Multifunctional MnO2 nanoparticles for tumor microenvironment modulation and cancer therapy.

MoS2-ALG-Fe/GOx hydrogel with Fenton catalytic activity for combined cancer photothermal, starvation, and chemodynamic therapy

Dual-activity nanozyme to initiate tandem catalysis for doubly enhancing ATP-depletion anti-tumor therapy

Advances and perspectives in organic sonosensitizers for sonodynamic therapy

Metal-organic frameworks (MOFs) have emerged as promising novel therapeutics for treating malignancies due to their tunable porosity, biocompatibility, and modularity to functionalize with various chemotherapeutics drugs. However, the design and synthesis of dual-stimuli responsive MOFs for controlled drug release in tumor microenvironments are vitally essential but still challenging. Meanwhile, the catalytic effect of metal ions selection and ratio optimization in MOFs for enhanced chemodynamic therapy (CDT) is relatively unexplored. Herein, a series of MnFe-based MOFs with pH/glutathione (GSH)-sensitivity are synthesized and then combined with gold nanoparticles (Au NPs) and cisplatin prodrugs (DSCP) as a cascade nanoreactor (SMnFeCGH) for chemo-chemodynamic-starvation synergistic therapy. H+ and GSH can specifically activate the optimal SMnFeCGH nanoparticles in cancer cells to release Mn2+/4+ /Fe2+/3+ , Au NPs, and DSCP rapidly. The optimal ratio of Mn/Fe shows excellent H2 O2 decomposition efficiency for accelerating CDT. Au NPs can cut off the energy supply to cancer cells for starvation therapy and strengthen CDT by providing large amounts of H2 O2 . Then H2 O2 is catalyzed by Mn2+ /Fe2+ to generate highly toxic •OH with the depletion of GSH. Meanwhile, the reduced DSCP accelerates cancer cell regression for chemotherapy. The ultrasensitivity cascade nanoreactor can enhance the anticancer therapeutic effect by combining chemotherapy, CDT, and starvation therapy.

Chemodynamic therapy (CDT) is an emerging tumor treatment; however, it is hindered by insufficient endogenous hydrogen peroxide (H2O2) and high glutathione (GSH) concentrations in the tumor microenvironment (TME). Furthermore, CDT has limited therapeutic efficacy as a monotherapy. To overcome these limitations, in this study, a nanoplatform is designed and constructed from Cu-doped mesoporous Prussian blue (CMPB)-encapsulated glucose oxidase (GOx) with a coating of hyaluronic acid (HA) modified with a nitric oxide donor (HN). In the proposed GOx@CMPB-HN nanoparticles, the dopant Cu2+ ions are crucial to combining and mutually promoting multiple therapeutic approaches, namely, CDT, photothermal therapy (PTT), and starvation therapy. The dopant Cu2+ ions in CMPB protect against reactive oxygen species to deplete the intracellular GSH in the TME. Additionally, the byproduct Cu+ ions act as a substrate for a Fenton-like reaction that activates CDT. Moreover, H2O2, which is another important substrate, is produced in large quantities through intracellular glucose depletion caused by the nanoparticle-loaded GOx, and the gluconic acid produced in this reaction further enhances the TME acidity and creates a better catalytic environment for CDT. In addition, Cu2+ doping greatly improves the mesoporous Prussian blue (MPB) photothermal conversion performance, and the resultant increase in temperature accelerates CDT catalysis. Finally, the HN coating enables the nanoparticles to actively target CD44 receptors in cancer cells and also enhances vascular permeability. Therefore, this coating has multiple effects, such as facilitating enhanced permeability and retention and deep laser penetration. In vitro and in vivo experiments demonstrate that the proposed GOx@CMPB-HN nanoplatform significantly inhibits tumor growth with the help of in situ enhanced synergistic therapies based on the properties of the TME. The developed nanoplatform has the potential to be applied to cancer treatment and introduces new avenues for tumor treatment research.

