Traditional tumor treatments, including chemotherapy, radiotherapy, photodynamic therapy, and photothermal therapy, are developed and used to treat different types of cancer. Recently, chemodynamic ...therapy (CDT) has been emerged as a novel cancer therapeutic strategy. CDT utilizes Fenton or Fenton-like reaction to generate highly cytotoxic hydroxyl radicals (•OH) from endogenous hydrogen peroxide (H
O
) to kill cancer cells, which displays promising therapeutic potentials for tumor treatment. However, the low catalytic efficiency and off-target side effects of Fenton reaction limit the biomedical application of CDT. In this regard, various strategies are implemented to potentiate CDT against tumor, including retrofitting the tumor microenvironment (e.g., increasing H
O
level, decreasing reductive substances, and reducing pH), enhancing the catalytic efficiency of nanocatalysts, and other strategies. This review aims to summarize the development of CDT and summarize these recent progresses of nanocatalyst-mediated CDT for antitumor application. The future development trend and challenges of CDT are also discussed.
Here, a Mn(III)-sealed metal–organic framework (MOF) nanosystem based on coordination between Mn(III) and porphyrin (TCPP) via a one-pot method was designed and constructed. Mn(III), as a sealer, ...not only quenched TCPP-based fluorescence but also inhibited reactive oxygen species (ROS) generation, which made MOFs an “inert” theranostic nanoparticle. Interestingly, upon endocytosis by tumor cells, MOFs were disintegrated into Mn(II) and free TCPP by intracellular glutathione (GSH) in tumor cells, owing to redox reaction between Mn(III) and GSH. This disintegration would lead to consumption of antioxidant GSH and activated Mn(II)-based magnetic resonance imaging (MRI) as well as TCPP-based fluorescent imaging. More importantly, such a GSH-regulated TCPP release could implement controllable ROS generation under irradiation, which avoided side effects (inflammation and damage of normal tissues). As a consequence, after unlocking by GSH, Mn(III)-sealed MOFs could significantly improve the therapeutic efficiency of photodynamic therapy by combining controlled ROS generation and GSH depletion after precise dual tumor homing.
This study reports a tumor-specific ROS-responsive nanoplatform capable of the combination of nitric oxide (NO)-based gas therapy and sensitized photodynamic therapy (PDT). The nanoplatform is ...constructed on porous coordination network (PCN), which contains NO donor L-Arg and is concurrently coated with cancer cell membrane (L-Arg@PCN@Mem). Under near infrared light (NIR) irradiation, L-Arg@PCN@Mem produces plenty of reactive oxygen species (ROS) directly for PDT therapy, while a part of ROS take the role of oxidative to converse L-Arg into NO for combined gas therapy. The results indicate that the transformation of ROS to NO can enhance PDT efficacy in hypoxic tumors owing to the ability of NO in freely diffusing into deep hypoxic tumor site. Moreover, homologous targeting function originated from the coating of cancer cells membrane further improves the tumor treatment effect owing to the biotargeting toward homologous tumors. This L-Arg@PCN@Mem nanoplatform provides a new therapy paradigm of overcoming the hypoxia barrier of tumor therapy, and holds great potential for the treatment of tumor and NO-related diseases.
A ROS-responsive L-Arg@PCN@Mem nanoplatform was prepared for NO-based gas therapy and NO-sensitized photodynamic therapy (PDT). This nanoplatform displayed synergistic effect to increase tumor oxidative/nitrification stress and suppress growth and proliferation of cancer cells with negligible side effects. Display omitted
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•The advance of post-synthetic modification (PSM) of MOFs in the past five years was reviewed.•Two increasingly apparent tendencies in PSM of exploring new types and tandem reactions ...were demonstrated.•Selected examples including several from China focus on new types and tandem PSM.
