Near-infrared (NIR) light-induced cancer therapy has gained considerable interest, but pure inorganic anti-cancer platforms usually suffer from degradation issues. Here, we designed metal-organic ...frameworks (MOFs) of Fe3O4/ZIF-8-Au25 (IZA) nanospheres through a green and economic procedure. The encapsulated Fe3O4 nanocrystals not only produce hyperthemal effects upon NIR light irradiation to effectively kill tumor cells, but also present targeting and MRI imaging capability. More importantly, the attached ultrasmall Au25(SR)18(-) clusters (about 2.5 nm) produce highly reactive singlet oxygen ((1)O2) to cause photodynamic effects through direct sensitization under NIR light irradiation. Furthermore, the Au25(SR)18(-) clusters also give a hand to the hyperthemal effect as photothermal fortifiers. This nanoplatform exhibits high biocompatibility and an enhanced synergistic therapeutic effect superior to any single therapy, as verified by in vitro and in vivo assay. This image-guided therapy based on a metal-organic framework may stimulate interest in developing other kinds of metal-organic materials with multifunctionality for tumor diagnosis and therapy.
Abstract Upon near-infrared (NIR) light irradiation, the Nd3+ doping derived down-conversion luminescence (DCL) in NIR region and thermal effect are extremely fascinating in bio-imaging and ...photothermal therapy (PTT) fields. However, the concentration quenching induced opposite changing trend of the two properties makes it difficult to get desired DCL and thermal effect together in one single particle. In this study, we firstly designed a unique NaGdF4 :0.3%Nd@NaGdF4 @NaGdF4 :10%Yb/1%Er@NaGdF4 :10%Yb @NaNdF4 :10%Yb multiple core-shell structure. Here the inert two layers (NaGdF4 and NaGdF4 :10%Yb) can substantially eliminate the quenching effects, thus achieving markedly enhanced NIR-to-NIR DCL, NIR-to-Vis up-conversion luminescence (UCL), and thermal effect under a single 808 nm light excitation simultaneously. The UCL excites the attached photosensitive drug (Au25 nanoclusters) to generate singlet oxygen (1 O2 ) for photodynamic therapy (PDT), while DCL with strong NIR emission serves as probe for sensitive deep-tissue imaging. The in vitro and in vivo experimental results demonstrate the excellent cancer inhibition efficacy of this platform due to a synergistic effect arising from the combined PTT and PDT. Furthermore, multimodal imaging including fluorescence imaging (FI), photothermal imaging (PTI), and photoacoustic imaging (PAI) has been obtained, which is used to monitor the drug delivery process, internal structure of tumor and photo-therapeutic process, thus achieving the target of imaging-guided cancer therapy.
Up‐conversion (UC) luminescent and porous NaYF4:Yb3+, Er3+@SiO2 nanocomposite fibers are prepared by electrospinning process. The biocompatibility test on L929 fibrolast cells reveals low ...cytotoxicity of the fibers. The obtained fibers can be used as anti‐cancer drug delivery host carriers for investigation of the drug storage/release properties. Doxorubicin hydrochloride (DOX), a typical anticancer drug, is introduced into NaYF4:Yb3+, Er3+@SiO2 nanocomposite fibers (denoted as DOX‐NaYF4:Yb3+, Er3+@SiO2). The release properties of the drug carrier system are examined and the in vitro cytotoxicity and cell uptake behavior of these NaYF4:Yb3+, Er3+@SiO2 for HeLa cells are evaluated. The release of DOX from NaYF4:Yb3+, Er3+@SiO2 exhibits sustained, pH‐sensitive release patterns and the DOX‐NaYF4:Yb3+, Er3+@SiO2 show similar cytotoxicity as the free DOX on HeLa cells. Confocal microscopy observations show that the composites can be effectively taken up by HeLa cells. Furthermore, the fibers show near‐infrared UC luminescence and are successfully applied in bioimaging of HeLa cells. The results indicate the promise of using NaYF4:Yb3+, Er3+@SiO2 nanocomposite fibers as multi‐functional drug carriers for drug delivery and cell imaging.
NaYF4:Yb3+, Er3+@SiO2 nanocomposite fibers, which are used as a novel anticancer drug carrier, are prepared using an electrospinning process. The fibers show the attractive properties of regular morphology, porous structure, good biocompatibility, and up‐conversion emission. The drug loading and release properties, cytotoxicity, cellular uptake, and cell imaging of nanocomposite fibers are investigated.
