H2O2 In Tumor Microenvironment Research Articles

Notch-targeted Therapeutic in Colorectal Cancer by Notch1 Attenuation via Tumor Microenvironment-Responsive Cascade DNA Delivery.

The Notch signaling is a key molecular pathway that regulates cell fate and development. Aberrant Notch signaling can lead to carcinogenesis and progression of malignant tumors. However, current therapies targeting Notch pathway lack specificity and induce high toxicity. In this report, we design a tumor microenvironment-responsive and injectable hydrogel to load plasmid DNA complexes as a cascade gene delivery system to achieve precise Notch-targeted gene therapy of colorectal cancer (CRC). The hydrogels were prepared through cross-linking between phenylboric acid groups-containing poly(oligo(ethylene glycol)methacrylate) (POEGMA) and epigallocatechin gallate (EGCG), which were used to load the complexes between plasmid DNA encoding short hairpin RNAs of Notch1 (shNotch1) and fluorinated polyamidoamine (PAMAM-F) (PAMAM-F/shNotch1). In response to low pH and H2O2 in tumor microenvironment, the hydrogel can be dissociated and release the complexes for precise delivery of shNotch1 into tumor cells and inhibit Notch1 activity to suppress malignant biological behaviors of CRC. In the subcutaneous tumor model of CRC, PAMAM-F/shNotch1-loaded hydrogels can accurately attenuate Notch1 activity and significantly inhibit tumor growth without affecting Notch signal in adjacent normal tissues. Therefore, this therapeutic system can precisely inhibit Notch1 signal in CRC with high responsiveness and low toxicity, providing a promising Notch-targeted gene therapeutic for human malignancy. This article is protected by copyright. All rights reserved.

Acid-etched layered double hydroxides armed with dual “Doorkeepers” for Immunomodulatory-NIR III photodynamic therapy of hepatocellular carcinoma

Immune checkpoint blockade (ICB) therapy for hepatocellular carcinoma (HCC) is limited due to its immunosuppressive tumor microenvironment (TME). Proinflammatory pyroptosis as a new schedule can induce immunogenic cell death (ICD), thereby reversing immunosuppressive TME and improving ICB efficiency. Herein, we report an acid-etched layered double hydroxides nanosheets (E-LDH)-based smart nanoplatforms armed with H2O2/pH dual “doorkeepers” (denoted as CTEP) targeting HCC to realize membrane-anchored photodynamic therapy (PDT) and evoke potent pyroptosis to effectively improve anti-tumor immunity. The hybrid Hepa1-6 cancer cell membrane (CM) and thylakoid (TK) membrane is cloaked on the surface of pH-(low)-insertion peptide (pHLIP) modified E-LDH to obtain CTEP. Once CTEP nanoplatforms arrive at tumor regions, the dual “doorkeepers” will orderly open to perform PDT precisely. Given the fact that TK membranes have the catalase mimetic function, CTEP is able to respond to high concentrations of H2O2 in TME and rupture the hybrid CM-TK membrane to expose pH-sensitive peptide pHLIP. Membrane-localized PDT can induce gasdermin-D (GSDMD) mediated pyroptosis, effectively stimulating tumor immunogenicity. Pyroptotic cell death releases damage-associated molecular patterns (DAMPs) and consequently robust IaCB ability. CTEP-evoked pyroptosis together with anti-PD-L1 blockade therapy activates adaptive immunity in HCC, successfully inhibiting the progression of primary and distant HCC tumors with mitigation of the side effects. This research has demonstrated that CTEP with excellent biocompatibility and homologous targeting ability can act as a potent pyroptosis inducer to improve immune efficacy. The combination of PDT and immunotherapy via a photo-pyroptosis pathway can be a smart strategy for HCC treatment.

An Adaptable Nanoprobe Integrated with Quantitative T1 -Mapping MRI for Accurate Differential Diagnosis of Multidrug-Resistant Lung Cancer.

