An intelligent responsive ZIF-8 co-delivery nanoplatform with multimodal synergistic technologies for closed-loop therapy of tumors.

Tailored to the peculiar tumor microenvironment, Fenton reaction-based chemodynamic therapy (CDT) has attracted considerable attention for tumor treatment. However, the efficacy of CDT is highly limited by both H2O2 overproduction and the low activity of catalysts at the tumor site. Herein, a novel magnetic targeting nanoplatform (γ-Fe2O3-GOx-DMSN) has been designed by simply depositing ultrasmall γ-Fe2O3 nanoparticles and natural glucose oxidase (GOx) into the large mesopores (∼13 nm) of dendritic mesoporous silica (DMSN) spheres for near-infrared (NIR) light-enhanced CDT efficacy. In this structure, GOx can effectively consume glucose in the tumor cells to induce a decrease in the pH value and generate a considerable amount of H2O2, both of which promote subsequent Fenton reaction. These ultrasmall γ-Fe2O3 nanoparticles not only serve as an efficacious Fenton catalyst for degradation of the increased H2O2 within the tumor to produce highly toxic hydroxyl radicals (•OH) but also exhibit high photothermal therapy (PTT) efficiency upon irradiation with 808 nm light. Importantly, the generated hypothermia can significantly accelerate the Fenton process, thereby enabling a synergetic PTT/hypothermia-enhanced CDT effect. Our work manifests a proof of concept of H2O2-evolving and NIR-enhanced CDT, providing a new perspective for cancer therapy.

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.

Non-stoichiometric cobalt sulfide nanodots enhance photothermal and chemodynamic therapies against solid tumor

The combination of chemotherapy (CT) and chemodynamic therapy (CDT) via nanoscale drug delivery systems has great potential for tumor therapy. Nevertheless, the low intracellular H2O2 and high reductive glutathione (GSH) levels, as well as the mildly acidic conditions (pH 5.8-6.8) of the tumor microenvironment (TME) still limit their further applications. To tackle these problems, a TME-modulating nanoreactor (denoted as Fe3O4-DOX@PDA-GOx@HA, FDPGH) was developed through a simple and practicable method to achieve multiply enhanced CDT synergized with CT, starvation therapy (ST), and photothermal therapy (PTT). Upon cellular uptake, the hyaluronic acid (HA) and PDA shells rapidly collapsed to release Fe3O4, glucose oxidase (GOx) and doxorubicin (DOX), and the overexpressed GSH could promote the reduction of Fe3+ to Fe2+, resulting in CDT activation. GOx-driven oxidation reaction not only produced H2O2 for enhanced CDT, but also killed tumor cells by initiating ST. In addition, the acid amplification caused by gluconic acid production in turn accelerated the degradation of FDPGH, promoting the Fenton reaction to enhance CDT. Most importantly, the nanoreactor had excellent photothermal performance to achieve PTT and PTT-enhanced CDT with the release of DOX into tumor tissue to achieve enhanced CT. This novel cascade nanoreactor with TME-modulating capability is intended to provide further inspiration for multimodal treatment paradigms.

Chemodynamic therapy (CDT) is a cancer treatment that converts endogenous H2O2 into hydroxyl radicals (˙OH) through Fenton reaction to destroy cancer cells. However, there are still some challenges in accelerating the Fenton reaction of CDT and improving the biodegradability of nanocatalysts. Herein, a multifunctional biomimetic BPQDs-Cu@GOD (BCG) Fenton nanocatalyst for boosting synergistically enhanced H2O2-guided and photothermal CDT of cancer is reported. Cu2+ in BCG can be reduced to Cu+ by black phosphorus quantum dots (BPQDs), triggering a Cu+-mediated Fenton-like reaction to degrade H2O2 and generate abundant ˙OH for cancer CDT. The loaded glucose oxidase (GOD) can consume the glucose in the tumor to produce abundant H2O2 for Fenton-like reaction. In addition, Cu2+ in BCG can react with GSH in tumor cells to alleviate the antioxidant capacity of tumor tissues, further improving the CDT efficacy. Furthermore, the photothermal performance of BPQDs can be enhanced by capturing Cu2+, improving the photoacoustic imaging and photothermal therapy (PTT) functions. More importantly, the enhanced photothermal performance can rapidly accelerate the Fenton-like reaction under NIR irradiation. Finally, Cu2+ can accelerate the degradation of BPQDs, which can reduce the retention of reagents. As a novel multifunctional biocompatible Fenton nanocatalyst, BCG have great potential in cancer therapy.

