A general organic acid/aldehyde-mediated catalytic oxidation mechanism of manganese oxide nanoparticles (MnO2, Mn3O4, and Mn2O3) was developed and their anticancer application was explored.

A B S T R A C T Reactive oxygen species (ROS) are important signal molecules and imbalanced ROS level could lead to cell death. Elevated ROS levels in tumor tissues offer an opportunity to design ROS-responsive drug delivery systems (DDSs) or ROS-based cancer therapies such as chemodynamic therapy. However, their anticancer efficacies are hampered by the ROS-consuming nature of these DDSs as well as the high concentration of reductive agents like glutathione (GSH). Here we developed a doxorubicin (DOX)-incorporated iron coordination polymer nanoparticle (PCFD) for efficient chemo-chemodynamic cancer therapy by using a cinnamaldehyde (CA)-based ROS-replenishing organic ligand (TCA). TCA can ROS-responsively release CA to supplement intracellular ROS and deplete GSH by a thiol-Michael addition reaction, which together with DOX-triggered ROS upregulation and Fe3 +-enabled GSH depletion facilitated efficient DOX release and enhanced Fenton reaction, thereby inducing redox dyshomeostasis and cancer cell death in a con-current apoptosis-ferroptosis way. Both in vitro and in vivo studies revealed that ROS-replenishing PCFD exhibited much better anticancer effect than ROS-consuming control nanoparticle PAFD. The ingenious ROS-replenishing strategy could be expanded to construct versatile ROS-responsive DDSs and ROS-based nanomedicines with potentiated anticancer activity.Statement of significanceWe develop a doxorubicin (DOX)-incorporated iron coordination polymer nanoparticle (PCFD) for effi-cient chemo-chemodynamic cancer therapy by using a cinnamaldehyde-based reactive oxygen species (ROS)-replenishing organic ligand. This functional ligand can ROS-responsively release cinnamaldehyde to supplement intracellular H2O2 and deplete glutathione (GSH) by a thiol-Michael addition reaction, which together with DOX-triggered ROS upregulation and Fe3 +-enabled GSH depletion facilitates efficient DOX release and enhanced Fenton reaction, thereby inducing redox dyshomeostasis and cancer cell death in a concurrent apoptosis-ferroptosis way. Both in vitro and in vivo studies reveal that ROS-replenishing PCFD exhibit much better anticancer effect than ROS consuming counterpart. This study provides a facile and straightforward strategy to design ROS amplifying nanoplatforms for cancer treatment.(c) 2022 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Despite the extensive explorations of nanoscale metal-organic frameworks (nanoMOFs) in drug delivery, the intrinsic bioactivity of nanoMOFs, such as anticancer activity, is severely underestimated owing to the overlooked integration of the hierarchical components including nanosized MOFs and molecular-level organic ligands and metal-organic complexes. Herein, we propose a de novo design of multifunctional bioactive nanoMOFs ranging from molecular to nanoscale level, and demonstrate this proof-of-concept by a copper-olsalazine (Olsa, a clinically approved drug for inflammatory bowel disease, here as a bioactive linker and DNA hypomethylating agent) nanoMOF displaying a multifaceted anticancer mechanism: (1) Cu-Olsa nanoMOF-mediated redox dyshomeostasis for enhanced catalytic tumor therapy, (2) targeting downregulation of cyclooxygenase-2 by the organic complex of Cu2+ and Olsa, and (3) Olsa-mediated epigenetic regulation. Cu-Olsa nanoMOF displayed an enzyme-like catalytic activity to generate cancericidal species ·OH and 1O2 from rich H2O2 in tumors, improved the expression of tumor suppressors TIMP3 and AXIN2 by epigenetic modulation, and fulfilled selective inhibition of colorectal cancer cells over normal cells. The hyaluronic acid-modified nanoMOF further verified the efficient suppression of CT26 colorectal tumor growth and metastasis in murine models. Overall, these results suggest that Olsa-based MOF presents a platform of epigenetic therapy-synergized nanomedicine for efficient cancer treatment and provides a powerful strategy for the design of intrinsically bioactive nanoMOFs. STATEMENT OF SIGNIFICANCE: Metal-organic frameworks (MOFs) with intrinsic bioactivities such as anticancer and antibacterial activity are of great interest. Herein, we reported a bioactive copper-olsalazine (Cu-Olsa) nanoMOF as a nanodrug for colorectal cancer treatment. This nanoMOF per se displayed enzyme-like catalytic activity to generate cancericidal species ·OH and 1O2 from rich H2O2 in tumors for nanocatalytic tumor therapy. Upon dissociation into small molecular copper-organic complex and olsalazine in cancer cells, COX-2 inhibition and epigenetic modulation were fulfilled for selective inhibition of colorectal cancer growth and metastasis.