Multidrug resistance (MDR) is one of the major factors causing failure of non-small-cell lung cancer (NSCLC) chemotherapy. Real-time and accurate differentiation between drug-resistant and sensitive NSCLC is of primary importance for guiding the subsequent treatments and improving the therapeutic outcome. However, there is no effective method to provide such an accurate differentiation. This study creates an innovative strategy of integrating H2 O2 -responsive nanoprobes with the quantitative T1 -mapping magnetic resonance imaging (MRI) technique to achieve an accurate differential diagnosis between drug-resistant and sensitive NSCLC in light of differences in H2 O2 content in the tumor microenvironment (TME). The result demonstrates that the synthesized MIL-53(Fe)@MnO2 nanocomposites possess an excellent capability of shortening the cancer longitudinal relaxation time (T1 ) when meeting H2 O2 in TME. T1 -mapping MRI could sensitively detect this T1 variation (about 2.6-fold that of T1-weighted imaging (T1 WI)) to accurately differentiate the H2 O2 content between drug-resistant and sensitive NSCLC. In addition, the quantitative data provided by the T1 -mapping MRI dedicates correct comparison across imaging tests and is more reliable than T1 WI, thus giving it a chance for precise assessment of the anti-cancer effect. This innovative strategy of merging TME adaptable nanoprobes with the quantitative MRI technique provides a new approach for the precise diagnosis of multidrug-resistant NSCLC.

Surface curvature-induced oriented assembly of sushi-like Janus therapeutic nanoplatform for combined chemodynamic therapy

BackgroundChemodynamic therapy (CDT) based on Fenton/Fenton-like reaction has emerged as a promising cancer treatment strategy. Yet, the strong anti-oxidation property of tumor microenvironment (TME) caused by endogenous glutathione (GSH) still severely impedes the effectiveness of CDT. Traditional CDT nanoplatforms based on core@shell structure possess inherent interference of different subunits, thus hindering the overall therapeutic efficiency. Consequently, it is urgent to construct a novel structure with isolated functional units and GSH depletion capability to achieve desirable combined CDT therapeutic efficiency.ResultsHerein, a surface curvature-induced oriented assembly strategy is proposed to synthesize a sushi-like novel Janus therapeutic nanoplatform which is composed of two functional units, a FeOOH nanospindle serving as CDT subunit and a mSiO2 nanorod serving as drug-loading subunit. The FeOOH CDT subunit is half covered by mSiO2 nanorod along its long axis, forming sushi-like structure. The FeOOH nanospindle is about 400 nm in length and 50 nm in diameter, and the mSiO2 nanorod is about 550 nm in length and 100 nm in diameter. The length and diameter of mSiO2 subunit can be tuned in a wide range while maintaining the sushi-like Janus structure, which is attributed to a Gibbs-free-energy-dominating surface curvature-induced oriented assembly process. In this Janus therapeutic nanoplatform, Fe3+ of FeOOH is firstly reduced to Fe2+ by endogenous GSH, the as-generated Fe2+ then effectively catalyzes overexpressed H2O2 in TME into highly lethal ·OH to achieve efficient CDT. The doxorubicin (DOX) loaded in the mSiO2 subunit can be released to achieve combined chemotherapy. Taking advantage of Fe3+-related GSH depletion, Fe2+-related enhanced ·OH generation, and DOX-induced chemotherapy, the as-synthesized nanoplatform possesses excellent therapeutic efficiency, in vitro eliminating efficiency of tumor cells is as high as ~ 87%. In vivo experiments also show the efficient inhibition of tumor, verifying the synthesized sushi-like Janus nanoparticles as a promising therapeutic nanoplatform.ConclusionsIn general, our work provides a successful paradigm of constructing novel therapeutic nanoplatform to achieve efficient tumor inhibition.

L-Arginine self-delivery supramolecular nanodrug for NO gas therapy.

