A polydopamine-gated biodegradable cascade nanoreactor for pH-triggered and photothermal-enhanced tumor-specific nanocatalytic therapy.

Despite the great potential of cascade catalytic reactions in tumor treatment, uncontrolled catalytic activities in vivo lead to inevitable off-target toxicity to normal tissues, which greatly hampers their clinical conversion. Herein, an intelligent cascade nanoreactor (hMnO2-Au@PDA, hMAP) was constructed by depositing glucose oxidase (GOx)-mimicking ultrasmall gold nanoparticles (Au NPs) into honeycomb-shaped manganese oxide (hMnO2) nanostructures and then coating them with polydopamine (PDA) to achieve pH-responsive and photothermal-enhanced nanocatalytic therapy. Upon exposure to the mild acidic tumor microenvironment (TME), the PDA gatekeeper would collapse, and the inner hMnO2 could simultaneously deplete glutathione (GSH) and generate Mn2+, while a considerable amount of H2O2 produced from the oxidation of glucose by GOx-mimicking Au NPs could accelerate the Mn2+-mediated Fenton-like reaction, yielding sufficient highly toxic ˙OH. More importantly, the pH-responsive cascade reaction between Au NPs and hMnO2 could be further enhanced by localized hyperthermia induced from PDA under near-infrared (NIR) laser irradiation, thereby inducing significant cell apoptosis in vitro and tumor inhibition in vivo. This work provided a promising paradigm by innovatively designing a TME-responsive and photothermal-enhanced cascade catalytic nanoreactor for safe and efficient cancer therapy.

Small-Molecule-Selective Organosilica Nanoreactors for Copper-Catalyzed Azide-Alkyne Cycloaddition Reactions in Cellular and Living Systems.

We reported the synthesis of a tris(triazolylmethyl)amine (TTA)-bridged organosilane, functioning as Cu(I)-stabilizing ligands, and the installation of this building block into the backbone of mesoporous organosilica nanoparticles (TTASi) by a sol-gel way. Upon coordinating with Cu(I), the mesoporous CuI-TTASi, with a restricted metal active center inside the pore, functions as a molecular-sieve-typed nanoreactor to efficiently perform Cu(I)-catalyzed alkyne-azide cycloaddition (CuAAC) reactions on small-molecule substrates but fails to work on macromolecules larger than the pore diameter. As a proof of concept, we witnessed the advantages of selective nanoreactors in screening protein substrates for small molecules. Also, the robust CuI-TTASi could be implanted into the body of animal models including zebrafish and mice as biorthogonal catalysts without apparent toxicity, extending its utilization in vivo ranging from fluorescent labeling to in situ drug synthesis.

Dual catalytic cascaded nanoplatform for photo/chemodynamic/starvation synergistic therapy.

In this study, manganese dioxide (MnO2) was attached to prussian blue (PB) by a one-pot method to prepare PBMO. Then, the GOD was loaded onto PBMO through the electrostatic interaction of hyaluronic acid (HA) to form tumor-targeted nanoplatform (PBMO-GH). Hydrogen peroxide (H2O2) and gluconic acid were produced through the GOD-catalyzed enzymatic reaction. Meanwhile, PB could not only catalyze H2O2 for oxygen generation to further promote glucose consumption but also possess the property of photothermal conversion. As a result, glucose was continuously consumed to achieve the starvation therapy (ST), and the photothermal therapy (PTT) could be realized under near-infrared (NIR) light. Besides, the Mn2+ generated by the reaction of MnO2 with glutathione (GSH) could exert Fenton-like reaction to produce highly toxic hydroxyl radicals (·OH) from H2O2, which thereby realized self-reinforcing chemodynamic therapy (CDT). In vitro and in vivo experiments demonstrated that PBMO-GH could effectively inhibit the growth of tumor cells via ST/CDT/PTT synergistic effect. Therefore, the as-prepared nanoplatform for multi-modal therapy will provide a promising paradigm for overcoming cancer.

Mesoporous Silica-Coated Silver Nanoframes as Drug-Delivery Vehicles for Chemo/Starvation/Metal Ion Multimodality Therapy.

