O2-Cu/ZIF-8@Ce6/ZIF-8@F127 Composite as a Tumor Microenvironment-Responsive Nanoplatform with Enhanced Photo-/Chemodynamic Antitumor Efficacy.

Hypoxia and overexpression of glutathione (GSH) are typical characteristics of the tumor microenvironment, which severely hinders cancer treatments. Here, we design a novel biodegradable therapeutic system, O2-Cu/ZIF-8@Ce6/ZIF-8@F127 (OCZCF), to simultaneously achieve GSH depletion and O2-enhanced combination therapy. Notably, the doped Cu2+ doubles the O2 storage capacity of the ZIF-8 matrix, which makes OCZCF an excellent pH-sensitive O2 reservoir for conquering tumor hypoxia, enhancing the photodynamic therapy (PDT) efficiency of chlorin e6 (Ce6) under 650 nm laser irradiation. Moreover, the released Cu2+ can act as a smart reactive oxygen species protector by consuming intracellular GSH. The byproduct Cu+ will undergo highly efficient Fenton-like reaction to achieve chemodynamic therapy (CDT) in the presence of abundant H2O2. The accompanying O2 will further alleviate hypoxia. The in vitro and in vivo experimental data indicate that OCZCF could cause remarkable tumor inhibition through enhanced synergetic PDT and CDT, which may open up a new path for cancer therapy.

Monodispersed Copper(I)-Based Nano Metal-Organic Framework as a Biodegradable Drug Carrier with Enhanced Photodynamic Therapy Efficacy.

Photodynamic therapy (PDT) has emerged as an alternative treatment of cancers. However, the therapeutic efficiency of PDT is severely limited by the microenvironment of insufficient oxygen (O2) supply and overexpression of glutathione (GSH) in the tumor. Herein, a biodegradable O2-loaded CuTz-1@F127 (denoted as CuTz-1-O2@F127) metal-organic framework (MOF) therapeutic platform is presented for enhanced PDT by simultaneously overcoming intracellular hypoxia and reducing GSH levels in the tumor. The Cu(I)-based MOF is capable of a Fenton-like reaction to generate •OH and O2 in the presence of H2O2 under NIR irradiation. Meanwhile, the CuTz-1-O2@F127 nanoparticles (NPs) can release adsorbed O2, which further alleviates intracellular hypoxia. In addition, the CuI in CuTz-1@F127 can react with intracellular GSH to reduce the excess GSH. In this way, the efficiency of PDT is greatly enhanced. After tail intravenous injection, the NPs show high antitumor efficacy through a synergistic effect under 808 nm laser irradiation. More importantly, the NPs are biodegradable. In vivo biodistribution and excretion experiments demonstrate that a total of nearly 90% of the NPs can be excreted via feces and urine within 30 d, which indicates significant prospects in the clinical treatment of cancers.

Intelligent Hollow Pt-CuS Janus Architecture for Synergistic Catalysis-Enhanced Sonodynamic and Photothermal Cancer Therapy.

As a noninvasive treatment modality, ultrasound (US)-triggered sonodynamic therapy (SDT) shows broad and promising applications to overcome the drawbacks of traditional photodynamic therapy (PDT) in combating cancer. However, the SDT efficacy is still not satisfactory without oxygen (O2) assistance. In addition, there is also much space to explore the SDT-based synergistic therapeutic modalities. Herein, a novel Pt-CuS Janus composed of hollow semiconductor CuS and noble metallic Pt was rationally designed and successfully synthesized. The hollow CuS shows a large inner cavity for loading sonosensitizer molecules (tetra-(4-aminophenyl) porphyrin, TAPP) to implement SDT. Moreover, the deposition of Pt not only enhances photothermal performance compared with those of CuS nanoparticles (NPs) due to the effect of the local electric field enhancement but also possesses nanozyme activity for catalyzing decomposition of endogenous overexpressed hydrogen peroxide (H2O2) to produce O2 that can overcome tumor hypoxia and augment the SDT-induced highly toxic reactive oxygen species (ROS) production for efficient cancer cell apoptosis. Importantly, the generated heat of Pt-CuS by 808 nm laser irradiation can accelerate the catalytic activity of Pt and elevate the O2 level that further facilitates SDT efficacy. Interestingly, the thermally sensitive copolymer coated around the Janus can act as a smart switch to regulate the catalytic ability of Pt and control TAPP release that has a significant effect on modulating the therapeutic effect. The synergistic catalysis-enhanced SDT efficiency and highly photothermal effect almost realized complete tumor resection without obvious reoccurrence and simultaneously displayed a highly therapeutic biosafety. Furthermore, the high optical absorbance allows the as-synthesized Pt-CuS Janus for photoacoustic (PA) imaging and NIR thermal imaging. This work develops a versatile nanoplatform for a multifunctional theranostic strategy and broadens the biological applications by rationally designing their structure.