NO gas therapy is a supplementary approach for tumor treatment due to the advantages of minimal invasion, little drug resistance, low side effect and amplified efficacy. l-Arginine (L-Arg), a natural NO source with good biocompatibility, can release NO under the stimulation of H2O2 in tumor microenvironment. However, the conventional l-Arg delivery systems via noncovalent loading usually lead to inevitable premature leakage of nano-cargos during blood circulation. In this work, an efficient l-Arg self-delivery supramolecular nanodrug (SDSND) for tumor treatment is demonstrated by combining Mannich reaction and π-π stacking. l-Arg links to (-)-epigallocatechin gallate (EGCG) with the assistance of formaldehyde through Mannich reaction, and then assembles into nanometer-sized particles via π-π stacking. The guanidine group of l-Arg and the phenolic hydroxyl groups of EGCG are preserved in the SDSNDs, which allows for accomplishing gas therapy by provoking tumor cell apoptosis and combining with EGCG to amplify apoptosis, respectively. In addition, the SDSNDs exhibit high biocompatibility and avoid the premature leakage of l-Arg in blood circulation, providing an alternative l-Arg delivery system for NO gas therapy. STATEMENT OF SIGNIFICANCE: NO gas therapy has attracted emerging interest in tumor treatment. However, the controlled NO release and the avoidance of premature leakage of NO donors remain challenging. In this work, L-Arginine (L-Arg) self-delivery supramolecular nanodrug for efficient tumor therapy is demonstrated through the Mannich reaction of L-Arg, (-)-epigallocatechin gallate (EGCG) and formaldehyde. Stimulated by tumor microenvironment, the guanidine groups of L-Arg allow for accomplishing NO release and thus provoking tumor cell apoptosis. The nanodrug also avoids the premature leakage of L-Arg in blood circulation. Moreover, the preserved phenolic hydroxyl groups of EGCG combine with L-Arg to amplify apoptosis. The nanodrug exhibits high biocompatibility and good therapeutic effect, providing an alternative L-Arg delivery system for NO gas therapy.

Multifunctional metal-polyphenol nanocomposite for melanoma targeted photo/chemodynamic synergistic therapy

Due to the hypoxic state of the tumor microenvironment (TME), photodynamic therapy (PDT) suffers from insufficient ROS production. The metal-polyphenol network-mediated Fenton reaction can generate reactive oxygen species (ROS) by consuming H2O2 in TME, improving the inadequate ROS generation problem of PDT. Therefore, synergistic therapy combining PDT and Fenton response-based CDT is a promising approach for cancer treatment. Herein, a metal-polyphenol nanocomposite was deposited with gallic acid grafted hyaluronic acid and Fe3+ to contrast a Ce6 nano-delivery system (Ce6@HSF NPs) for melanoma synergistic therapy. Ce6@HSF NPs could be used as a Fenton reagent to induce the ·OH production and enhance the PDT effect of Ce6 to a certain extent. After 4 h of cellular uptake, the fluorescence intensity of Ce6 in the Ce6@HSF NPs group was higher than 3 times that in the Ce6 group. The intracellular ROS generation level of the Ce6@HSF NPs (L) group combining CDT and PDT was higher than that of the Ce6 group and Ce6@HSF NPs group. In vitro and in vivo anti-melanoma studies show that Ce6@HSF NPs (L) group exhibited better anti-melanoma than other groups. Together, Ce6@HSF NPs provide a promising synergistic treatment potential for melanoma.

Lactate oxidase/vSIRPα conjugates efficiently consume tumor-produced lactates and locally produce tumor-necrotic H2O2 to suppress tumor growth

Aggressive tumor formation often leads to excessive anaerobic glycolysis and massive production and accumulation of lactate in the tumor microenvironment (TME). To significantly curb lactate accumulation in TME, in this study, lactate oxidase (LOX) was used as a potential therapeutic enzyme and signal regulatory protein α variant (vSIRPα) as a tumor cell targeting ligand. SpyCatcher protein and SpyTag peptide were genetically fused to LOX and vSIRPα, respectively, to form SC-LOX and ST-vSIRPα and tumor-targeting LOX/vSIRPα conjugates were constructed via a SpyCatcher/SpyTag protein ligation system. LOX/vSIRPα conjugates selectively bound to the CD47-overexpressing mouse melanoma B16-F10 cells and effectively consumed lactate produced by the B16-F10 cells, generating adequate amounts of hydrogen peroxide (H2O2), which induces drastic necrotic tumor cell death. Local treatments of B16-F10 tumor-bearing mice with LOX/vSIRPα conjugates significantly suppressed B16-F10 tumor growth in vivo without any severe side effects. Tumor-targeting vSIRPα may allow longer retention of LOX in tumor sites, effectively consuming surrounding lactate in TME and locally generating adequate amounts of cytotoxic H2O2 to suppress tumor growth. The approach restraining the local lactate concentration and H2O2 in TME using LOX and vSIRPα could offer new opportunities for developing enzyme/targeting ligand conjugate-based therapeutic tools for tumor treatment.