Sonodynamic therapy, with advantages in large tissue penetration depth and great controllability, is a promising type of non-invasive cancer treatment method. Developing sonosensitizers with high reactive oxygen species (ROS) quantum yield and the ability to regulate tumor microenvironment to achieve enhanced performances in sonodynamic therapy would thus be rather attractive. Herein, vanadium (V) doped TiO2 (V-TiO2) nanospindles with glutathione-depleting properties are fabricated for enhanced sonodynamic cancer therapy. Due to doping of the V element, the bandgap of V-TiO2 nanospindles is reduced, increasing the efficiency of ultrasound-triggered ROS production compared to that of pure TiO2 nanoparticles. More interestingly, the doping of V also makes V-TiO2 nanospindles an effective Fenton-like agent, which can catalyze the generation of highly toxic hydroxyl radicals (•OH) from endogenous H2O2 in the tumor, thus enabling cancer-killing through chemodynamic therapy. In addition, the V doping also endows V-TiO2 nanospindles with the function of glutathione depletion, further amplifying the oxidative stress generated by chemodynamic-sonodynamic therapy. In vitro cell experiments and in vivo animal experiments demonstrate that V-TiO2 nanospindles can effectively kill cancer by the combined chemodynamic-sonodynamic therapy, significantly improving the tumor treatment outcomes. Importantly, V-TiO2 with the ultrasmall spindle morphology can be quickly excreted from the body, without causing any long-term toxicity. This work illustrates that doping TiO2 with other special elements is a meaningful strategy to fabricate nanostructures with interesting functions useful in biomedicine.

Urchin-like piezoelectric ZnSnO3/Cu3P p-n heterojunction for enhanced cancer sonodynamic therapy

Cascade nanozymes based on the “butterfly effect” for enhanced starvation therapy through the regulation of autophagy

Nanocatalytic medicine has been emerging as a highly promising strategy for cancer therapeutics since it enables tumor suppression by in situ generating toxic agents within tumors through catalytic reactions without using conventional highly toxic and nonselective chemodrugs. In the last several years, a number of nanocatalytic medicines have been used to steer catalytic reactions in endogenous or exogenous stimuli-activated cancer therapy, such as chemodynamic therapy, photodynamic therapy, and sonodynamic therapy. In particular, transitional metal-based nanocatalytic medicines with excellent catalytic activity and selectivity show significant clinical potentials, and significant progress has been achieved very recently. In this review, three types of typical transitional metal (Fe, Mn, and Cu)-based nanocatalytic medicines are summarized, followed by detailed discussions on their catalytic mechanisms. Of note, the obstacles and challenges that will be encountered in the design and further clinical conversion of transitional metal-based nanocatalytic medicine in the future are also outlooked.

Chapter 4 - Role of nanotechnology in cancer therapies: recent advances, current issues, and approaches

Chemodynamic therapy (CDT), a novel cancer therapeutic strategy defined as the treatment using Fenton or Fenton-like reaction to produce •OH in the tumor region, was first proposed by Bu, Shi, and co-workers in 2016. Recently, with the rapid development of Fenton and Fenton-like nanomaterials, CDT has attracted tremendous attention because of its unique advantages: 1) It is tumor-selective with low side effects; 2) the CDT process does not depend on external field stimulation; 3) it can modulate the hypoxic and immunosuppressive tumor microenvironment; 4) the treatment cost of CDT is low. In addition to the Fe-involved CDT strategies, the Fenton-like reaction-mediated CDT strategies have also been proposed, which are based on many other metal elements including copper, manganese, cobalt, titanium, vanadium, palladium, silver, molybdenum, ruthenium, tungsten, cerium, and zinc. Moreover, CDT has been combined with other therapies like chemotherapy, radiotherapy, phototherapy, sonodynamic therapy, and immunotherapy for achieving enhanced anticancer effects. Besides, there have also been studies that extend the application of CDT to the antibacterial field. This review introduces the latest advancements in the nanomaterials-involved CDT from 2018 to the present and proposes the current limitations as well as future research directions in the related field.

The application of oxaliplatin (L-OHP) in colorectal cancer chemotherapy has attracted considerable attention. However, its toxic side effects have hindered its clinical use. This study aims to develop a nanoparticle-based drug delivery system using L-OHP as the therapeutic agent, designated as NGMP. NGMP is designed to possess targeting capability, pH responsiveness, and MR imaging functionality. The ultimated goal of this system is to achieve a synergistic effect in colorectal cancer treatment by combining starvation therapy, chemodynamic therapy, and chemotherapy. NGMP delivers Manganese dioxide (MnO2) into tumor cells, where the acidic and glutathione (GSH)-rich tumor microenvironment (TME) rapidly triggers its degradation. This reaction liberates L-OHP, glucose oxidase (GOX), and Mn2+ ions. The released Mn2+ catalyzes a Fenton-like reaction with endogenous hydrogen peroxide (H2O2), producing abundant reactive oxygen species (ROS) and driving oxidative damage-induced cell death. Concurrent GSH depletion sensitizes tumor cells to ROS and chemotherapeutic agents, thereby amplifying cytotoxicity. GOX-mediated glucose consumption induces metabolic starvation (starvation therapy), simultaneously replenishes H2O2, and lowers the local pH, thereby establishing a positive feedback loop that synergistically enhances both starvation therapy and chemodynamic therapy. Collectively, these effects result in self-amplifying, multimodal tumor eradication. NGMP is cloaked with natural killer cell membranes (NKm) to enhance tumor specificity and modulate immune responses. This coating enables immune evasion, facilitates active tumor targeting, and promotes immunotherapeutic synergy. Compared with free L-OHP, NGMP demonstrates superior antitumor efficacy, greater biocompatibility, and integrated diagnostic functionality. These combined features position NGMP as a potential theranostic platform for colorectal cancer.

