly improved in terms of enhanced combined anti-tumor efficiency and reduced side effects by responding to significant abnormalities such as high concentrations of GSH in the tumor microenvironment (TME).
RESUMEN
Radiotherapy is inevitably accompanied by some degree of radiation resistance, which leads to local recurrence and even therapeutic failure. To overcome this limitation, herein, we report the room-temperature synthesis of an iodine- and ferrocene-loaded covalent organic framework (COF) nanozyme, termed TADI-COF-Fc, for the enhancement of radiotherapeutic efficacy in the treatment of radioresistant esophageal cancer. The iodine atoms on the COF framework not only exerted a direct effect on radiotherapy, increasing its efficacy by increasing X-ray absorption, but also promoted the radiolysis of water, which increased the production of reactive oxygen species (ROS). In addition, the ferrocene surface decoration disrupted redox homeostasis by increasing the levels of hydroxyl and lipid peroxide radicals and depleting intracellular antioxidants. Both in vitro and in vivo experiments substantiated the excellent radiotherapeutic response of TADI-COF-Fc. This study demonstrates the potential of COF-based multinanozymes as radiosensitizers and suggests a possible treatment integration strategy for combination oncotherapy.
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Neoplasias Esofágicas , Yodo , Estructuras Metalorgánicas , Humanos , Estructuras Metalorgánicas/farmacología , Metalocenos , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/radioterapiaRESUMEN
Biothiols, including glutathione (GSH) and cysteine, are important reductants that maintain intracellular redox homeostasis. Recent studies have demonstrated that cysteine deprivation is a more effective antitumor strategy than GSH depletion. However, the lack of highly chemoselective and tumor-specific cysteine-consuming reagents limits the practical application of cysteine deprivation. Herein, we report a vinyl-decorated nanoscale covalent organic framework (COF) prepared in aqueous solution at room temperature. After encapsulating a Ru(II)-based photocatalyst, the obtained Ru(II)@COF-V efficiently catalyzes the thiol-ene click reaction between vinyl and cysteine upon visible-light irradiation. Ru(II)@COF-V preferentially accumulates in lipid droplets of tumor cells via lipid raft- and caveolin-related endocytosis and induces lipid peroxidation and ferroptosis by consuming cysteine, exhibiting powerful therapeutic activity against colon cancer. We believe that this study both enriches the ambient synthesis of nanoscale COFs and highlights the feasibility of intracellular photochemical reactions for tumor therapy.
Asunto(s)
Ferroptosis , Estructuras Metalorgánicas , Neoplasias , Humanos , Cisteína , GlutatiónRESUMEN
Small interfering RNA (siRNA)-mediated gene silencing is a promising therapeutic approach. Herein, we report the ambient synthesis of a positively charged iminium-linked covalent organic framework by a three-component one-pot reaction. Through anion exchange and siRNA adsorption, the resulting multifunctional siRNA@ABMBP-COF, which possesses both the HK2 inhibitor 3-bromopyruvate and SLC7A11 siRNA, exhibits powerful synergistic antitumor activity against fibrosarcoma via the ferroptosis and apoptosis pathways.
RESUMEN
Ferroptosis, distinct from apoptosis, is a regulated form of cell death caused by lipid peroxidation that has attracted extensive research interest since it was first defined in 2012. Over the past five years, an increasing number of studies have revealed the close relationship between ferroptosis and materials chemistry, in particular nanobiotechnology, and have concluded that nanotechnology-triggered ferroptosis is an efficient and promising antitumor strategy that provides an alternative therapeutic approach, especially for apoptosis-resistant tumors. In this review, we summarize recent advances in ferroptosis-induced tumor therapy at the intersection of materials chemistry, redox biology, and tumor biology. The biological features and molecular mechanisms of ferroptosis are first outlined, followed by a summary of the feasible strategies to induce ferroptosis using nanomaterials and the applications of ferroptosis in combined tumor therapy. Finally, the existing challenges and future development directions in this emerging field are discussed, with the aim of promoting the progress of ferroptosis-based oncotherapy in materials science and nanoscience and enriching the antitumor arsenal.