In-situ activation of CuAl-LDH nanosheets to catalyze bioorthogonal chemistry in vivo in tumor microenvironment for precise chemotherapy and chemodynamic therapy

Precise activation of therapeutic molecules in tumor tissues is the key step to ensure targeted antitumor performance and reduce adverse effects towards normal tissues and organs. Although the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC), i.e., bioorthogonal chemistry, has been used for the rapid synthesis of anticancer drugs in cells, it remains a great challenge to realize precise in vivo drug synthesis in tumor sites for precise cancer treatment. In this work, we first report the in-situ activation of CuAl-layered double hydroxide (CuAl-LDH) nanosheets to realize Cu(I)-catalyzed bioorthogonal chemistry in vivo in tumor microenvironment (TME) for precise chemotherapy and chemodynamic therapy (CDT). The Cu(II) ions in the biocompatible CuAl-LDH nanosheets can be in-situ reduced to Cu(I) ions partially by the overexpressed glutathione in TME. The generated Cu(I) can serve as a catalyst to catalyze the CuAAC reaction between alkyne and azide in TME, thus realizing in vivo drug synthesis for precise chemotherapy. Meanwhile, the generated Cu(I) can catalyze the Fenton-like reaction to generate toxic hydroxyl radicals (⋅OH) from H2O2 in TME for CDT. Therefore, CuAl-LDHs can be used for the targeted synergistic chemotherapy and CDT to achieve highly precise and efficient elimination of cancer cells in vitro and inhibition of tumors in vivo.

Copper Peroxides Based Multiple Tumor Microenvironment Regulation for Enhanced Photodynamic/Chemodynamic Synergistic Therapy

AbstractHypoxia, overexpressed glutathione (GSH) and depletable H2O2 in tumor microenvironment (TME) are three major obstacles to the development of reactive oxygen species (ROS)‐mediated antitumor therapy. Herein, a photodynamic/chemodynamic synergistic therapeutic nanoagent, DMOS@CuO2/ICG‐HA (DCI), is synthesized based on copper peroxide (CuO2) and indocyanine green (ICG) co‐loaded disulfide‐bond‐incorporated dendritic mesoporous organosilica (DMOS), with modification of hyaluronic acid (HA). The DCI nanocomposites (NCs) can realize multiple TME regulating ability through releasing H2O2/O2 and depleting GSH under acidic condition. Besides, the released Cu2+ can contribute to T1‐weighted magnetic resonance imaging (MRI) in vitro and in vivo. After accumulating at the tumor sites, the DCI NCs can overcome the hypoxia and produce high level of ROS to induce cell apoptosis upon laser irradiation. Hence, the as‐prepared DCI nanoagent can realize MRI‐guided synergistic photodynamic/chemodynamic therapy with enhanced antitumor efficacy.

Dual-targeting nanozyme for tumor activatable photo-chemodynamic theranostics

Tumor phototheranostics holds a great promise on account of its high spatiotemporal resolution, tumor-specificity, and noninvasiveness. However, physical limitation of light penetration and “always on” properties of conventional photothermal-conversion agents usually cause difficulty in accurate diagnosis and completely elimination of tumor. Meanwhile, nanozymes mediated Fenton reactions can well utilize the tumor microenvironment (TME) to generate hydroxyl radicals for chemodynamic therapy (CDT), but limited by the concentration of H2O2 in TME and the delivery efficiency of nanozymes. To overcome these problems, a dual-targeting nanozyme (FTRNPs) is developed for tumor-specific in situ theranostics, based upon the assembling of ultrasmall Fe3O4 nanoparticles, 3,3’,5,5’-tetrameth-ylbenzidine (TMB) and the RGD peptide. The FTRNPs after H2O2 treatment exhibits superior photothermal stability and high photothermal conversion efficiency (η = 50.9%). FTRNPs shows extraordinary accumulation and retention in the tumor site by biological/physical dual-targeting, which is 3.54-fold higher than that without active targeting. Cascade-dual-response to TME for nanozymes mediated Fenton reactions and TMB oxidation further improves the accuracy of both photoacoustic imaging and photothermal therapy (PTT). The tumor inhibition rate of photo-chemodynamic therapy is ~ 97.76%, which is ~ 4-fold higher than that of PTT or CDT only. Thus, the combination of CDT and PTT to construct “turn on” nanoplatform is of great significance to overcome their respective limitations. Considering its optimized “all-in-one” performance, this new nanoplatform is expected to provide an advanced theranostic strategy for the future treatment of cancers.Graphical abstract