In the past five years, post-synthetic modification (PSM) has become a very useful strategy in systematically functionalizing metal–organic frameworks (MOFs) by modifying the linker, metal node, pore character, and surface environment for the purpose of increasing the structural stability and introducing desired properties. In this review, we intend to demonstrate the two major trends in PSM including the mushrooming of new types of reaction and the combination of multi-steps PSM. The selected examples illustrate three promising PSM classes, post-synthetic metal exchange (PSME), post-synthetic ligand exchange (PSLE) and post-synthetic elimination and insertion (PSE&I). Combined with the well-developed covalent PSM and dative PSM, tandem PSM which constitutes of multistep and different types of reaction adds to the step-by-step improvement of catalytic activity, regulating magnetism and others. These recent advances in PSM not only open new paths to improve the function of MOFs, but also reveal the unprecedented reaction complexity of crystalline solids.
A multifunctional prodrug, designated as TPP‐L‐GEM, is fabricated to realize image‐guided in situ tumor photodynamic therapy (PDT) with red light activatable chemotherapy. Gemcitabine is conjugated ...with a fluorescent photosensitizer, meso‐tetraphenylporphyrin (TPP), by a reactive oxygen species cleavable thioketal linker. Under the irradiation of low‐energy red light, TPP can generate singlet oxygen and damage tumor cells by photodynamic therapy. Simultaneously, the thioketal linkage can be cleaved by singlet oxygen and result in a cascaded gemcitabine release, causing sustained cell damage by chemotherapy. With the combination of PDT and cascaded chemotherapy, TPP‐L‐GEM shows significant tumor therapeutic efficacy in vitro and in vivo. Furthermore, the inherent fluorescent property of TPP endows the TPP‐L‐GEM prodrug with noninvasive drug tracking capability, which is favorable for image‐guided tumor therapy.
A red light activatable multifunctional prodrug is fabricated to realize in situ tumor photodynamic therapy (PDT) with cascaded chemotherapy. This multifunctional prodrug demonstrates a new strategy for image‐guided combination therapy of PDT with cascaded chemotherapy.
Chemodynamic therapy (CDT) can efficiently destroy tumor cells via Fenton reaction in the presence of H
O
and a robust catalyst. However, it has faced severe challenges including the limited amounts ...of H
O
and inefficiency of catalysts. Here, an adenosine triphosphate (ATP)-responsive autocatalytic Fenton nanosystem (GOx@ZIF@MPN), incorporated with glucose oxidase (GOx) in zeolitic imidazolate framework (ZIF) and then coated with metal polyphenol network (MPN), was designed and synthesized for tumor ablation with self-supplied H
O
and TA-mediated acceleration of Fe(III)/Fe(II) conversion. In the ATP-overexpressed tumor cells, the outer shell MPN of GOx@ZIF@MPN was degraded into Fe(III) and tannic acid (TA) and the internal GOx was exposed. Then, GOx reacted with the endogenous glucose to produce plenty of H
O
, and TA reduced Fe(III) to Fe(II), which is a much more vigorous catalyst for the Fenton reaction. Subsequently, self-produced H
O
was catalyzed by Fe(II) to generate highly toxic hydroxyl radical (•OH) and Fe(III). The produced Fe(III) with low catalytic activity was quickly reduced to reactive Fe(II) mediated by TA, forming an accelerated Fe(III)/Fe(II) conversion to guarantee efficient Fenton reaction-mediated CDT. This autocatalytic Fenton nanosystem might provide a good paradigm for effective tumor treatment.
Selectively cuting off the nutrient supply and the metabolism pathways of cancer cells would be a promising approach to improve the efficiency of cancer treatment. Here, a cancer targeted cascade ...bioreactor (designated as mCGP) was constructed for synergistic starvation and photodynamic therapy (PDT) by embedding glucose oxidase (GOx) and catalase in the cancer cell membrane-camouflaged porphyrin metal–organic framework (MOF) of PCN-224 (PCN stands for porous coordination network). Due to biomimetic surface functionalization, the immune escape and homotypic targeting behaviors of mCGP would dramatically enhance its cancer targeting and retention abilities. Once internalized by cancer cells, mCGP was found to promote microenvironmental oxygenation by catalyzing the endogenous hydrogen peroxide (H2O2) to produce oxygen (O2), which would subsequently accelerate the decomposition of intracellular glucose and enhance the production of cytotoxic singlet oxygen (1O2) under light irradiation. Consequently, mCGP displayed amplified synergistic therapeutic effects of long-term cancer starvation therapy and robust PDT, which would efficiently inhibit the cancer growth after a single administration. This cascade bioreactor would further facilitate the development of complementary modes for spatiotemporally controlled cancer treatment.