The combination of chemotherapy with chemodynamic therapy (CDT) presents a potential strategy for cancer treatment. However, the insufficient exogenous catalytic ions, low endogenous hydrogen peroxide (H2O2) level, and overexpressed glutathione (GSH) in the tumor microenvironment challenge the efficacy of CDT. In addition, chemotherapy is constrained by the poor tumor accumulation ability, drug resistance, and severe system toxicity. To address these challenges, herein, we fabricated a pH-, reduction-, and NIR light-sensitive nanodrug delivery system, PDDC NPs, based on doxorubicin (DOX) and cisplatin for the combined chemotherapy, CDT, and mild photothermal therapy (PTT) against cancer. The “all-in-one” nanodrug, PDDC NPs, was constructed by the Cu2+-driven coordination of free DOX•HCl and tandem prodrug D-Pt-D, which was formed by the conjugation of cisplatin and norcantharidin, while polydopamine (PDA) was developed for the subsequent coating. In tumor cells, the elevated GSH reduces the platinum(IV) prodrug and Cu2+ in PDDC nanoparticles to active platinum(II) and Cu+, thereby inducing drug release, GSH depletion, and nanoparticle disassembly. The released DOX and platinum(II) in tumor cells can induce the production of reactive oxygen species, including •OH and H2O2, thereby amplifying the CDT efficacy induced by the Fenton-like reaction of Cu+. Additionally, the PDDC NPs possess photothermal conversion ability due to the PDA coating. This work provides a comprehensive strategy integrating “GSH depletion, H2O2 production, and Fenton-like reaction” with multidrug chemotherapy and mild PTT for cancer treatment.

A multivalent polyphenol–metal-nanoplatform for cascade amplified chemo-chemodynamic therapy

Cell membrane covered polydopamine nanoparticles with two-photon absorption for precise photothermal therapy of cancer

Starvation therapy kills tumor cells via consuming glucose to cut off their energy supply. However, since glucose oxidase (GOx)-mediated glycolysis is oxygen-dependent, the cascade reaction based on GOx faces the challenge of a hypoxic tumor microenvironment. By decomposition of glycolysis production of H2 O2 into O2 , starvation therapy can be enhanced, but chemodynamic therapy is limited. Here, a close-loop strategy for on demand H2 O2 and O2 delivery, release, and recycling is proposed. The nanoreactor (metal-protein-polyphenol capsule) is designed by incorporating two native proteins, GOx and hemoglobin (Hb), in polyphenol networks with zeolitic imidazolate framework as sacrificial templates. Glycolysis occurs in the presence of GOx with O2 consumption and the produced H2 O2 reacts with Hb to produce highly cytotoxic hydroxyl radicals (•OH) and methemoglobin (MHb) (Fenton reaction). Benefiting from the different oxygen carrying capacities of Hb and MHb, oxygen on Hb is rapidly released to supplement its consumption during glycolysis. Glycolysis and Fenton reactions are mutually reinforced by oxygen supply, consuming more glucose and producing more hydroxyl radicals and ultimately enhancing both starvation therapy and chemodynamic therapy. This cascade nanoreactor exhibits high efficiency for tumor suppression and provides an effective strategy for oxygen-mediated synergistic starvation therapy and chemodynamic therapy.

Carrier-free nanoparticles for cancer theranostics with dual-mode magnetic resonance imaging/fluorescence imaging and combination photothermal and chemodynamic therapy.

The combination of chemodynamic therapy (CDT) and photothermal therapy (PTT) has proven to be successful in combating the challenges associated with cancer therapy. A combination of these therapies can maximize the benefits of each therapeutic modality through endogenous reduction-oxidation (redox) reaction and external laser power induction. In the current work, we have designed a copper-aluminum layered double hydroxide (CuAl-LDH) loaded doxorubicin (DOX) by a co-precipitation method; the surface was coated with polydopamine (PDA). The synthesized CuAl-LDH@DOX@PDA nanocarrier (NC) served as a Fenton-like catalyst with photothermal properties. It is well known that metal ion incorporated NCs can induce intracellular depletion of reduced glutathione (GSH) levels along with the reduction of Cu2+ to Cu+. The Cu+ ions in turn react with DOX leading to the generation of intracellular hydrogen peroxide (H2O2) molecules to produce the highly toxic hydroxyl radicals (•OH) through a Fenton-like reaction. The enhanced absorption of CuAl@DOX@PDA at 810 nm, greatly improved the photothermal efficiency in comparison with bare CuAl-LDH and CuAl-LDH@DOX. In vitro studies revealed the tremendous CDT/PTT efficacy of CuAl@DOX@PDA in suppressing A549 cancer cells. Furthermore, reactive oxygen species (ROS) assays and intracellular levels of various ROS cascade biomolecules support our findings in the efficient destruction of cancer cells through synergistic CDT/PTT therapy.

