Jiaxun Wan

Biodegradation and Toxicity of Protease/Redox/pH Stimuli-Responsive PEGlated PMAA Nanohydrogels for Targeting Drug delivery.

The application of nanomaterials in intelligent drug delivery is developing rapidly for treatment of cancers. In this paper, we fabricated a new kind of protease/redox/pH stimuli-responsive biodegradable nanohydrogels with methacrylic acid (MAA) as the monomer and N,N-bis(acryloyl)cystamine (BACy) as the cross-linker through a facile reflux-precipitation polymerization. After that, the polyethylene glycol (PEG) and folic acid (FA) were covalently grafted onto the surface of the nanohydrogels for enhancement of their long in vivo circulation lifetime and active targeting ability to the tumor cells and tissues. This kind of nanohydrogels could be disassembled into short polymer chains (Mn<1140; PDI<1.35) both in response to glutathione (GSH) through reduction of the sensitive disulfide bonds and protease by breakage of the amido bonds in the cross-linked networks. The nanohydrogels were utilized to simultaneously load both hydrophilic drug doxorubicin (DOX) and hydrophobic drug paclitaxel (PTX) with high drug loading efficiency. The cumulative release profile showed that the drug release from the drug-loaded nanohydrogels was significantly expedited by weak acidic (pH 5.0) and reducing environment (GSH), which exhibited an distinct redox/pH dual stimuli-responsive drug release to reduce the leakage of drugs before they reach tumor site. In addition, the in vitro experiment results indicated that the multidrug-loaded system had synergistic effect on cancer therapy. Meanwhile, the acute toxicity and intravital fluorescence imaging studies were adopted to evaluate the biocompatibility and biotoxicity of the nanohydrogels, the experimental results showed that the PEG modification could greatly enhance the long in vivo circulation lifetime and reduce the acute toxicity (LD50: from 138.4 mg/kg to 499.7 mg/kg) of the nanohydrogels.

Dual-Mode Encoded Magnetic Composite Microsphere Based on Fluorescence Reporters and Raman Probes as Covert Tag for Anticounterfeiting Applications.

Utilizing fluorescence reporters and SERS probes as the security labels, a series of dual-mode encoded magnetic composite microspheres with micrometer size was designed and prepared for anticounterfeiting applications. At first, the micro-meter-sized melamine formaldehyde microspheres with different fluorescence molecules (FMF) were prepared by precipitation polymerization, and then the magnetite composite microspheres (FMF/MNPs) were fabricated by direct immobilization of magnetic nanoparticles (MNPs) onto the surface of FMF microspheres. After deposition of Ag nanoparticles (Ag-NPs) onto FMF/MNPs microspheres, the SERS probes were absorbed onto the surface of Ag-NPs, and then a protection layer of silica was coated on the composite microspheres by Stöber method. The combination of different fluorescence reporters and SERS probes greatly increased the encoding complexity and volume for high-level anticounterfeiting. The structure of the dual-encoded FMF/MNPs/Ag-NPs/SiO2 composite microspheres was characterized by FESEM, TEM, FLS(fluorescence spectrometer), XRD, VSM, UV-vis and EDS. The embedded magnetic nanoparticles enable the composite microspheres to be quickly isolated from the marked latex paint by magnet at the concentration of as low as 1 ppm, and the covert tag information can be read out even from one composite microsphere. In addition, the covert security information in the marked coating film can be also read out in situ and the existence of the composite microspheres does not influence the visible appearance of the coating film. All the above outstanding properties will make these dual-mode encoded composite microspheres as advanced security tags for next-generation anticounterfeiting applications.

