In-situ fabrication of novel Au nanoclusters-Cu2+@sodium alginate/hyaluronic acid nanohybrid gels for cuproptosis enhanced photothermal/photodynamic/chemodynamic therapy via tumor microenvironment regulation.

Multimodal combined therapy (MCT) is an emerging avenue to eliminate tumor cells by the synergistic effect of various therapeutic methods. However, the complex tumor microenvironment (TME) is becoming the key barrier to the therapeutic effect of MCT due to the excessive existence of H+ ions, H2O2, and glutathione (GSH), the lack of O2, and the relaxation of ferroptosis. To overcome these limitations, smart nanohybrid gels with excellent biocompatibility, stability and targeting function were prepared by using gold nanoclusters as cores and an in situ cross-linking composite gel of sodium alginate (SA)/hyaluronic acid (HA) as the shell. The obtained Au NCs-Cu2+@SA-HA core-shell nanohybrid gels possessed near-infrared light response synergistically benefitting photothermal imaging guided photothermal therapy (PTT) and photodynamic therapy (PDT). Meanwhile, the H+-triggered release of Cu2+ ions from the nanohybrid gels not only induces cuproptosis to avoid the relaxation of ferroptosis, but also catalyzes H2O2 in the TME to generate O2 to simultaneously improve the hypoxic microenvironment and PDT effect. Furthermore, the released Cu2+ ions could consume the excessive GSH to form Cu+ ions effectively, which caused the formation of hydroxyl free radicals (·OH) to kill tumor cells, synergistically realizing GSH consumption-enhanced PDT and chemodynamic therapy (CDT). Hence, the novel design in our work provides another research avenue for cuproptosis-enhanced PTT/PDT/CDT via TME modulation.

A multi-responsive Au NCs@PMLE/Ca2+ antitumor hydrogel formed in situ on the interior/surface of tumors for PT imaging-guided synergistic PTT/O2-enhanced PDT effects.

At present, although phototherapy and related imaging have proven to be promising cancer diagnosis and treatment strategies, the free diffusion of photosensitizers into normal tissues can cause side effects, and the efficiency of photodynamic therapy (PDT) can also be limited by the tumor hypoxic microenvironment. Herein, we designed and prepared a new cancer nanoplatform containing Au nanoclusters (NCs)@Premna microphylla leaf extract (PMLE) with both responsiveness to near-infrared (NIR) laser irradiation and tumor microenvironment (TME) by facile redox and coordination reactions. Then, the Au NCs@PMLE/Ca2+ hydrogel was constructed in situ inside and on the surface of tumors for locoregional antitumor activity under 808 nm laser irradiation. The Au NCs@PMLE nanoplatform showed distinguished performance in killing cancer cells and alleviating tumor hypoxia by enhancing the temperature of the tumor sites and producing reactive oxygen species (ROS) under NIR irradiation as well as catalyzing hydrogen peroxide (H2O2) decomposition in TME for oxygen (O2) generation via catalase in PMLE. The ultra-small size of about 3 nm of the Au NCs in this nanoplatform was obtained using the biological molecules present in PMLE as reductants and coordination agents simultaneously, which also demonstrated the outstanding capability of photothermal (PT) imaging and photothermal therapy (PTT) towards tumors. Furthermore, the Au NCs@PMLE/Ca2+ hydrogel formed in situ through natural PMLE and intrinsic Ca2+ in TME could not only improve the biocompatibility of the nanoplatform and stability of Au NCs but was also highly concentrated around the tumor thus enhancing the therapeutic efficiency and inhibiting its migration to normal tissues, decreasing the side effects. The results of the experiments confirmed that the Au NCs@PMLE/Ca2+ hydrogel possessed PT imaging-guided NIR laser/TME-responsive synergetic cancer PTT/O2-enhanced PDT and remarkable locoregional antitumor effect for cancer therapy. This work may open a new versatile route for multi-responsive localized cancer therapeutic nanoplatforms.

Self-assembled Au4Cu4/Au25 NCs@liposome tumor nanotheranostics with PT/fluorescence imaging-guided synergetic PTT/PDT.