Cutting off the energy supply by glucose oxidase (GOx) to starve cancer cells has been a feasible and efficient oncotherapy strategy. The employment of GOx can effectively starve tumor cells by aerobic hydrolysis of glucose hopefully strengthening the abnormality (including the decrease in pH, the increase of hypoxia, and toxic hydrogen peroxide) in the tumor microenvironment (TME). On this basis, we designed and fabricated a GOx-conjugated yolk-shell Ag@mSiO2 nanoframe with Ag NPs and GOx-conjugated mesoporous silica as the yolk and the shell, respectively, to make full use of changes the GOx induces in TME. Specifically, lower pH and H2O2 could accelerate the transformation of Ag nanoparticles to poisonous Ag ions. At the same time, the anabatic hypoxia condition in turn activated chemotherapy drug tirapazamine (TPZ) to exert a chemotherapeutic effect, thereby achieving effective chemo/starvation and metal ion multimodality therapy. The drug release experiment in vitro demonstrated that the GOx is the key to the nanocarriers, which can activate the whole system. The excellent cellular uptake performances of nanocarriers were corroborated by a confocal laser scanning microscope (CLSM). In addition, its superb cancer-killing effect has been confirmed by cytotoxicity and apoptosis experiments. These results indicated that the drug-delivery system achieved the cascade cancer-killing process in situ and synergistic chemo/starvation/metal ion therapy, which has a bright prospect for treating cancer.

A CD44-targeted Cu(ii) delivery 2D nanoplatform for sensitized disulfiram chemotherapy to triple-negative breast cancer.

Recent studies have suggested that the anticancer activity of disulfiram (DSF, an FDA-approved alcohol-abuse drug) is Cu-dependent. Low system toxicity and explicit pharmacokinetic characteristics of DSF necessitate safe and effective Cu supplementation in local lesion for further applications. Herein, we presented a new conceptual 'nanosized coordination transport' strategy of Cu(ii) that was realized in porphyrin-based metal-organic frameworks, Sm-TCPP, with strong binding ability to Cu(ii) due to their coordination interactions. Sm-TCPP(Cu) was coated by hyaluronic acid (HA) that termed by Sm-TCPP(Cu)@HA, acting as 'beneficial horse' to target the tumor-localized HA receptor (CD44), thus liberating Cu(ii) ions in cellular overexpressed reductants. The CD44-mediated Cu(ii) accumulation efficiency of Sm-TCPP(Cu)@HA was benchmarked in vitro and vivo against the free TCPP (Cu) via ICP-MS analysis. More importantly, the sensitization effects of Sm-TCPP(Cu)@HA on the anticancer activity of DSF were demonstrated in vivo and in vitro. This study offered a new class of targeted Cu supplements to sensitize DSF for the effective treatment of cancer and established a versatile methodology for constructing a safe and specific delivery of metal ions within living organisms.

Photothermal-reinforced and glutathione-triggered in Situ cascaded nanocatalytic therapy.

Tumor microenvironment (TME)-responsive nanoformulations that catalyze a cascade of intracellular redox reactions showed promise for tumor treatment with high specificity and efficiency. In this study, we report Cu2+-doped zeolitic imidazolate frameworks-coated polydopamine nanoparticles (PDA@Cu/ZIF-8 NPs) for glutathione-triggered and photothermal-reinforced sequential catalytic therapy against breast cancer. In the TME, the PDA@Cu/ZIF-8 NPs could initially react with antioxidant glutathione (GSH), inducing GSH depletion and Cu+ generation. Whereafter, the generated Cu+ would catalyze local H2O2 to produce highly toxic hydroxyl radicals (·OH) through an efficient Fenton-like reaction even in weakly acidity. Importantly, the PDA could exert excellent photothermal conversion effect to simultaneously accelerate GSH consumption and improve the Fenton-like reaction for further expanding the intracellular oxidative stress, which innovatively achieves a synergistic photothermal-chemodynamic therapy for highly efficient anticancer treatment.

A novel versatile yolk-shell nanosystem based on NIR-elevated drug release and GSH depletion-enhanced Fenton-like reaction for synergistic cancer therapy.