DNA decorated Cu9S5 nanoparticles as NIR light responsive drug carriers for tumor chemo-phototherapy.

Recently, near-infrared (NIR) light responsive drug delivery systems have attracted much attention for tumor therapy. Herein, we have successfully constructed a smart nanocarrier system Cu9S5-PEI-DNA-DOX (labelled as CPD-DOX) based on the self-assembly of hydrophobic Cu9S5 nanoparticles (NPs), poly(ethylene imine) (PEI), double-stranded DNA (dsDNA) segments and the anti-cancer drug doxorubicin (DOX). Among them, Cu9S5 NPs can serve as a nano-transducer for absorbing and converting near-infrared light to heat. Then, the hydrophobic layer of Cu9S5 NPs is coated with the dendritic polymer PEI through a simple approach. According to the temperature of the tumor tissue and the photothermal effect of Cu9S5 NPs, we specially designed a DNA sequence with a suitable melting temperature for NIR-light-promoted denaturation of DNA helices and drug release when DOX intercalated into the dsDNA through noncovalent interaction. Notably, the DOX-loaded dsDNA can be decorated on the surface of Cu9S5 NPs by convenient electrostatic adsorption rather than chemical bonding. The experimental results show that dsDNA can maintain a stable helical structure under physiological conditions but unzip the helix to release DOX upon NIR irradiation. Therefore, DOX can be safely delivered and released into cancer cells to exert anticancer effects. Based on in vitro cell cytotoxicity experiments, the CPD-DOX system has a synergistic effect for cancer cell apoptosis or death because of both the cytotoxicity of light-triggered DOX release and the Cu9S5-NP-mediated photothermal ablation effect. It is expected that the facile synthesis and low cost nanocarrier can improve the anticancer effect in contrast to the single chemotherapy or photothermal therapy mode.

Construction of Hierarchical Polymer Brushes on Upconversion Nanoparticles via NIR-Light-Initiated RAFT Polymerization.

Photoinduced reversible addition-fragmentation chain transfer (RAFT) polymerization generally adopts high-energy ultraviolet (UV) or blue light. In combination with photoredox catalyst, the excitation light wavelength was extended to the visible and even near-infrared (NIR) region for photoinduced electron transfer RAFT polymerization. In this report, we introduce for the first time a surface NIR-light-initiated RAFT polymerization on upconversion nanoparticles (UCNPs) without adding any photocatalyst and construct a functional inorganic core/polymer shell nanohybrid for application in cancer theranostics. The multilayer core-shell UCNPs (NaYF4:Yb/Tm@NaYbF4:Gd@NaNdF4:Yb@NaYF4), with surface anchorings of chain transfer agents, can serve as efficient NIR-to-UV light transducers for initiating the RAFT polymerization. A hierarchical double block copolymer brush, consisting of poly(acrylic acid) (PAA) and poly(oligo(ethylene oxide)methacrylate-co-2-(2-methoxy-ethoxy)ethyl methacrylate) (PEG for short), was grafted from the surface in sequence. The targeting arginine-glycine-aspartic (RGD) peptide was modified at the end of the copolymer through the trithiolcarbonate end group. After loading of doxorubicin, the UCNPs@PAA-b-PEG-RGD exhibited an enhanced U87MG cancer cell uptake efficiency and cytotoxicity. Besides, the unique upconversion luminescence of the nanohybrids was used for the autofluoresence-free cell imaging and labeling. Therefore, our strategy verified that UCNPs could efficiently activate RAFT polymerization by NIR photoirradiation and construct the complex nanohybrids, exhibiting prospective biomedical applications due to the low phototoxicity and deep penetration of NIR light.