Exploring and developing a new type of nanoplatform with diagnosis and treatment to effectively cure tumors and reduce side effects has become a hot spot for researchers and is of great significance. Herein, a cancer theranostic nanoplatform with dual-imaging, dual-phototherapy and laser-responsiveness to tumor microenvironment was successfully assembled by liposome (Lip) co-loaded with oil-soluble Au4Cu4 nanoclusters (NCs) and water-soluble Au25 NCs via a simple film hydration method and subsequent extraction process. The prepared Au4Cu4/Au25@Lip nanoplatform with core-shell structure and about 50 nm of uniform sphere shape presented highly biocompatible, stability and passive targeting due to the enhanced permeability and retention (EPR) effect. Furthermore, the Lip composed of lecithin and cholesterol has good affinity with the cell membrane, which can realize the effective accumulation of photosensitizers at the tumor site, so that improving phototherapy effect and reducing the damage to normal tissue. The loaded oil-soluble Au4Cu4 NCs were firstly and pleasantly surprised to find possessed not only ideal photodynamic effect, but also preferable catalysis towards endogenous hydrogen peroxide (H2O2) decomposition to produce oxygen (O2) for improving the tumor hypoxic environment besides the excellent photoluminescence ability while the water-soluble Au25 NCs own outstanding photothermogenesis effect and also photoluminescence performance. The in vitro and in vivo experiment results proved that in the Au4Cu4/Au25@Lip nanoplatform, the performances of both NCs were complementary, which presenting considerable photothermal/fluorescence imaging (PTI/FI)-guided synergistic photothermal therapy (PTT)/O2-enhanced photodynamic therapy (PDT) effect for the tumor under the irradiation of near infrared (NIR) laser. This work provides a useful inspiration and paves a new way for the assembly of NCs or namomaterials with different properties into an integrated anti-tumor theranostic nanoplatform.

An effective NIR laser/tumor-microenvironment co-responsive cancer theranostic nanoplatform with multi-modal imaging and therapies.

Cancer is still a major threat to human health at present. Developing new types of integrated nanoplatforms for the accurate diagnosis and effective treatment of cancer is very significant. Herein, an intelligent dual-stage core-shell cancer theranostic nanoplatform (Fe3+@Au1Ag24@PbP) with NIR laser/tumor-microenvironment (TME) co-responsiveness and multi-modal imaging-therapy was successfully prepared, which was composed of the precisely structured oil-soluble Au1Ag24 nanoclusters (NCs) and Fe3+ ions easily assembled within the oil and aqueous phases of the polyethylene glycol (PEG) block grafted polyketal (PK) copolymer (PK-b-PEG, PbP) vesicles, respectively. In this system, we were delighted to find that the prepared Au1Ag24 NCs possess multi-photoresponsive properties, endowing the nanoplatform with photoacoustic (PA)/photothermal (PT) imaging and synergetic photothermal therapy (PTT)/photodynamic therapy (PDT) for cancer under near-infrared (NIR) laser irradiation. On the other hand, Fe3+ ions exhibit multi-TME response and regulation behaviors, including as catalysts for the decomposition of endogenous hydrogen peroxide (H2O2) in the solid tumor to produce O2 and as the oxidizing agent for the consumption of the intracellular GSH to avoid the reduction of the generated 1O2; therefore, the synchronously formed Fe2+ ions from the redox of Fe3+ with GSH could further react with H2O2 to produce hydroxyl radical (˙OH), which induced ferroptosis-based cancer treatment. The PbP shell possesses TME/pH sensitivity for controlled drug release and passive targeting, causing a large increase in Au1Ag24/Fe3+ accumulation within the weakly acidic tumor region and reducing the side effects on normal tissues. Both in vitro and in vivo experiments demonstrate that the Fe3+@Au1Ag24@PbP nanoplatform presented excellent PA/PT imaging-guided synergetic PTT/PDT/ferroptosis effects toward tumor cells and tumors. This integrating multi-responsive and multi-modal theranostic nanoplatform paves a new way for effective cancer therapy.

4-in-1 Fe3O4/g-C3N4@PPy-DOX nanocomposites: Magnetic targeting guided trimode combinatorial chemotherapy/PDT/PTT for cancer.