H2O2/pH Dual-Responsive Biomimetic Nanoenzyme Drugs Delivery System for Enhanced Tumor Photodynamic Therapy

Phototherapy has been recognized as a photochemical process to treat tumor via induce cancer cells necrosis and death, with minimal invasiveness, higher selectivity, and few side effects. However, the therapy effects of phototherapy are often compromised by the hypoxia, high levels of hydrogen peroxide, and glutathione of tumor microenvironment (TME). Therefore, we constructed a catalase-like activity bionic metal–organic framework drugs delivery system (FA-EM@MnO2/ZIF-8/ICG) with tumor microenvironment controllable releasing. In this system, photosensitizer indocyanine green (ICG) was introduced into zeolite imidazole salt skeleton 8 (ZIF-8) by one-step methods, forming ZIF-8/ICG nano-platform, which can effectively avoid ICG-induced phototoxicity and aggregation-induced quenching during transport. MnO2 with catalase-like activity was coated on the surface of ZIF-8/ICG nano-platform, which made it have the ability of self-supplying O2 under the condition of H2O2 in TME. Exposure under near-infrared light can alleviate the anoxic TME, thus improving the phototherapy efficiency. In addition, folate-functionalized erythrocyte membrane is coated on the surface of MnO2/ZIF-8/ICG, which can endow FA-EM@MnO2/ZIF-8/ICG with the ability of targeted drug administration and immune elimination avoidance. Therefore, FA-EM@MnO2/ZIF-8/ICG nano-platform has the catalase-like activity, which can alleviate the oxidative stress state of TME and provide a beneficial environment for photodynamic therapy of tumor.

Near-Infrared-II Activatable Symbiotic 2D Carbon-Clay Nanohybrids for Dual Imaging-Guided Combinational Cancer Therapy.

Two-dimensional (2D) nanomaterials hold great potential for cancer theranostic applications, yet their clinical translation faces great challenges of high toxicity and limited therapeutic/diagnostic modality. Here, we have created a kind of symbiotic 2D carbon-2D clay nanohybrids, which are composed of a novel 2D carbon nanomaterial (carbon nanochips, or CNC), prepared by carbonizing a conjugated polymer polydiiodobutadiyne, and a 2D layered aluminosilicate clay mineral montmorillonite (MMT). Intriguingly, with the formation of the nanohybrids, MMT can help the dispersion of CNC, while CNC can significantly reduce the hemolysis and toxicity of MMT. The symbiotic combination of CNC and MMT also leads to a synergistic anti-cancer theranostic effect. CNC has a strong absorption and high photothermal conversion efficiency in the second near-infrared region (NIR-II, 1000-1700 nm), while MMT contains Fe3+ that can facilitate the generation of reactive oxygen species from highly expressed H2O2 in tumor microenvironment. The nanohybrids not only enable a synergy of photothermal therapy and chemodynamic therapy to suppress the extremely rapid growth of RM1 tumors in mice but also allow for dual photoacoustic and magnetic imaging to guide the drug delivery and NIR-II irradiation execution, hence establishing a highly efficient and biosafe "all-in-one" theranostic platform for precision nanomedicine.