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Antineoplásicos/farmacología , Ferroptosis/efectos de los fármacos , Nanoestructuras/química , Neoplasias/tratamiento farmacológico , Antineoplásicos/química , Humanos , Nanotecnología , Neoplasias/patología , Tamaño de la Partícula , Propiedades de SuperficieRESUMEN
Cancer nanomedicine is one of the most promising domains that has emerged in the continuing search for cancer diagnosis and treatment. The rapid development of nanomaterials and nanotechnology provide a vast array of materials for use in cancer nanomedicine. Among the various nanomaterials, covalent organic frameworks (COFs) are becoming an attractive class of upstarts owing to their high crystallinity, structural regularity, inherent porosity, extensive functionality, design flexibility, and good biocompatibility. In this comprehensive review, recent developments and key achievements of COFs are provided, including their structural design, synthesis methods, nanocrystallization, and functionalization strategies. Subsequently, a systematic overview of the potential oncotherapy applications achieved till date in the fast-growing field of COFs is provided with the aim to inspire further contributions and developments to this nascent but promising field. Finally, development opportunities, critical challenges, and some personal perspectives for COF-based cancer therapeutics are presented.
RESUMEN
Herein, we report a microporous carbon nanomaterial that was generated from a nanoscale covalent organic framework precursor via a simple pyrolysis approach. The obtained carbon-based nanoparticles possessed a broad NIR absorption capacity and exhibited a high level of photothermal conversion ability (η = 50.6%) in the NIR-II biowindow. Its excellent PTT antitumor efficiency was fully evidenced by in vitro and in vivo experiments under 1064 nm laser irradiation.
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Carbono/química , Estructuras Metalorgánicas/química , Nanoestructuras/química , Terapia Fototérmica/métodos , Espectroscopía Infrarroja Corta/métodos , Animales , Humanos , Células MCF-7 , Ratones , Microscopía Electrónica de Rastreo , Microscopía Electrónica de Transmisión , Porosidad , Difracción de Polvo , Nanomedicina Teranóstica , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
We demonstrate herein an effective cascade reaction for combined photodynamic and starvation therapy in treating breast tumors based on a photosensitizer and CO prodrug decorated NMOF. The PDT-induced ROS can further trigger CO release, and the high antitumor efficiency derived from both 1O2 and CO is well confirmed by in vitro assays and in vivo trials.
Asunto(s)
Compuestos de Boro/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Estructuras Metalorgánicas , Nanoestructuras , Fármacos Fotosensibilizantes/uso terapéutico , Monóxido de Carbono/química , Femenino , Humanos , Manganeso/química , Profármacos/uso terapéutico , Oxígeno Singlete/químicaRESUMEN
Despite the excellent photodynamic and photothermal properties of organic molecular photosensitizers (PSs) and photothermal agents (PTAs), such as porphyrin and naphthalocyanine, their poor water solubility severely impedes their biological applications. Covalent organic frameworks (COFs), as an emerging class of organic crystalline porous materials, possess free active end groups (bonding defects) and large inner pores, which make them an ideal type of nanocarriers for loading hydrophobic organic molecular PSs and PTAs by both bonding defect functionalization (BDF) and guest encapsulation approaches to obtain multifunctional nanomedicines for PDT/PTT combination therapy. In this work, we report a nanoscale COF (NCOF) prepared via a facile synthetic approach under ambient conditions. Furthermore, a dual-modal PDT/PTT therapeutic nanoagent, VONc@COF-Por (3), is successfully fabricated by stepwise BDF and guest encapsulation processes. The covalently grafted porphyrinic PS (Por) and the noncovalently loaded naphthalocyanine PTA (VONc) are independently responsible for the PDT and PTT functionalities of the nanoagent. Upon visible (red LED) and NIR (808 nm laser) irradiation, VONc@COF-Por (3) displayed high 1O2 generation and photothermal conversion ability (55.9%), consequently providing an excellent combined PDT/PTT therapeutic effect on inhibiting MCF-7 tumor cell proliferation and metastasis, which was well evidenced by in vitro and in vivo experiments. We believe that the results obtained herein can significantly promote the development of NCOF-based multifunctional nanomedicines for biomedical applications.