Multifunctional Magnetic Gd3+‐Based Coordination Polymer Nanoparticles: Combination of Magnetic Resonance and Multispectral Optoacoustic Detections for Tumor‐Targeted Imaging in vivo

To overcome traditional barriers in optical imaging and microscopy, optoacoustic-imaging has been changed to combine the accuracy of spectroscopy with the depth resolution of ultrasound, achieving a novel modality with powerful in vivo imaging. However, magnetic resonance imaging provides better spatial and anatomical resolution. Thus, a single hybrid nanoprobe that allows for simultaneous multimodal imaging is significant not only for cutting edge research in imaging science, but also for accurate clinical diagnosis. A core-shell-structured coordination polymer composite microsphere has been designed for in vivo multimodality imaging. It consists of a Fe3 O4 nanocluster core, a carbon sandwiched layer, and a carbocyanine-Gd(III) (Cy-Gd(III) ) coordination polymer outer shell (Fe3 O4 @C@Cy-Gd(III) ). Folic acid-conjugated poly(ethylene glycol) chains are embedded within the coordination polymer shell to achieve extended circulation and targeted delivery of probe particles in vivo. Control of Fe3 O4 core grain sizes results in optimal r2 relaxivity (224.5 × 10(-3) m(-1) s(-1) ) for T2 -weighted magnetic resonance imaging. Cy-Gd(III) coordination polymers are also regulated to obtain a maximum 25.1% of Cy ligands and 5.2% of Gd(III) ions for near-infrared fluorescence and T1 -weighted magnetic resonance imaging, respectively. The results demonstrate their impressive abilities for targeted, multimodal, and reliable imaging.

Zinc finger-inspired nanohydrogels with glutathione/pH triggered degradation based on coordination substitution for highly efficient delivery of anti-cancer drugs

Biodegradable materials used for drug delivery are of great demand due to their ability to degrade into low molecular weight species and further excrete from the body by metabolism. Herein, we report a new kind of zinc(II) crosslinked poly(methacrylic acid) nanohydrogels (ZCLNs) inspired by zinc finger proteins with dual stimuli-triggered degradation (glutathione and pH) for the first time. Compared with the disulfide bond crosslinked nanohydrogels, this new kind of ZCLNs is beneficial to the degradation of a wide range of cells, including normal cells. Ex vivo fluorescence images showed that the DOX-loaded folate-PEG conjugated zinc(II)-crosslinked polymeric nanohydrogels (FPZCLNs-15) preferentially accumulated in tumor tissue and the accumulation in normal tissues was much less compared with DOX-loaded PZCLNs-15 (non-targeted nanohydrogels) and free DOX, the FPZCLNs-15 (targeting system) delivered DOX to the tumor site with approximately 3.6- and 1.6-fold higher than free DOX and PZCLNs-15, respectively. Meanwhile, the PZCLNs-15 and FPZCLNs-15 reduced the concentration of DOX in the heart by 3.2- and 5.0-fold respectively, as compared to the free DOX. Moreover, a superior tumor growth inhibition and negligible damage to normal organs like the heart and kidney, which is reported to be vulnerable to DOX-associated side effects, are further demonstrated.

Preparation of Pt(IV)-crosslinked polymer nanoparticles with an anti-detoxifying effect for enhanced anticancer therapy

Cisplatin is a widely-used chemotherapeutic drug in the clinic against a range of cancers. However, its anti-cancer efficacy and bioavailability are severely affected by systemic toxicity as well as drug resistance, which are mainly due to indiscriminate body distribution, low tumor accumulation and glutathione (GSH)-related drug detoxification. In this study, we prepared for the first time a new kind of Pt(IV)-crosslinked polymer nanoparticle with small, uniform size and high loading of cisplatin (60.8%). Such a kind of polymer nanodrug could keep its structural integrity during blood circulation to afford higher tumor accumulation via the EPR effect and receptor-mediated targeting effect, yet rapidly self-disintegrate to release drugs in response to tumor intracellular bio-reducing molecules, such as glutathione (GSH), resulting in efficient cancer cell inhibition and reduced systemic toxicity in vivo. Meanwhile, some of the cellular GSH molecules are depleted and transformed into an oxidized GSSG form to decrease their chelating interaction with platinum drugs, which attenuate their detoxifying effect on the Pt(II) species and may have an advantage for overcoming the tumor resistance to cisplatin induced by GSH. Moreover, the maximum tolerated dose of drug could be greatly enhanced (>3 fold), which improved the bioavailability of the nanodrug at relatively high doses. The present work provides a novel drug self-crosslinked design tactic and might open a new window for clinical cancer treatment.