Reactive oxygen species (ROS)-based nanocatalytic tumor therapy is alluring owing to the capability to generate highly cytotoxic ∙OH radicals from tumoral H2O2. However, the antitumor efficacy is highly dependent on the radical generation efficiency and challenged by the high levels of antioxidative glutathione (GSH) in cancer cells. Herein, we report an IR-780 decorated, GSH-depleting Fe3O4@MIL-100 (IFM) nanocomposite for photo-enhanced tumor catalytic therapy by extensive production of ∙OH, which is realized by an integration of excellent peroxidase-like activity of IFM, selective upregulation of tumoral H2O2 by β-lapachone, and localized hyperthermia by near infrared light irradiation. IFM shows potentiated antiproliferative effect in 4T1 cancer cells by ∙OH overproduction and glutathione scavenging, inducing intracellular redox dyshomeostasis and cell death by concurrent apoptosis and ferroptosis. In vivo antitumor investigation further demonstrates photoacoustic and fluorescence imaging-guided combinational therapy with a tumor inhibition rate of 96.4%. This study provides a strategy of photo-enhanced nanocatalytic tumor therapy by tumor-specific H2O2 amplification and hyperthermia.

Metal-organic frameworks (MOFs) are a class of important porous, crystalline materials composed of metal ions (clusters) and organic ligands. Owing to the unique redox chemistry, photochemical and electrical property, and catalytic activity of Cu2+/+, copper-based MOFs (Cu-MOFs) have been recently and extensively explored in various biomedical fields. In this review, we first make a brief introduction to the synthesis of Cu-MOFs and their composites, and highlight the recent synthetic strategies of two most studied representatives, three-dimensional HKUST-1 and two-dimensional Cu-TCPP. The recent advances of Cu-MOFs in the applications of cancer treatment, bacterial inhibition, biosensing, biocatalysis, and wound healing are summarized and discussed. Furthermore, we propose a prospect of the future development of Cu-MOFs in biomedical fields and beyond.

Chemo-photothermal therapy is a promising combination treatment of cancer owing to the synergistic anticancer effect via different anticancer mechanisms. Nanotheranostics integrating facile preparation and tunable loading of chemotherapeutics and photothermal agents are of great interest owing to the prospect of efficient combinational cancer treatment and large-scale manufacture towards clinical translation. Herein, we present an "insitu drug generation and controllable loading" strategy to fabricate nanotheranostic agents with such merits and demonstrate the feasibility by the aqueous-phase one-pot synthesis of BSD nanoparticles (NPs), where cancericidal copper diethyldithiocarbamate (Cu(DTC)(2)) and photothermal copper sulfide (CuS) were in-situ synthesized by the reactions of Cu2+ and corresponding anions (DTC and S2-) in water and efficiently loaded by using bovine serum albumin as a nanocarrier. This design avoids using organic solvents and realizes high loading efficiency of Cu(DTC)(2) and CuS, whose composition ratio was dictated by the feeding ratios of DTC/S-2. BSD NPs maintained the excellent photothermal effect, photostability, and photoacoustic imaging capacity of CuS at a high S-2/DTC ratio, while exhibited enhanced photothermal effect at a low ratio of S-2/DTC owing to the formation of Cu (DTC)(2)-dispersed CuS nanodots. The optimal BSD-1:1 showed a photothermal conversion efficiency of 49.5%, enhanced cellular uptake and cytotoxicity upon laser treatment, and efficient ablation of B16 melanoma tumor by photoacoustic imaging-guided therapy. The facile, tunable nature of this strategy presages that this platform could be expanded to construct diverse, modular metal-based nanosystems for multimodal imaging and therapy.