Hypoxia in the tumor microenvironment (TME) greatly limits the tumor-killing therapeutic efficacy of sonodynamic therapy (SDT); this phenomenon is further exacerbated by increased glutathione (GSH) levels in cancer cells. Simultaneously, cancer starvation therapy is increasingly recognized nowadays as a promising clinical translation, but the efficacy of glucose oxidase (GOx)-based starvation therapy is also limited by the lack of oxygen in the tumor. Glycer-aldehyde-3-phosphate dehydrogenase (GAPDH) is a key glycolytic enzyme and can therefore be a target for starvation therapy in the absence of oxygen engagement. Here, we proposed thiol-ene click reactions based on a two-dimensional metal-organic framework (MOF) modification for tumor treatments to enable the combination of SDT and starvation therapy. Experimental studies demonstrated that the prepared material could consume GSH and GAPDH free from oxygen in TME, which benefited from the thiol-ene click reactions between the MOFs and thiol substances in cancer cells. Further experiments in vitro and in vivo indicated the prepared MOF materials could kill cancer cells efficiently. This study is expected to create a promising avenue for thiol-ene click reactions in SDT and starvation therapy for cancer.

Specific chemical reactions only happen in the tumor region and produce abundant special chemicals to in situ trigger a train of biological and pathological effects that may enable tumor-specific curative effects to treat cancer without causing serious side effects on normal cells or organs. Chemodynamic therapy (CDT) is a rising tactic for cancer therapy, which induces cancer cell death via a localized Fenton reaction. However, the tumor therapeutic effect is limited by the efficiency of the chemical reaction and relies heavily on the catalyst. Here, we constructed hollow porous carbon coated FeS2 (HPFeS2@C)-based nanocatalysts for triple-enhanced CDT. Tannic acid was encapsulated in HPFeS2@C for reducing Fe3+ to Fe2+, which had a better catalytic activity to accelerate the Fenton reaction. Afterward, glucose oxidase (GOx) in nanocatalysts could consume glucose in the tumor microenvironment and in situ synchronously produce H2O2, which could improve Fenton reaction efficiency. Meanwhile, the consumption of glucose could lead to the starvation effect for cancer starvation therapy. The photothermal effects of HPFeS2@C could generate heat, which further sped up the Fenton process and implemented synergetic photothermal therapy/starvation therapy/CDT. The biodistribution of nanoparticles was investigated by multimodal magnetic resonance, ultrasound, and photoacoustic imaging. These nanocatalysts could trigger the catalytic Fenton reaction at a high degree, which might provide a good paradigm for nanocatalytic tumor therapy.

PurposeThis study aimed to develop a composite nanozyme system (Au/PB-Ce6-HA) based on gold nanoparticles (AuNPs) and Prussian blue nanoparticles (PBNPs) to combat tumor hypoxia and insufficient endogenous hydrogen peroxide (H2O2) deficiency, thus enhancing the efficacy of sonodynamic therapy (SDT) and starvation therapy for liver cancer.MethodsThe Au/PB-Ce6-HA system was constructed by in situ embedding AuNPs on PBNPs, loading the sonosensitizer Chlorin e6 (Ce6), and surface-coating with thiolated hyaluronic acid (HA-SH). The system was evaluated both in vitro and in vivo to assess its ability to catalyze glucose to generate H2O2, decompose H2O2 to produce oxygen, and generate highly toxic reactive oxygen species (ROS) under ultrasound irradiation.ResultsThe Au/PB-Ce6-HA nanozymes demonstrated high catalytic activity, thus significantly improving SDT and starvation therapy. Specifically, the system effectively deprived tumors of their energy supply by generating H2O2, while simultaneously producing oxygen to enhance cytotoxic ROS generation under ultrasound irradiation. Both in vivo and in vitro studies further demonstrated a synergistic effect in inhibiting tumor growth while enhancing therapeutic efficacy.ConclusionAn intelligent composite nanomaterial was successfully developed, combining starvation therapy and sonodynamic therapy to significantly enhance the treatment of liver cancer. The Au/PB-Ce6-HA nanozyme system demonstrated excellent synergy in both in vitro and in vivo settings, offering a promising strategy for cancer therapy.