Microwave-assisted hydrothermal crystallization: an ultrafast route to MSP@mTiO2 composite microspheres with a uniform mesoporous shell

An ultrafast, green and efficient microwave-assisted hydrothermal crystallization method was developed to convert the amorphous titania shell of MSP@TiO2 to uniform mesoporous anatase structure for highly selective and effective enrichment of phosphopeptides.

Water-Soluble Metalated Covalent Organic Nanobelts with Improved Bioavailability for Protein Transportation

An available pathway to prepare the ionized covalent organic nanosheets (iCONs) has been proposed by a metal-assisted aqueous-phase exfoliation route from covalent organic frameworks. The soluble and belt-shaped iCONs could immobilize a large quantity of proteins (2.73 mg/mg, BSA/iCONs) and hence serve as transporters to enhance the protein uptake by cancer cells. Meanwhile, their energy-dependent endocytosis pathway via clathrin-coated pits has been proved as well.

Synthesis of indocyanine green functionalized comblike poly(aspartic acid) derivatives for enhanced cancer cell ablation by targeting the endoplasmic reticulum

Undesired gene expression can lead to severe diseases such as cancers. Oncogenic proteins or survival factors encoded by oncogenes can sustain cancer cell survival and proliferation. Considering that proteins are manufactured and transported by the endoplasmic reticulum (ER), the destroying of oncogenic proteins within the ER could cut-off the process of undesired gene expression. In this study, a new type of ER targeting strategy was developed based on the coordination interaction of the Ca(II) ion rich ER lumen with the carboxyl group of poly(aspartic acid) (PAsp). A comblike polymer PAsp-g-(PEG-ICG) was rationally designed and successfully prepared by grafting azido-modified polyethylene glycol (PEG) and the azido-modified photosensitizer indocyanine green (ICG) onto alkynyl-modified PAsp through the copper(I)-catalyzed alkyne–azide cycloaddition (CuAAC). Here, ICG not only shows its importance as an imaging agent that reveals the distribution of PAsp-g-(PEG-ICG) micelles both at tissue and subcellular levels, but also acts as a protein destructive agent to generate reactive oxygen species (ROS) resulting in protein denaturation. Moreover, chemotherapeutic drugs, such as paclitaxel, can be easily encapsulated into PAsp-g-(PEG-ICG) (PTX@PAsp-g-(PEG-ICG)) in up to 28% drug loading capacity with excellent stability. The experimental results proved that the as-prepared PTX@PAsp-g-(PEG-ICG) micelles exhibited selective accumulation in the ER lumen of cancer cells. Thus, a 10-fold enhancement of ROS was obtained by incubating cancer cells with PAsp-g-(PEG-ICG) micelles at a PTX concentration of 1.0 μg ml−1 under laser irradiation (0.2 W cm−2, 785 nm, 30 s) for 24 h, leading to disruption of proteins in the ER that caused ER stress-induced cancer cell apoptosis up to 76%. In a cytotoxicity test, U-87 MG glioma cells incubated with PTX@PAsp-g-(PEG-ICG) at the PTX concentration of 2.5 μg ml−1 were reduced to nearly 0% of cell viability upon 24 h laser irradiation (2 W cm−2, 785 nm, 30 s), in comparison with free PTX that showed 60% cell viability under the same conditions, indicating that photodynamic therapy (PDT) remarkably enhanced chemotherapeutic effects. With the good combination of PDT and chemotherapy, the PTX@PAsp-g-(PEG-ICG) micelles offer unprecedented advantages by effectively targeting the ER and displayed a prolonged retention time in the tumors of U-87 MG bearing nude mice, providing great promise for manipulating biomaterial design to achieve the intended ER targeted delivery for non-invasive cancer therapy.