RESUMO
Hypoxia, chronic inflammation, and elevated reactive oxygen species (ROS) production induced by hyperglycemia pose formidable challenges to the healing of diabetic chronic wounds, often resulting in impaired recovery. Currently, sustainable and eco-friendly therapeutic approaches targeting this multifaceted problem remain uncharted. Herein, we develop a unique three-functional covalent organic framework (COF)-modified microalgae gel designed for the preparation and treatment of chronic diabetic wounds. The gel comprises an oxygen-releasing basic fibroblast growth factor (bFGF) microalgae matrix, augmented by an ROS-responsive COF. Although two of these components have been reported to be used in wound healing, the combination of all three functions represents an innovative approach to synergize the treatment of chronic diabetic wounds. Therefore, we propose a new concept of "ligand interlocking" with three functional synergistic effects. Specifically, the COF has a similar effect to the "double Excalibur", which binds bFGF to promote angiogenesis and proliferation and inhibit the inflammatory response of chronic wounds and binds live microalgae to eliminate ROS and release dissolved oxygen to alleviate the hypoxia of wounds. Moreover, in vivo experiments and RNA sequencing analyses similarly demonstrated that the COF-modified microalgae gel reduced the inflammatory cascade cycle in the wound site and promoted vascular and tissue regeneration. We posit that the COF-modified microalgae gel represents a promising strategy for the active in vivo delivery of therapeutics to the wound body in intensive care unit settings.
Assuntos
Diabetes Mellitus , Estruturas Metalorgânicas , Microalgas , Humanos , Fator 2 de Crescimento de Fibroblastos , Espécies Reativas de Oxigênio , Géis , Hipóxia , Oxigênio , HidrogéisRESUMO
Covalent organic frameworks (COFs) have garnered enormous attention in anti-cancer therapy recently. However, the intrinsic drawbacks such as poor biocompatibility and low target-specificity greatly restrain the full clinical implementation of COF. Herein, we report a biomimetic multifunctional COF nanozyme, which consists of AIEgen-based COF (TPE-s COF) with encapsulated gold nanoparticles (Au NPs). The nanozyme was co-cultured with HepG2 cells until the cell membrane was fused with lipophilic TPE-s COF-Au@Cisplatin. By using the cryo-shocking method, we fabricated an inactivated form of the TPE-s COF-Au@Cisplatin nanozyme endocytosed in the HepG2 cell membrane (M@TPE-s COF-Au@Cisplatin), which lost their proliferative ability and pathogenicity. Upon laser irradiation, the M@TPE-s COF-Au@Cisplatin nanozymes cleaved, thereby releasing the TPE-s COF-Au nanozyme and Cisplatin to exert their photothermal and drug therapeutic effect. This work opens a new avenue to the synthesis of tumor-derived fluorescent TPE-s COF-Au nanozymes for highly efficient, synergetic, and targeted chemo-photothermal combination therapy of liver cancer.
RESUMO
Covalent organic frameworks (COFs) have revealed enormous application prospects for cancer therapeutics recently, but their assembly systems face considerable challenges, such as the codelivery of hydrophobic and hydrophilic protein drugs with different physicochemical properties for in vivo delivery and release, as well as endosomal/lysosomal escape of protein drugs. To address these issues, we leveraged the high specific surface area, lipotropism, and structural tunability of boronate ester-linked COFs (COF-1) for the construction of advanced drug delivery systems. We first encapsulated the small-molecule drug doxorubicin (DOX) into a lipophilic COF (COF-1@DOX) and immobilized the functional protein drug ribonuclease A (RNase A) on the surface of the COF (RNase A-COF-1@DOX). We then created a novel composite delivery system (RNase A-COF-1@DOX gel) by cross-linking an albumin-oxygenated hydrogel (gel) network into the pores of COFs, allowing targeted codelivery of protein and small-molecule drugs in vivo. Using in-living body and multichannel fluorescence imaging, we analyzed the in vivo codelivery of protein and small-molecule drugs in a Lewis lung carcinoma (LLC) model. Finally, we applied the RNase A-COF-1@DOX gel to treat lung cancer in mice. This study paves an avenue for constructing COF-based drug delivery systems for lung cancer treatment and holds the potential to be extended to other types of cancer for more effective and targeted therapeutic treatments.
Assuntos
Neoplasias Pulmonares , Estruturas Metalorgânicas , Animais , Camundongos , Hidrogéis/farmacologia , Ribonuclease Pancreático , Neoplasias Pulmonares/tratamento farmacológico , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Ribonucleases , Estruturas Metalorgânicas/farmacologiaRESUMO
For decades, covalent organic frameworks (COFs) have attracted wide biomedical interest due to their unique properties including ease of synthesis, porosity, and adjustable biocompatibility. Versatile COFs can easily encapsulate various therapeutic drugs due to their extremely high payload and porosity. COFs with abundant functional groups can be surface-modified to achieve active targeting and enhance biocompatibility. In this paper, the latest developments of COFs in the biomedical field are summarized. First, the classification and synthesis of COFs are discussed. Cancer diagnosis and treatment based on COFs are studied, and the advantages and limitations of each method are discussed. Second, the specific preparation methods to obtain specific therapeutic properties are summarized. Finally, based on the combination and modification of COFs with various components, this review system summarizes different combination therapies. In addition, the main challenges faced in COF research and prospects for applying COFs to cancer diagnosis and treatment are evaluated. This review provides enlightening insights into the interdisciplinary research on COFs and applications in biomedicine, which highlight the great expectations for their further clinical transformation.
Assuntos
Estruturas Metalorgânicas , Neoplasias , Humanos , Estruturas Metalorgânicas/uso terapêutico , Neoplasias/diagnóstico , PorosidadeRESUMO
Chronic itch, a distressing symptom of many cutaneous and systemic diseases, significantly impairs quality of life. However, its underlying molecular mechanism is still unclear. Mas-related G protein-coupled receptor A3 (MrgprA3) is considered an itch-specific receptor. MrgprA3 neurons are identified as a class of itch-specific neurons, but the role of MrgprA3 in chronic itch remains elusive. An acetone-ether-water (AEW) model as a histamine-independent itch model is often used in the study of chronic pruritus. In this study, behavioral tests, immunostaining, cell culture, calcium imaging, and other experiments were carried out to examine the expression of MrgprA3. The results showed that the scratching bouts induced by chloroquine increased significantly under the AEW condition; the density of MrgprA3 sensory fibers in the AEW-treated skin area and the number of MrgprA3 neurons in dorsal root ganglia from the AEW model mice also increased significantly. Further analysis showed that the MrgprA3 in mRNA level was also increased after AEW treatment. These results indicated that MrgprA3 played a crucial role in chronic pruritus in the AEW model.