In this study, a versatile doxorubicin (DOX)-loaded yolk-shell nano-particles (HMCMD) assembled with manganese dioxide (MnO2) as the core and copper sulfide (HMCuS) as the mesoporous (∼ 6.4 nm) shell, was designed and synthesized. The resulting HMCMD possess excellent photothermal conversion efficiency. The DOX release from the yolk-shell nanoparticles could be promoted by laser irradiation, which increased the chemotherapy of DOX. Meanwhile, Mn2+ could be released from the HMCMD through a redox reaction between MnO2 and abundant glutathione (GSH) in tumor cells. The released Mn2+ could promote the decomposition of the intracellular hydrogen peroxide (H2O2) by Fenton-like reaction to generate the highly toxic hydroxyl radicals (·OH), thus exhibiting the effective chemodynamic therapy (CDT). Additionally, the efficiency of Mn2+-mediated CDT could be effectively enhanced by NIR irradiation. Further modification of polyethylene glycol (PEG) would improve the water solubility of the HMCMD to promote the uptake by MCF-7 cells. Hence, the HMCMD with synergistic effects of chemotherapy and chemodynamic/photothermal therapy would provide an alternative strategy in antitumor research.

Hypoxia-augmented and photothermally-enhanced ferroptotic therapy with high specificity and efficiency.

The rigorous reaction conditions (sufficient H2O2 and a low pH value) of an efficient Fenton reaction limit its further biomedical translation. Therefore, it is urgent to improve the efficacy of the Fenton reaction at the tumor site for efficient ferroptotic therapy. Herein, a hypoxia-responsive-Azo-BSA functionalized biomimetic nanoreactor (Fe(iii)-GA/GOx@ZIF-Azo), encapsulating ultrasmall ferric-gallic acid coordination polymer nanoparticles (Fe(iii)-GA) and glucose oxidase (GOx) into a zeolitic imidazolate framework (ZIF), was constructed for tumor ablation through an intensive Fenton reaction accelerated by not only sustained Fe2+ and H2O2 supply but also low pH and photothermal stimulation. Moreover, Azo achieved charge reversal in a hypoxia microenvironment caused by the sustained oxygen consumption by GOx, which resulted in selective and enhanced tumor accumulation based on the hypoxia-activated positive feedback cellular uptake. This rationally designed biomimetic nanoreactor might lay a foundation for the clinical translation of ferroptotic therapy.

Biomimetic Platinum Nanozyme Immobilized on 2D Metal-Organic Frameworks for Mitochondrion-Targeting and Oxygen Self-Supply Photodynamic Therapy.

Photodynamic therapy (PDT) as a noninvasive therapy mode has attracted considerable attention in the field of oncotherapy. However, the PDT efficacy is restricted either by the tumor hypoxia environment or the inherent properties of photosensitizers (PSs) including bad water solution, photobleaching, and easy aggregation. Herein, we designed and synthesized a new two-dimensional (2D) metal-organic framework, Sm-tetrakis(4-carboxyphenyl)porphyrin (TCPP) nanosheets, by assembling transition metal ions (Sm3+) and PSs (TCPP), on which the catalase (CAT)-mimicking platinum nanozymes were then in situ grown for sufficient oxygen supply during PDT. The prepared Sm-TCPP with nanoplate morphology (∼100 nm in diameter) and ultrathin thickness (<10 nm) showed significantly enhanced 1O2 generation capacity due to the improved physicochemical properties and the enhanced intersystem crossing from heavy Sm nodes. More importantly, the CAT-mimicking Pt nanozyme on the Sm-TCPP nanosheets could effectively convert over-expressed H2O2 in the tumor microenvironment into O2 to relieve tumor hypoxia. Further, the triphenylphosphine (TPP) molecule was introduced to Sm-TCPP-Pt to develop a mitochondrion-targeting and O2 self-supply PDT system. The in vitro and in vivo experimental results based on the MCF-7 breast cancer model revealed that Sm-TCPP-Pt/TPP could relieve tumor hypoxia and the generated reactive oxygen species nearby intracellular mitochondria significantly induced cell apoptosis. This study offers an engineering strategy to integrate 2D PS-based metal-organic frameworks and nanozymes into a nanoplatform to surmount the pitfalls of traditional PDT.