We engineered metal-phenolic capsules with both high targeting and low nonspecific cell binding properties. The capsules were prepared by coating phenolic-functionalized hyaluronic acid (HA) and ...poly(ethylene glycol) (PEG) on calcium carbonate templates, followed by cross-linking the phenolic groups with metal ions and removing the templates. The incorporation of HA significantly enhanced binding and association with a CD44 overexpressing (CD44+) cancer cell line, while the incorporation of PEG reduced nonspecific interactions with a CD44 minimal-expressing (CD44−) cell line. Moreover, high specific targeting to CD44+ cells can be balanced with low nonspecific binding to CD44– cells simply by using an optimized feed-ratio of HA and PEG to vary the content of HA and PEG incorporated into the capsules. Loading an anticancer drug (i.e., doxorubicin) into the obtained capsules resulted in significantly higher cytotoxicity to CD44+ cells but lower cytotoxicity to CD44– cells.
Radiotherapy (RT) based on DNA damage and reactive oxygen species (ROS) generation has been clinically validated in various types of cancer. However, high dose‐dependent induced toxicity to tissues, ...non‐selectivity, and radioresistance greatly limit the application of RT. Herein, an oxygen‐enriched X‐ray nanoprocessor Hb@Hf‐Ce6 nanoparticle is developed for improving the therapeutic effect of RT‐radiodynamic therapy (RDT), enhancing modulation of hypoxia tumor microenvironment (TME) and promoting antitumor immune response in combination with programmed cell death protein 1 (PD‐1) immune checkpoint blockade. All functional molecules are integrated into the nanoparticle based on metal‐phenolic coordination, wherein one high‐Z radiosensitizer (hafnium, Hf) coordinated with chlorin e6 (Ce6) modified polyphenols and a promising oxygen carrier (hemoglobin, Hb) is encapsulated for modulation of oxygen balance in the hypoxia TME. Specifically, under single X‐ray irradiation, radioluminescence excited by Hf can activate photosensitizer Ce6 for ROS generation by RDT. Therefore, this combinatory strategy induces comprehensive antitumor immune response for cancer eradication and metastasis inhibition. This work presents a multifunctional metal‐phenolic nanoplatform for efficient X‐ray mediated RT‐RDT in combination with immunotherapy and may provide a new therapeutic option for cancer treatment.
Oxygen‐enriched X‐ray nanoprocessor Hb@Hf‐Ce6 nanoparticles are developed for improving therapeutic effect of radiotherapy‐radiodynamic therapy, enhancing modulation of hypoxia tumor microenvironment, and promoting antitumor immune response in combination with anti‐PD‐1 antibody. This work presents the favorable metal‐phenolic X‐ray nanoprocessor, which could open new avenues for cancer treatment based on nanomedicine.
A series of hollow and luminescent capsules have been fabricated by covering luminescent Gd2O3:Yb/Tm nanoparticles on the surface of uniform hollow mesoporous silica capsules (HMSCs), which were ...obtained from an etching process using Fe3O4 as hard templates. X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), high-resolution transmission electron microscopy (HRTEM), up-conversion (UC) fluorescence spectra, and N2 adsorption–desorption were used to characterize these samples. It is found that the as-prepared products have mesoporous pores, large specific surface, and high dispersity. In particular, the size, shape, surface area, and interior space of the composites can be finely tuned by adjusting the size and morphology of the magnetic cores. Under 980 nm near-infrared (NIR) laser irradiation, the composites show characteristic blue UC emissions of Tm3+ even after carrying doxorubicin hydrochloride (DOX). The drug-release test reveals that the capsules showed an apparent sustained release character and released in a pH-sensitive manner. Interestingly, the UC luminescence intensity of the drug-carrying system increases with the released DOX, realizing the possibility to track or monitor the released drug by the change of UC fluorescence simultaneously, which should be highly promising in anticancer drug delivery and targeted cancer therapy.
Clinical updates suggest conserving metastatic sentinel lymph nodes (SLNs) of breast cancer (BC) patients during surgery; however, the immunoadjuvant potential of this strategy is unknown. Here we ...leverage an immune-fueling flex-patch to animate metastatic SLNs with personalized antitumor immunity. The flex-patch is implanted on the postoperative wound and spatiotemporally releases immunotherapeutic anti-PD-1 antibodies (aPD-1) and adjuvants (magnesium iron-layered double hydroxide, LDH) into the SLN. Genes associated with citric acid cycle and oxidative phosphorylation are enriched in activated CD8
T cells (CTLs) from metastatic SLNs. Delivered aPD-1 and LDH confer CTLs with upregulated glycolytic activity, promoting CTL activation and cytotoxic killing via metal cation-mediated shaping. Ultimately, CTLs in patch-driven metastatic SLNs could long-termly maintain tumor antigen-specific memory, protecting against high-incidence BC recurrence in female mice. This study indicates a clinical value of metastatic SLN in immunoadjuvant therapy.