Enzyme-like copper-encapsulating magnetic nanoassemblies for switchable T1-weighted MRI and potentiating chemo-/photo-dynamic therapy

Photodynamic therapy (PDT) has become a promising cancer treatment due to in situ generation of cytotoxic reactive oxygen (ROS); however, it remains limited by the hypoxia of tumor microenvironment (TME) and penetration depth of laser. Herein, we developed a kind of GSH-/H2O2-responsive copper-encapsulating magnetic nanoassemblies (MNSs) for switchable T1-weighted magnetic resonance imaging (MRI) and enzyme-like activity potentiating PDT of cancer. MNSs were rationally constructed using the chelation effect of copper ions (Cu2+) with polyacrylic acid-coated ultrasmall iron oxide nanoparticles (UIONPs). After uptake by tumor cells, the incorporated Cu2+ of MNSs was reduced to Cu+ through the intracellular GSH, which resulted in the disassembly of MNSs accompanied by the “silenced” MR signal shifting to a positive state. Sequentially, the generated Cu+ manifested peroxidase-like activity, catalyzing local H2O2 in TME to cytotoxic ·OH for chemodynamic therapy. Furthermore, Cu2+ and UIONPs could decompose H2O2 to O2, thus providing extra oxygen necessary for enhancing the PDT effect of photosensitizer IR-780. Finally, IR-780-loading MNSs (MNSs@IR-780) under laser irradiation significantly inhibited tumor growth and prolonged the survival of gastric MGC-803 tumor-bearing mice. Therefore, this study provides a versatile nanoplatform as a tumor-responsive theragnostic agent. Statement of significanceTumor hypoxia and penetration depth of laser severely hindered the PDT of cancer. Valence-convertible metal ions (VCMI, e.g., Cu2+/Cu+, Fe3+/Fe2+) have been reported as Fenton-like agents disintegrating H2O2 to O2 to enhance PDT. Tumor-delivery of VCMI is of essential importance for in situ triggering of a Fenton-like reaction. We thereby developed magnetic nanoassemblies (MNSs) to encapsulate Cu2+ and load photosensitizer (IR-780). Stimulated by GSH and H2O2, MNSs performed catalase/peroxidase-like activity that provided extra O2 for PDT and catalyzed H2O2 to ·OH for CDT. Consequently, IR-780-loading MNSs under laser irradiation significantly inhibit the tumor growth due to effective tumor delivery of Cu2+ and IR-780. This study might offer a feasible nanoplatform for tumor-delivery of metal ions and drugs.

Programmable phthalocyanine-iron-based nanoreactor for fluorescence/magnetic resonance dual-modality imaging-guided sono/chemodynamic therapies

Although specific responsive theranostics biomaterials were essencial for precision medicine, the univariate responsive strategy was restricted by high false-positive rates. Herein, we designed a novel phthalocyanine-iron-based complex FeS2@PcD, as a theranostics nanoreactor, which was program-regulated by bivariate factors of H+ and H2O2 in tumor microenvironment (TME). We found that FeS2@PcD had the excellent capability of tumor fluorescence imaging (FLI), with a 52.21-fold increase in fluorescence signal by the programmable response, while the signal of the univariate factor was almost unchanged. We also revealed that FeS2@PcD reacted with H+ to release PcD and produced Fe2+, then Fe2+ was further oxidized by H2O2 to produce Fe3+, finally recovering the fluorescence of PcD whose fluorescence activity was significantly suppressed due to the photoinduced electron transfer (PET) effect. Notably, except for fluorescence signal, magnetic resonance (MR) signal and sonosensitive activity of FeS2@PcD also changed from “OFF” state to “ON” state under the programmable regulation of H+ and H2O2. The program-regulated strategy based on FeS2@PcD realized specific fluorescence and MR dual-modality imaging-guided sono/chemodynamic therapies, representing a promising precision medicine approach.

Bioinspired poly(cation-π) micelles drug delivery platform for improving chemotherapy efficacy.

Cation-π interactions widely exist in biological systems and play important roles in driving the self-assembly of biological molecules, stabilizing protein structures, and mediating molecular recognitions. Herein, a novel bioinspired poly(cation-π) micelles drug delivery platform is designed and constructed, based on the block copolymers with random cationic-aromatic sequences (amphiphilic cation-π polymer). Compared to the polymeric micelles formed by conventional amphiphilic block copolymers which are commonly limited to hydrophobic drugs loading, the engineered poly(cation-π) micelles can serve as a universal nanocarrier for a wide variety of hydrophobic and hydrophilic drugs with π-structure. It is found that due to the strong cation-π interactions integrated in the core of poly(cation-π) micelles, this nanosystem performs improved structural stability and higher drug loading capability. Especially, in the oxidation-responsive poly(cation-π) micelles as proof-of-concept, the process of stimuli-induced drug release is found significantly accelerated under the biologically relevant level of H2O2 in tumor microenvironment. Furthermore, the mechanism of cation-π interaction enhanced H2O2-sensitivity of poly(cation-π) micelles is proposed, and the improving anti-tumor efficacy is demonstrated in both in vitro and in vivo models. This work broadens the construction strategy of polymeric micelles and offers a universal drug delivery platform for efficient tumor chemotherapy.