A small-sized and stable 2D metal-organic framework: a functional nanoplatform for effective photodynamic therapy.

The efficiency of photosensitizers in tumor photodynamic therapy (PDT) often compromises their poor water solubility, low extinction coefficients, photobleaching, and dissatisfactory reactive oxygen species (ROS) generation efficiency. Herein, a nanoscale 2D metal-organic framework, Sm-H2TCPP nanosheets, was first synthesized by Sm3+-driven coordination with a porphyrin derivative (tetrakis(4-carboxyphenyl)porphyrin (H2TCPP)) for highly effective PDT of breast cancer. The prepared Sm-H2TCPP possessed nanoplate morphology with ultrathin thickness at the sub-10 nm level and an ultrasmall plane size at the sub-100 nm level. Compared with free H2TCPP, the prominent ROS generation capacity of the well-defined Sm-H2TCPP nanosheets is mainly attributed to their improved physicochemical properties and the enhanced intersystem crossing caused by heavy Sm nodes. The significantly improved PDT efficacy of the Sm-H2TCPP nanosheets was further investigated in vitro and in vivo based on the MCF-7 breast cancer model. It is envisaged that the Sm-H2TCPP nanosheets will offer a new avenue for the development of a new class of potential PDT agents.

Photothermal-Enhanced Inactivation of Glutathione Peroxidase for Ferroptosis Sensitized by an Autophagy Promotor.

Until now, ferroptotic therapeutic strategies remain simple, although ferroptosis has aroused extensive interest owing to its escape from the biocarriers of conventional therapeutic modalities. Herein, we construct a photothermal (PT)- and autophagy-enhanced ferroptotic therapeutic modality based on MnO2@HMCu2-xS nanocomposites (HMCMs) for efficient tumor ablation. The HMCMs possess PT-enhanced glutathione (GSH) depletion capability, thereby inducing PT-enhanced ferroptosis via the reinforced inactivation of glutathione peroxidase 4 (GPX4). Thereafter, the GSH-responsed Mn2+ release could generate reactive oxygen species (ROS) by a Fenton-like reaction to reinforce the intracellular oxidative stress for the lipid hydroperoxide (LPO) accumulation in ferroptosis. Additionally, an autophagy promotor rapamycin (Rapa) was loaded into HMCM for sensitizing cells to ferroptosis due to the indispensable role of autophagy in the ferroptosis process. The in vitro and in vivo data demonstrated that the HMCM exhibited superior anticancer effect in human breast cancer models and that the combined therapeutic system afforded the next generation of ferroptotic therapy for combatting malignant tumors.

Enhanced cellular uptake of near-infrared triggered targeted nanoparticles by cell-penetrating peptide TAT for combined chemo/photothermal/photodynamic therapy.

Recently, the emergence of cell-penetrating peptides (CPPs) like TAT has greatly improved the efficiency of cancer therapy by enhancing cellular uptake of nanomaterials. Here, we designed a near-infrared (NIR) triggered TAT-based targeted nanoplatform (cRGD@TAT-DINPs), which co-delivered anticancer drug doxorubicin (DOX) and biocompatible dye indocyanine green (ICG) to realize combined chemo/photothermal/photodynamic therapy of cancer in vitro. The resulting nanoparticles showed favorable monodispersity and colloidal stability. Impressively, the DOX could be released in a promoted manner once the nanoparticles were exposed to NIR light. Confocal laser scanning microscopy (CLSM) and flow cytometry analysis demonstrated an immensely enhanced cellular accumulation of DOX after the simultaneous introduction of targeted ligand cRGD and CPP TAT. In addition, the obtained nanoparticles exhibited explosive temperature elevation and reactive oxygen species (ROS) generation mediated by encapsulated ICG under NIR irradiation, and in vitro cytotoxicity assay confirmed the cRGD@TAT-DINPs had an increasing cytotoxicity and excellent synergistic inhibition capacity. Thus, TAT-based nanosystems provide a high-efficient drug delivery strategy for optimizing combined therapy efficiency of cancer.

Cisplatin and Ce6 loaded polyaniline nanoparticles: An efficient near-infrared light mediated synergistic therapeutic agent.