At present, cancer has become a major disease threatening human health worldwide. Therefore, developing targeting guided multimode synergetic therapy has become one of the hot spots in current antitumor research and is also a great challenge. Herein, a new Fe3O4/g-C3N4@PPy-DOX nanocomposite containing magnetic iron oxide (Fe3O4) nanoparticles (NPs), lamellar structure of graphite-like carbon nitride (g-C3N4) and polypyrrole (PPy) shell with the loaded anti-tumor drug doxorubicin hydrochloride (DOX) was designed and prepared. The monodisperse Fe3O4 nanoparticles (NPs) with the diameter of 20 nm endowed the nanocomposite with the magnetic targeting ability, reducing damage to normal tissues. It is very interesting that the Fe3O4 NPs also possessed photosensitizer function for photodynamic therapy (PDT). The g-C3N4 sheets as the photocatalysis towards the degradation of water for generating O2 could effectively improve the hypoxia of solid tumors and increase the efficiency of PDT. In addition, PPy has high light-to-heat conversion efficiency, so was chosen for the cancer photothermal therapy (PTT). Finally, an anticancer drug (DOX) was loaded on the nanocomposite because the presence of mesoporous structure. Thus, the prepared Fe3O4/g-C3N4@PPy-DOX nanocomposites exhibit synergetic chemotherapy/PTT/enhanced PDT antitumor effect. This study provides an inspiration for combining targeting and multimodality to improve the anticancer efficiency.

A dual-targeting Fe3O4@C/ZnO-DOX-FA nanoplatform with pH-responsive drug release and synergetic chemo-photothermal antitumor in vitro and in vivo.

Designing a proper intelligent platform to target cancer cells accurately and reducing its toxic side effects on normal tissues remain a challenge in medicine application. Herein, a novel dual-targeted and tumor microenvironment-triggered Fe3O4@carbon(C)/ZnO-doxorubicin (DOX) -folic acid (FA) drug delivery system with porous structure was designed and fabricated for the first time. The co-presence of Fe3O4 core and FA molecules functioned successfully could successfully realize the magnetic targeting and cancer cell-specific targeting. In addition, pH-responsive ZnO and porous carbon both derived directly from zinc-2-methylimidazolate complex (Zn-ZIF) could play the roles of "gatekeeper" and photothermal agent, respectively. The former could efficiently block the drug within mesoporous in blood environment for decreasing the damage to the normal tissues and achieving the controlled DOX release in the simulated and real acidic tumor microenvironment. And the latter could exhibit the intrinsic photothermal conversion efficiency upon 638 nm laser irradiation. Therefore, the Fe3O4@C/ZnO-DOX-FA nanoplatform integrated dual targeting, controlled chemotherapy with photothermal therapy (PTT) for cancer, displaying a significantly superior synergistic anticancer efficiency both in vitro and in vivo experiments to either monotherapy. Above results suggested the prepared nanoplatforms might be a promising candidate for effectively synergetic therapeutics to cancers.

A structurally precise AgxAu25-x nanocluster based cancer theranostic platform with tri-targeting/in situ O2-generation/aggregation enhanced fluorescence imaging/photothermal-photodynamic therapies.

The photothermal and photodynamic performances of structurally precise oil-soluble AgxAu25-x (x ≤ 13) nanoclusters were first explored and they were solubilized into new assemblies to form a versatile cancer theranostic platform with tri-targeting/in situ O2-generation/aggregation enhanced fluorescence imaging/photothermal-photodynamic therapy effects, which will provide an important reference for precision theranostics at the atomic level in future.

Tailoring the photoluminescence of atomically precise nanoclusters.