Synthesis of Dual-Response MnO2 Nanospheres as Multifunctional Drug Carriers

Recently, hollow structures have attracted much attention due to their high specific surface area, clear interior space, low density and good permeability. Among them, manganese dioxide (MnO2) hollow structure has also been widely studied for catalysis, drug delivery and energy storage. Based on the characteristics of low pH and high GSH concentration in tumor microenvironment, it is possible to develop an intelligent drug delivery system with pH/GSH response based on hollow mesoporous MnO2 nanospheres. In addition, the excellent physical and chemical properties of MnO2 nanomaterials provide conditions for its synergistic photothermal therapy. For example, Mn2+ released after manganese dioxide reacts with GSH can enhance T1-MAGNETIC resonance (MR) imaging. Meanwhile, manganese dioxide can also react with H2O2 in tumor microenvironment to release oxygen and alleviate tumor hypoxia. In order to prevent drug loss during delivery, a GSH-responsive hollow mesoporous manganese dioxide microsphere was selected as the drug carrier in this paper, and a series of studies were carried out on the performance of the carrier. Hollow mesoporous MnO2 nanospheres with particle size below 100 nm were prepared by hydrothermal method, and their response to tumor microenvironment was simulated in vitro. It has been proved that hollow mesoporous MnO2 nanospheres can be desorbed at low pH and GSH response, and can be used to deliver drugs or photothermal agents, as well as for collaborative cancer imaging and treatment.

Tumor microenvironment self-regulation: Bimetallic metal nanozyme-derived multifunctional nanodrug for optimizable cascade catalytic reaction-synergetic anti-tumor theranostics

The tumor microenvironment (TME) responsive multimodal theranostic nanoplatforms have attracted great attentions for precision medicine. To design well-defined cascade catalytic therapy and achieve the synergistic effect of different components in a nanoplatform, herein a spindle-shaped nanodrug termed as FeCu-GOx PNzyme-MTO was constructed by in-situ growth of bimetallic metal nanozyme (FeCu PNzyme), and simultaneous encapsulation of glucose oxidase (GOx) as well as fluorescent and chemotherapeutic mitoxanthrone (MTO). Interestingly, the obtained FeCu-GOx PNzyme is able to efficiently upregulate endogenous H2O2 level and down-regulate acidity via inducing the catalytic decomposition of intratumoral glucose to gluconic acid and H2O2 in TME, which is benefit to the cascade catalytic reactions for chemodynamic therapy (CDT). After efficient loading of MTO, such intelligent nanozyme triggers reactive oxygen species (ROS) generation in situ with tumor stimuli, self-augment ROS level upon intrinsic photothermal-conversion efficiency (53.05%) and glutathione (GSH) depletion, and specifically TME-responsive release of MTO to achieve high chemotherapeutic efficacy and biosafety. Both in vitro cellular assays and in vivo tumor-xenograft experiments proved that the tumor-specific cytotoxicity, biodegradability and potent antitumor efficiency of nanodrug, with co-contributions from highly cytotoxic ROS generated and precise drug delivery within tumors. This work thus presents the friendly construction of biocompatible FeCu-GOx PNzyme-MTO as effective nanodrug to provided a promising strategy for a new perspective on effective tumor therapy.

Strategies for enhancing cancer chemodynamic therapy performance.