Lipid-polymer hybrid nanoparticle was suggested to be a new and promising drug delivery agent due to the suitable particle size and controllable release. However, the low drug loading capacity has been a critical problem in the improvement of the nano-carrier systems. At present work, we have designed and developed smart nanoparticles with cholesterol-cisplatin (IV) conjugate contained to enhance the drug loading capacity. The predesigned drug delivery system showed enhanced synergistic effect through co-delivery of cisplatin and Ce6 and the drug released in a controllable way due to the polyaniline mediated photothermal conversion. The prepared polyaniline nanoparticles showed a favorable particle size of 109.6 nm and spread harmoniously in aqueous solution. Moreover, the near infrared radiation (NIR) stimulus-responsive characteristic of the polyaniline nanoparticles prompts the release of cisplatin from the nanoparticles inside the cytoplasm and the αvß3/αvß5 integrins targeted ligands (cRGD) enhanced the cellular uptake of the polyaniline nanoparticles in receptor-overexpressing MCF-7 cells. Furthermore, the singlet oxygen generated by Ce6 further enhances the cytotoxicity and obtained the expected synergistic effect with cisplatin. Thus, the prepared cRGD-conjugated co-delivery of cisplatin and Ce6 polyaniline nanoparticles consider to be a promising nanoplatform in nano-biomedicine.

Decoration of Cisplatin on 2D Metal-Organic Frameworks for Enhanced Anticancer Effects through Highly Increased Reactive Oxygen Species Generation.

Herein, a biocompatible 2D metal-organic frameworks (Cu-TCPP(Fe)) based on TCPP(M) (TCPP = tetrakis (4-carboxyphenyl) porphyrin, M = Fe) and copper ion were synthesized as a novel drug carrier. Sequentially, the cisplatin was loaded on the merge of carboxyl-rich Cu-TCPP(Fe) through forming favorable carboxyl-drug interactions. The prepared Pt/Cu-TCPP(Fe) showed highly enhanced cytotoxicity than that of free cisplatin in human pulmonary carcinoma A549 cells, whereas inverse inhibitory effects were observed in human normal BEAS-2B cells. Further, the mechanism of action about the desirable results was also elaborated. Our study highlighted the potential synergies between the nanocarrier and the anticancer drugs.

Single-Layered Two-Dimensional Metal-Organic Framework Nanosheets as an in Situ Visual Test Paper for Solvents.

Through a facile-operating ultrasonic force-assisted liquid exfoliation technology, the single-layered two-dimensional (2D) [Co(CNS)2(pyz)2] n (pyz = pyrazine) nanosheets, with a thickness of sub-1.0 nm, have been prepared from the bulk precursors. The atomically thickness and the presence of abundant sulfur atoms with high electronegativity arrayed on the double surfaces of the sheets are making this kind of 2D MOF (metal-organic framework) nanosheets highly sensitive to intermolecular interactions. As a result, it can be well dispersed in all kinds of solvents to give a stable colloidal suspension that can be maintained for at least one month, accompanied by significant solvatochromic behavior and various optical properties, which thus have shown the potential to be practically applicated as in situ visual test paper for solvent identification and solvent polarity measurements. More importantly, combined with a smartphone, this kind of 2D-MOF nanosheets can be developed into in situ visual test paper to identify isomers and determine the polarity of mixed solvents quantitatively and qualitatively, suggesting the promising application of a portable, economical, and in situ visual test strategy in real world.

Iron Oxide Nanocarrier-Mediated Combination Therapy of Cisplatin and Artemisinin for Combating Drug Resistance through Highly Increased Toxic Reactive Oxygen Species Generation.