Thiol-Ene Click Reaction as a Facile and General Approach for Surface Functionalization of Colloidal Nanocrystals.

Oleic acid (OA) and/or oleylamine (OAm) are generally used as the surface ligands for stabilization of inorganic nanocrystals (NCs). The hydrophobic and inert surface of the NCs limits their applications such as in biomedical areas. Hence, surface modifications are essential in many physical and chemical processes. Here, a facile and versatile strategy is reported for the modification of NCs by ultraviolet-induced thiol-ene chemistry, in which thiol-terminated poly(ethylene glycol) (HSPEG) and its derivatives can react directly with double bonds in OA/OAm ligands to form covalent linking within one step. Through this strategy, various hydrophobic NCs with different compositions and morphologies are able to be transferred into water combining with functionalization of active groups. As a proof-of-concept, this strategy is successfully used to construct a sensor for detecting avidin based on upconverting luminescence analysis. Therefore, this strategy provides a new tool for designing and tuning the surface properties of NCs for different applications.

A Hollow-Structured CuS@Cu2 S@Au Nanohybrid: Synergistically Enhanced Photothermal Efficiency and Photoswitchable Targeting Effect for Cancer Theranostics.

It is of great importance in drug delivery to fabricate multifunctional nanocarriers with intelligent targeting properties, for cancer diagnosis and therapy. Herein, hollow-structured CuS@Cu2 S@Au nanoshell/satellite nanoparticles are designed and synthesized for enhanced photothermal therapy and photoswitchable targeting theranostics. The remarkably improved photothermal conversion efficiency of CuS@Cu2 S@Au under 808 nm near-infrared (NIR) laser irradiation can be explained by the reduced bandgap and more circuit paths for electron transitions for CuS and Cu2 S modified with Au nanoparticles, as calculated by the Vienna ab initio simulation package, based on density functional theory. By modification of thermal-isomerization RGD targeting molecules and thermally sensitive copolymer on the surface of nanoparticles, the transition of the shielded/unshielded mode of RGD (Arg-Gly-Asp) targeting molecules and shrinking of the thermally sensitive polymer by NIR photoactivation can realize a photoswitchable targeting effect. After loading an anticancer drug doxorubicin in the cavity of CuS@Cu2 S@Au, the antitumor therapy efficacy is greatly enhanced by combining chemo- and photothermal therapy. The reported nanohybrid can also act as a photoacoustic imaging agent and an NIR thermal imaging agent for real-time imaging, which provides a versatile platform for multifunctional theranostics and stimuli-responsive targeted cancer therapy.

808 nm photocontrolled UCL imaging guided chemo/photothermal synergistic therapy with single UCNPs-CuS@PAA nanocomposite.

Recently, incorporating multiple components into one nanostructured matrix to construct a multifunctional nanomedical platform has attracted more and more attention for simultaneous anticancer diagnosis and therapy. Herein, a novel anti-cancer nanoplatform has been successfully developed by coating a uniform shell of poly(acrylic acid) (PAA) on the surface of CuS-decorated upconversion nanoparticles (UCNPs). Benefiting from the enhanced 808 nm-excited UCL intensity of the multilayer UCNPs, the unique photothermal properties of CuS and the pH-responsive drug release capacity of the PAA shell, such a nanoplatform design of UCNPs-CuS@PAA (labeled UCP) offers a new route to achieve 808 nm-excited UCL imaging guided chemo/photothermal combination therapy. We have found that the combined chemo/photothermal therapy can significantly improve the therapeutic efficacy compared with chemotherapy or photothermal therapy (PTT) alone. Moreover, the pH/NIR-dependent drug delivery properties, 808 nm-excited UCL imaging, as well as in vitro/in vivo biocompatibility tests were also investigated in detail. These results show promising applications of UCP nanoparticles as a novel theranostic agent for the detection and treatment of tumors.

Synthesis of highly monodispersed Ga-soc-MOF hollow cubes, colloidosomes and nanocomposites.

Ga-soc-MOF hollow cubes with an average size of about 300 nm were prepared by a polyvinylpyrrolidone (PVP) assisted acid etching process. Colloidosomes with sizes of around 5-10 µm composed of single-layer tetrakaidecahedron building blocks (BBs) were synthesized for the first time. Au@Ga-soc-MOF nanocomposites with excellent catalytic properties were obtained.