Due to their atomically precise structures and intriguing chemical/physical properties, metal nanoclusters are an emerging class of modular nanomaterials. Photo-luminescence (PL) is one of their most fascinating properties, due to the plethora of promising PL-based applications, such as chemical sensing, bio-imaging, cell labeling, phototherapy, drug delivery, and so on. However, the PL of most current nanoclusters is still unsatisfactory-the PL quantum yield (QY) is relatively low (generally lower than 20%), the emission lifetimes are generally in the nanosecond range, and the emitted color is always red (emission wavelengths of above 630 nm). To address these shortcomings, several strategies have been adopted, and are reviewed herein: capped-ligand engineering, metallic kernel alloying, aggregation-induced emission, self-assembly of nanocluster building blocks into cluster-based networks, and adjustments on external environment factors. We further review promising applications of these fluorescent nanoclusters, with particular focus on their potential to impact the fields of chemical sensing, bio-imaging, and bio-labeling. Finally, scope for improvements and future perspectives of these novel nanomaterials are highlighted as well. Our intended audience is the broader scientific community interested in the fluorescence of metal nanoclusters, and our review hopefully opens up new horizons for these scientists to manipulate PL properties of nanoclusters. This review is based on publications available up to December 2018.

Engineered Targeted Hyaluronic Acid-Glutathione-Stabilized Gold Nanoclusters/Graphene Oxide-5-Fluorouracil as a Smart Theranostic Platform for Stimulus-Controlled Fluorescence Imaging-Assisted Synergetic Chemo/Phototherapy.

A theranostic platform with integrated diagnostic and therapeutic functions as well as specific targeted and controlled combination therapy to enhance treatment efficacy is of great importance for a wide range of biomedical applications. Here, we first attempted to develop biocompatible hyaluronic acid (HA)-glutathione (GSH) conjugate stabilized gold nanoclusters (GNCs) combined with graphene oxide (GO), accompanied by loading 5-fluorouracil (5FU), as a novel theranostic platform (HG-GNCs/GO-5FU, HG refers to HA-GSH). Multifunctional HG-GNCs possessed excellent fluorescence, photosensitivity and specific targeting ability to the cancer cells while their fluorescence and singlet oxygen generation could be strongly inhibited by GO and then effectively restored by lysosomal hyaluronidase in tumor cells. The sustained and complete release of 5FU from HG-GNCs/GO could also be stimulated successively by enzymatic degradation of HA and light-induced heat effect of GO under laser irradiation so that turn-on cell imaging-assisted synergistic therapeutic strategies associated with triple enzyme/light-controlled chemo/photothermal/photodynamic therapy could be achieved at the same time, reducing greatly the side effects of materials to normal cells. Our study presents a novel strategy to combine targeting and bioimaging with triple therapies to enhance the antitumor effect.

Improved fluorescence imaging and synergistic anticancer phototherapy of hydrosoluble gold nanoclusters assisted by a novel two-level mesoporous canal structured silica nanocarrier.

A novel integrated system composed of hydrosoluble gold nanoclusters (AuNCs), two-level mesoporous canal silica, gelatin and folic acid was for the first time designed and synthesized, which could conquer poor stability of AuNCs and shows aggregation-enhanced fluorescence imaging, cancer cell-specific targeting, and synergistic photothermal/photodynamic therapies for the goal of personalized nanotheranostics.

RGO/AuNR/HA-5FU nanocomposite with multi-stage release behavior and efficient antitumor activity for synergistic therapy.

A reduced graphene oxide (RGO)/gold nanorod (AuNR)/hydroxyapatite (HA) nanocomposite was designed and successfully synthesized for the first time. An anticancer drug, 5-fluorouracil (5FU), was chosen as a model drug to be loaded in RGO/AuNR/HA. The fabricated RGO/AuNR/HA-5FU showed robust, selective targeting and penetrating efficiency against HeLa cells due to the good compatibility and nontoxicity of HA, and showed excellent synergetic antitumor effects through combined chemotherapy (CT) by 5FU and photothermal therapy (PTT) by both RGO and AuNRs under near-infrared (NIR) laser irradiation. More importantly, this synergistic dual therapy based on RGO/AuNR/HA can also minimize side effects in normal cells and exhibits greater antitumor activity because of a multi-stage drug release ability triggered by the pH sensitivity of HA in the first stage and the combined photothermal conversion capabilities of RGO and AuNRs by means of the NIR laser irradiation in the second stage. This study suggests that the novel RGO/AuNR/HA multi-stage drug delivery system may represent a promising potential application of multifunctional composite materials in the biomedical field.