Inflammatory processes are often accompanied by oxidative stress and lipid peroxidation, which might lead to cellular and organ damage. Carnosic acid (CA), an active component found in rosemary, ...exhibits pharmacological properties including antioxidative, anti-inflammatory, and antiviral effects. The aim of this research was to investigate whether CA can mitigate lipopolysaccharide (LPS)-induced oxidative stress and inflammatory responses in poultry and to understand its underlying mechanisms. We administered CA to broiler chickens via oral gavage and treated them with LPS, followed by analysis of the effects of different dosages of CA on body weight, antioxidative capacity, and inflammatory factors. Carnosic acid had no significant impact on the body weight of broiler chickens. However, serum analysis indicated that the middle dose of CA effectively enhanced the antioxidative capacity and reduced levels of oxidative stress and inflammation-related factors. Moreover, in the liver, CA demonstrated the ability to regulate the expression of proteins such as heat shock protein 60 (HSP60), heat shock protein 70 (HSP70), and P38 mitogen-activated protein kinase (P38), suggesting its protective role against liver damage induced by LPS. In the intestinal tract of broiler chickens, CA regulated the expression and localization of proteins including HSP60, HSP70, NFE2 like bZIP transcription factor 2 (Nrf2), and P38, while also influencing the expression of inflammatory markers such as protein tyrosine phosphatase receptor type C (CD45), and connexin (Cx). These findings revealed the potential protective mechanisms of CA in alleviating oxidative stress and inflammatory damage induced by LPS in poultry. Carnosic acid notably enhanced the chickens' antioxidative capacity by modulating the expression of key proteins, thereby reducing oxidative stress and inflammatory response levels. This study provides a deeper comprehension of the protective mechanisms of CA and its potential impact on avian health.
In this article, an adenosine-triphosphate-regulated (ATP-regulated) ion transport nanosystem SQU@PCN, porphyrinic porous coordination network (PCN) incorporated with squaramide (SQU) was designed ...and synthesized for homeostatic perturbation therapy (HPT) and sensitizing photodynamic therapy (PDT) of tumors. It was found that this nanotransporter SQU@PCN easily accumulated in tumor sites while avoiding metabolic clearance and side effects. In response to a high expression of ATP in the tumor, SQU@PCN was decomposed because of the strong coordination of ATP with metal ligand of PCN. Subsequently, incorporated SQU was released and then simultaneously transported chloride ions across membrane of the cell and lysosome along with the chloride ion concentration gradient. On one hand, influx of chloride ions by SQU increased intracellular ion concentration, which disrupted ion homeostasis and further induced tumor cell apoptosis. On the other hand, SQU-medicated coupling transport of H+/Cl– across the lysosomal membrane alkalized the lysosome, resulting in inhibition of autophagy. This SQU-mediated autophagy inhibition would sensitize PCN-based PDT since activated autophagy by traditional PDT would resist and weaken the therapeutic efficacy. In vivo animal test results revealed that combined HPT and sensitized PDT could realize tumor eradication while blocking metastasis, which provided a paradigm for complementary multimodal tumor treatment.
Drug delivery systems (DDSs) with biocompatibility and precise drug delivery are eagerly needed to overcome the paradox in chemotherapy that high drug doses are required to compensate for the poor ...biodistribution of drugs with frequent dose-related side effects. In this work, we reported a metal-organic framework (MOF) based tumor targeting DDS developed by a one-pot, and organic solvent-free "green" post-synthetic surface modification procedure, starting from the nanoscale MOF MIL-101. Owing to the multifunctional surface coating, premature drug release from this DDS was prevented. Due to the pH responsive benzoic imine bond and the redox responsive disulfide bond at the modified surface, this DDS exhibited tumor acid environment enhanced cellular uptake and intracellular reducing environment triggered drug release. In vitro and in vivo results showed that DOX loaded into this DDS exhibited effective cancer cell inhibition with much reduced side effects.
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