Combination therapy with multiple drugs through a multi-pronged assault as a strategy to combat cisplatin resistance shows great potential in biochemical therapy for cancer. However, inherent issues such as low drug loading and the poor synergistic effects of multiple drugs partially limit the further application of combination therapy. Here, we synthesized a new compound, ART-Chol, by coupling artemisinin and cholesterol as a base material combined with cyclic (Arg-Gly-Asp-d-Phe-Lys)]-poly(ethylene glycol) distearoylphosphatidylcholine (cRGD-PEG-DSPE) and phospholipids to form a magnetic liposome cRGD-AFePt@NPs encapsulating superparamagnetic ferric oxide nanoparticles and cisplatin for achieving high drug loading and a better synergistic effect. The cRGD-AFePt@NPs could be effectively internalized and responsively release loading cargos under alternating magnetic field irradiation due to local hyperthermia generated from magnetic nanoparticles by hysteresis loss and Néel relaxation. The generated Fe2+/Fe3+ from Fe3O4 NPs in the acid lysosomes motivated cisplatin and catalyzed the Fe-dependent anticancer drug artemisinin (ART) to generate highly toxic ROS through the Fenton reaction, which greatly enhances the anticancer effect of cisplatin with minimized side effects. In vitro cytotoxicity tests demonstrated that the cRGD-AFePt@NPs exhibited a 15.17-fold lower IC50 value of free cisplatin (IC50 = 32.47 µM) against A549/R cells. Further flow-cytometry tests also showed obviously increased intracellular ROS generation and cell apoptosis rates. We highlight the potential for Fe2+/Fe3+-mediated combination therapy of cisplatin and ART for circumventing cisplatin drug resistance.

Enhanced highly toxic reactive oxygen species levels from iron oxide core-shell mesoporous silica nanocarrier-mediated Fenton reactions for cancer therapy.

In this study, iron oxide core-shell mesoporous silica nanoparticles (Fe3O4@MSN) were prepared via the hydrolysis of tetraethyl orthosilicate on the surfaces of Fe3O4 nanoparticles, and these were further conjugated with folate (PEG-FA) and mitochondrial targeting triphenylphosphonium (TPP) to form Fe3O4@MSN-TPP/PEG-FA. A reactive oxygen species (ROS) promoting synergistic combined chemotherapy platform was designed through Fe3O4@MSN-TPP/PEG-FA encapsulating doxorubicin (DOX) and 3-amino-1,2,4-triazole (AT) for cancer therapy. DOX could stimulate the activation of nicotinamide adenine dinucleotide phosphate oxidases (NOXs), which change oxygen into superoxide radicals, which could be further triggered to produce hydrogen peroxide (H2O2) using the superoxide dismutase (SOD) enzyme. AT, as a catalase inhibitor, was employed to inhibit catalase activity to protect the production of H2O2. Thereafter, H2O2 was catalyzed with the help of Fe2+/Fe3+ to form highly toxic free hydroxyl radicals through Fenton reactions, which could induce cell death via synergistic DOX therapy. From in vitro assays, the prepared DOX/AT-loaded Fe3O4@MSN-TPP/PEG-FA showed remarkable inhibition efficiency (3.23% cell viability and 88.1% cell apoptosis) towards MGC-803 cells. This work has created a novel approach to gradually promote the production of ROS and combine this with chemotherapy to enhance anticancer efficacy.

Near infrared radiated stimulus-responsive liposomes based on photothermal conversion as drug carriers for co-delivery of CJM126 and cisplatin.

Synergistic therapy has caused increasing interest in recent treatment of cancer owing to its preferable therapeutic efficiency to most single antineoplastic protocol. Herein, we design a co-delivery two drugs nanosystem based on biodegradable liposomes, loading cisplatin, Indocyanine green (ICG), and CJM126 coupled with cholesterol derivative (CJM-Chol) for the purpose of synergistic therapy. The obtained nanoparticles showed a uniform diameter of 103.8nm and a favorable morphology. The investigation on near infrared radiated (NIR) responsive release showed that NIR mediated photothermal conversion induced a controllable drug release from liposomes. Furthermore, the designed liposomes (only 50µg/mL) displayed an inspiring photothermal conversion efficiency and received a high temperature (65.6°C, Tm=42°C) when exposed to an 808nm near infrared laser (1.54W, 5min). Besides, it turned out that the delivery system could be efficiently endocytosed by tumor cells, which attributed to its admirable biocompatibility and the targeting role of folate. The prepared nanoparticles showed significantly excellent inhibitory effect (3.05% cell viability in 24h) on MDA-MB-231 cells when added irradiation as compared with free cisplatin (28.41%) or treatment without NIR (11.24%) in our study. Our research highlights the present nanoparticles provide a promising strategy for targeted delivery and photothermal treatment.