Nanofibers are long, wire-like materials with nanoscale diameters and specific length diameter ratios. Nanofibers have porous reticular networks with remarkably high specific surface areas and ...significant interconnectivity between pores, allowing for the chemical modification and loading of drugs. Metallized nanofibers are novel materials that enhance the performance of attributes of conventional nanofibers by combining metals with nanofibers through electrostatic spinning doping, chemical modification, and loading approaches. Due to their unique physical and chemical properties, metallized nanofibers are diverse, rapidly developed materials in the fields of physical chemistry, materials science, and battery preparation. To date, with improvement in advanced preparation techniques and biocompatibility levels for materials, metallized nanofiber applications are gradually expanding into the biomedical field due to their excellent thermal and electrical conductivities and unique metal properties. In this review, the applications of metallized nanofibers in biomedicine are summarized. It is suggested to prepare metallized multifunctional nanofibers for tissue engineering, drug delivery, tumor treatment, wound healing, and biosensing applications by taking safety and stability as the main material selection guidelines. Finally, the development of nanofibers for biomedical applications is summarized and discussed.
Metal–phenolic networks (MPNs) are a versatile class of self-assembled materials that are able to form functional thin films on various substrates with potential applications in areas including drug ...delivery and catalysis. Different metal ions (e.g., FeIII, CuII) and phenols (e.g., tannic acid, gallic acid) have been investigated for MPN film assembly; however, a mechanistic understanding of the thermodynamics governing MPN formation remains largely unexplored. To date, MPNs have been deposited at low ionic strengths (<5 mM), resulting in films with typical thicknesses of ∼10 nm, and it is still unclear how a bulk complexation reaction results in homogeneous thin films when a substrate is present. Herein we explore the influence of ionic strength (0–2 M NaCl) on the conformation of MPN precursors in solution and how this determines the final thickness and morphology of MPN films. Specifically, the film thickness increases from 10 nm in 0 M NaCl to 12 nm in 0.5 M NaCl and 15 nm in 1 M NaCl, after which the films grow rougher rather than thicker. For example, the root-mean-square roughness values of the films are constant below 1 M NaCl at 1.5 nm; in contrast, the roughness is 3 nm at 1 M NaCl and increases to 5 nm at 2 M NaCl. Small-angle X-ray scattering and molecular dynamics simulations allow for comparisons to be made with chelated metals and polyelectrolyte thin films. For example, at a higher ionic strength (2 M NaCl), sodium ions shield the galloyl groups of tannic acid, allowing them to extend away from the FeIII center and interact with other MPN complexes in solution to form thicker and rougher films. As the properties of films determine their final performance and application, the ability to tune both thickness and roughness using salts may allow for new applications of MPNs.
Summary
Aminoglycosides are one of the oldest classes of antimicrobials that are being used in current clinical practice, especially on multi‐drug resistant Gram‐negative pathogenic bacteria. ...However, the serious side effects at high dosage such as ototoxicity, neuropathy and nephrotoxicity limit their applications in clinical practice. Approaches that potentiate aminoglycoside killing could lower down their effective concentrations to a non‐toxic dosage for clinical treatment. In this research, we screened a compound library and identified sanguinarine that acts synergistically with various aminoglycosides. By checkerboard and dynamical killing assay, we found that sanguinarine effectively potentiated aminoglycoside killing on diverse bacterial pathogens, including Escherichia coli, Acinetobacter baumannii, Klebsiella pneumonia and Pseudomonas aeruginosa. The mechanistic studies showed an elevated intracellular ROS and DNA oxidative level in the bacterial cells treated by a combination of sanguinarine with aminoglycosides. Furthermore, an enhanced level of sanguinarine was observed in bacteria in the presence of aminoglycosides, suggesting that aminoglycosides promote the uptake of sanguinarine. Importantly, sanguinarine was shown to promote the elimination of persister cells and established biofilm cells both in vivo and in vitro. Our study provides a novel insight for approaches to lower down the clinical dosages of aminoglycosides.
Aminoglycosides primarily interact with the bacterial ribosomes and result in protein misfolding and ROS production. Insertion of abnormal proteins into the cell membrane increases the membrane permeability and leads to enhanced uptake of sanguinarine. The sanguinarine acts synergistically with aminoglycoside to generate high level of ROS and results in bacterial death.
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