Reversing the hypoxic and immunosuppressive tumor microenvironment (TME) is crucial for treating malignant melanoma. Seeking a robust platform for the effective reversion of hypoxic and immunosuppressive TME may be an excellent solution to revolutionizing the current landscape of malignant melanoma treatment. Here, we demonstrated a transdermal and intravenous dual-administration paradigm. A tailor-made Ato/cabo@PEG-TK-PLGA NPs were administrated transdermally to melanoma with the help of a gel spray containing a skin-penetrating material borneol. Nanoparticles encased Ato and cabo were released and thereby reversed the hypoxic and immunosuppressive tumor microenvironment (TME). Ato/cabo@PEG-TK-PLGA NPs were synthesized through a self-assembly emulsion process, and the transdermal ability was assessed using Franz diffusion cell assembly. The inhibition effect on cell respiration was measured by OCR, ATP, and pO2 detection and in vivo photoacoustic (PA) imaging. The reversing of the immunosuppressive was detected through flow cytometry analysis of MDSCs and T cells. At last, the in vivo anti-tumor efficacy and histopathology, immunohistochemical analysis and safety detection were performed using tumor-bearing mice. The transdermally administrated Ato/cabo@PEG-TK-PLGA NPs successfully spread to the skin surface of melanoma and then entered deep inside the tumor with the help of a gel spray and a skin puncturing material borneol. Atovaquone (Ato, a mitochondrial-respiration inhibitor) and cabozantinib (cabo, a MDSCs eliminator) were concurrently released in response to the intratumorally overexpressed H2O2. The released Ato and cabo respectively reversed the hypoxic and immunosuppressive TME. The reversed hypoxic TME offered sufficient O2 for the intravenously administrated indocyanine green (ICG, an FDA-approved photosensitizer) to produce adequate amount of ROS. In contrast, the reversed immunosuppressive TME conferred amplified systemic immune responses. Taken together, we developed a transdermal and intravenous dual-administration paradigm, which effectively reversed the hypoxic and immunosuppressive tumor microenvironment in the treatment of the malignant melanoma. We believe our study will open a new path for the effective elimination of the primary tumors and the real-time control of tumor metastasis.

Glucose oxidase-embedded mesoporous polydopamine nanoparticles produce CO for synergistic tumor starvation, chemodynamic, and photothermal therapy.

The combination of multidrug chemotherapy and photothermal therapy (PTT) enhances cancer therapeutic efficacy. Herein, we develop a simple and smart pH/NIR dual-stimulus-responsive degradable mesoporous CoFe2O4@PDA@ZIF-8 sandwich nanocomposite. The mesoporous CoFe2O4 core acts as T2-weighted magnetic resonance (MR) imaging probe, PTT agent, and loading platform of hydrophilic doxorubicin (DOX). A polydopamine (PDA) layer is used to avoid the premature leakage of DOX before arriving at tumor site, enhance PTT efficiency, and facilitate the integration of ZIF-8 (a kind of metal-organic framework). The ZIF-8 shell serves to encapsulate hydrophobic camptothecin (CPT) and as the switch for the pH and NIR stimulation-responsive release of the two drugs. Therefore, T2-weighted MR imaging-guided multidrug chemotherapy and PTT synergistic treatment is achieved. Two kinds of anticancer drugs, hydrophilic DOX and hydrophobic CPT, are successfully loaded in CoFe2O4 and ZIF-8, respectively, so no mutual interference between the two drugs exists. A unique two-stage stepwise release process is exhibited for CPT and DOX with an interval of 12 h to improve the anticancer efficacy under the acidic microenvironment of tumor tissue. NIR irradiation achieves the burst drug-release and PTT after laser stimulation, simultaneously. With this smart design, high drug concentration is achieved at the tumor site by quick release, especially for the therapeutic drugs that show nonlinear pharmacokinetics, and PTT is integrated efficiently. Furthermore, negligible biotoxicity and a remarkable synergic antitumor effect of the hybrid nanocomposites are validated by HepG2 cells and tumor-bearing mice as models. Our multidrug delivery-releasing composite improves tumor therapeutic efficiency significantly compared with a single-drug chemotherapy system. The simple multifunctional composite system can be applied as an effective platform for personal nanomedicine with diagnosis, smart drug delivery, and cancer treatment through its remarkable photothermal property and controllable multidrug release.

Despite being more effective than single treatments for cancer, combination therapy poses a challenge in integrating multiple modalities. In this study, we propose a nanoplatform (CuS@GOx@ES) that integrates chemodynamic therapy (CDT), starvation therapy (ST), photothermal therapy (PTT), and copper-induced toxicity for enhanced cancer treatment. CuS nanoparticles, with their large surface area, are ideal for CDT, while glucose oxidase (GOx) depletes tumor glucose for ST and catalyzes H2O2 production for a Fenton-like reaction. The glucose depletion generates gluconic acid, which accelerates CuS degradation and Cu2+ release, enhancing both CDT and copper-induced toxicity. CuS also exhibits excellent photothermal properties and enhances PTT under 808 nm NIR irradiation. The increased temperature further amplifies the effects of CDT and copper-induced toxicity. Additionally, CuS serves as an exogenous source of copper, releasing Cu2+ into the tumor microenvironment (TME), where it binds to the copper ion carrier ES for targeted delivery to tumor cells, inducing copper-induced toxicity and tumor cell death. The CuS@GOx@ES nanoplatform effectively combines CDT, PTT, ST, and copper-induced toxicity, creating a synergistic effect where the treatments enhance each other to achieve superior therapeutic outcomes.