Chemodynamic therapy (CDT) has emerged to be a frontrunner amongst reactive oxygen species-based cancer treatment modalities. CDT utilizes endogenous H2O2 in tumor microenvironment (TME) to produce cytotoxic hydroxyl radicals (•OH) via Fenton or Fenton-like reactions. While possessing advantages such as tumor specificity, no need of external stimuli, and low side effects, practical applications of CDT are still impeded owing to the heterogeneity, complexity, and reductive environment of TME. Over the past couple of years, strategies to enhance CDT for efficient tumor regression are in rapid development in synergy with the growth of nanomedicine. In this review, we initially outline the fundamental understanding of Fenton and Fenton-like reactions and their relationship with CDT. Subsequently, the development in the design of nanosystems for CDT is highlighted in a general manner. Furthermore, recent advancement of the strategies to augment Fenton reactions in TME for enhanced CDT is discussed in detail. Finally, perspectives toward the future development of CDT for better therapeutic outcome are presented. This review is expected to draw attention for collaborative research on CDT in the best interest of its future clinical applications.

Combined Prussian Blue Nanozyme Carriers Improve Photodynamic Therapy and Effective Interruption of Tumor Metastasis

IntroductionPhotodynamic therapy (PDT) as a new technique for theranostics is to kill tumor cells by activating photosensitizer and interacting with oxygen (O2) to produce reactive oxygen species (ROS). However, the hypoxic tumor microenvironment (TME) may constrain the efficacy of PDT. Moreover, the lack of O2 in TME also up-regulates the expression of HIF-1α and promotes tumor metastasis, which is also a leading cause of death for terminal cancer patients.MethodsPrussian blue (PBs) was firstly synthesized by hydrothermal method, which was then etched by hydrochloric acid to obtained hollow Prussian blue nanoparticles (HPBs). Afterwards, Au-Pt nanozymes were in situ growing on the HPBs by reduction method to prepare Au-Pt@HPBs (APHPBs). Owing to the hollow structure of APHPBs, photosensitizer Ce6 can be easily and efficiently loaded into it to obtain Ce6-Au-Pt@HPBs (Ce6-APHPBs). After ce6-APHPBS regulation, photoacoustic imaging and hypoxic fluorescence imaging were then used to evaluate changes in hypoxic TME in vivo. Finally, under the assistant of Ce6-APHPBs, we evaluated the inhibitory effect of enhanced PDT on primary and metastatic tumors.ResultsWe first designed and synthesized Ce6 loaded hollow prussian blue nanoparticles with Au-Pt nanozymes grown in situ on it. Both in vitro and in vivo experiments show that the prepared Ce6-APHPBs have good biosafety and could effectively degrade the overexpressed H2O2 in TME to generate O2, further relieve the hypoxic TME and thus enhance the effect of PDT. At the same time, the increasing O2 content could also reduce the expression of HIF-1α at the tumor site, which could reduce lung metastasis.ConclusionCe6-APHPBs designed by us could not only efficiently enhance PDT but also regulate TME to reduce tumor metastasis and prolong survival of mice, which provide a novel idea and strategy for clinical PDT and metastatic tumor.

Oxygen Self-Supply Engineering-Ferritin for the Relief of Hypoxia in Tumors and the Enhancement of Photodynamic Therapy Efficacy.

Hypoxia is a hallmark of the tumor microenvironment (TME) that promotes tumor development and metastasis. Photodynamic therapy (PDT) is a promising strategy in the treatment of tumors, but it is limited by the lack of oxygen in TME. In this work, an O2 self-supply PDT system is constructed by co-encapsulation of chlorin e6 (Ce6) and a MnO2 core in an engineered ferritin (Ftn), generating a nanozyme promoted PDT nanoformula (Ce6/Ftn@MnO2 ) for tumor therapy. Ce6/Ftn@MnO2 exhibits a uniform small size (15.5nm) and high stability due to the inherent structure of Ftn. The fluorescence imaging and immunofluorescence analysis demonstrate the pronounced accumulation of Ce6/Ftn@MnO2 in the tumors of mice, and the treatment significantly decreases the expression of hypoxia-inducible factor (HIF)-1α. The Ce6/Ftn@MnO2 nanoplatform exerts a more potent anti-tumor efficacy with negligible damage to normal tissues compared to the treatment with free Ce6. Moreover, the weak acidity and the presence of H2 O2 in TME significantly enhances the r1 relativity of Ce6/Ftn@MnO2 , resulting in a prominent enhancement of MRI imaging in the tumor. This bio-mimic Ftn strategy not only improves the in vivo distribution and retention of Ce6, but also enhances the effectiveness and precision of PDT by TME modulation.