Yangjun Chen

Multidentate zwitterionic chitosan oligosaccharide modified gold nanoparticles: stability, biocompatibility and cell interactions

Surface engineering of nanoparticles plays an essential role in their colloidal stability, biocompatibility and interaction with biosystems. In this study, a novel multidentate zwitterionic biopolymer derivative is obtained from conjugating dithiolane lipoic acid and zwitterionic acryloyloxyethyl phosphorylcholine to the chitosan oligosaccharide backbone. Gold nanoparticles (AuNPs) modified by this polymer exhibit remarkable colloidal stabilities under extreme conditions including high salt conditions, wide pH range and serum or plasma containing media. The AuNPs also show strong resistance to competition from dithiothreitol (as high as 1.5 M). Moreover, the modified AuNPs demonstrate low cytotoxicity investigated by both MTT and LDH assays, and good hemocompatibility evaluated by hemolysis of human red blood cells. In addition, the intracellular fate of AuNPs was investigated by ICP-MS and TEM. It showed that the AuNPs are uptaken by cells in a concentration dependent manner, and they can escape from endosomes/lysosomes to cytosol and tend to accumulate around the nucleus after 24 h incubation but few of them are excreted out of the cells. Gold nanorods are also stabilized by this ligand, which demonstrates robust dispersion stability and excellent hemocompatibility. This kind of multidentate zwitterionic chitosan derivative could be widely used for stabilizing other inorganic nanoparticles, which will greatly improve their performance in a variety of bio-related applications.

Field Tests on Pile-Supported Embankments over Soft Ground

When designing embankments over soft soils, geotechnical engineers face many challenges. These include potential bearing failure, intolerable settlement, and global or local instability. Pile-supported embankments have been emerged as an effective alternative successfully adopted worldwide to solve these problems. This paper focuses on three cases in which pile-supported embankments were used for constructing highways in the eastern coastal region of China. Each case provides a description of the soil profile, construction procedure, and field monitoring of the settlements, earth pressures, and pore-water pressures. Field monitored data from contact pressures acting on the piles and the soils, to the settlements of the piles and the soils are reported and discussed. The development of the earth pressures both on the piles and the soils shows that there was a significant soil arching in the embankment, and the measured earth pressures acting on the piles are much higher than that acting on the soils betwee...

Zwitterionic drug nanocarriers: a biomimetic strategy for drug delivery.

Nanomaterials self-assembled from amphiphilic functional copolymers have emerged as safe and efficient nanocarriers for delivery of therapeutics. Surface engineering of the nanocarriers is extremely important for the design of drug delivery systems. Bioinspired zwitterions are considered as novel nonfouling materials to construct biocompatible and bioinert nanocarriers. As an alternative to poly(ethylene glycol) (PEG), zwitterions exhibit some unique properties that PEG do not have. In this review, we highlight recent progress of the design of drug nanocarriers using a zwitterionic strategy. The possible mechanism of stealth properties of zwitterions was proposed. The advantages of zwitterionic drug nanocarriers deriving from phosphorylcholine (PC), carboxybetaine (CB), and sulfobetaine (SB) are also discussed.

A biomimic pH-sensitive polymeric prodrug based on polycarbonate for intracellular drug delivery

A biodegradable and endosomal pH-sensitive polymeric prodrug poly(5-methyl-5-allyloxycarbonyl-1,3-dioxan-2-one)-graft-12-acryloyloxy dodecyl phosphorylcholine-co-6-maleimidocaproyl-doxorubicin (PMAC-graft-(ADPC-co-Mal-DOX) was synthesized by ring-opening polymerization (ROP) and “click” reaction. DOX was conjugated to the polymer by hydrazone bonds which would result in a pH-sensitive controlled release of drug. The polymeric prodrug can form a self-assembled micellar structure which was confirmed by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Flow cytometry and fluorescence microscopy results demonstrated that prodrug micelles could be internalized by cancer cells remarkably. In vitro drug release studies showed that the release of DOX was faster at endosomal pH (pH = 5.0) than at normal physiological environment (pH = 7.4). Moreover, this prodrug exhibited high cytotoxicity against HepG2 cells and HeLa cells, indicating its great potential for cancer therapy.

IR-780 Loaded Phospholipid Mimicking Homopolymeric Micelles for Near-IR Imaging and Photothermal Therapy of Pancreatic Cancer

IR-780 iodide, a near-infrared (near-IR) fluorescent dye, can be utilized as an effective theranostic agent for both imaging and photothermal therapy. However, its lipophilicity limits its further biomedical applications. Herein, we synthesized a phospholipid mimicking amphiphilic homopolymer poly(12-(methacryloyloxy)dodecyl phosphorylcholine) (PMDPC) via reversible addition-fragmentation chain transfer (RAFT) polymerization. The amphiphilic homopolymer PMDPC can be self-assembled into micelles and used for the encapsulation of IR-780. The IR-780 loaded micelles (PMDPC-IR-780) exhibited low cytotoxicity in the dark, whereas remarkable photothermal cytotoxicity to pancreatic cancer cells (BxPC-3) was observed upon near-IR laser irradiation. We further investigated in vivo biodistribution of PMDPC-IR-780 micelles. Higher accumulation of PMDPC-IR-780 than that of free IR-780 in tumor tissue was verified, which might be ascribed to the enhanced permeability and retention (EPR) effect and long circulation time benefiting from the zwitterionic phosphorylcholine surface. Therefore, the IR-780 loaded phospholipid mimicking homopolymeric micelles could have great potential for cancer theranostics.

pH- and NIR Light-Responsive Polymeric Prodrug Micelles for Hyperthermia-Assisted Site-Specific Chemotherapy to Reverse Drug Resistance in Cancer Treatment.

Despite the exciting advances in cancer chemotherapy over past decades, drug resistance in cancer treatment remains one of the primary reasons for therapeutic failure. IR-780 loaded pH-responsive polymeric prodrug micelles with near infrared (NIR) photothermal effect are developed to circumvent the drug resistance in cancer treatment. The polymeric prodrug micelles are stable in physiological environment, while exhibit fast doxorubicin (DOX) release in acidic condition and significant temperature elevation under NIR laser irradiation. Phosphorylcholine-based biomimetic micellar shell and acid-sensitive drug conjugation endow them with prolonged circulation time and reduced premature drug release during circulation to conduct tumor site-specific chemotherapy. The polymeric prodrug micelles combined with NIR laser irradiation could significantly enhance intracellular DOX accumulation and synergistically induce the cell apoptosis in DOX-resistant MCF-7/ADR cells. Meanwhile, the tumor site-specific chemotherapy combined with hyperthermia effect induces significant inhibition of MCF-7/ADR tumor growth in tumor-bearing mice. These results demonstrate that the well-designed IR-780 loaded polymeric prodrug micelles for hyperthermia-assisted site-specific chemotherapy present an effective approach to reverse drug resistance.

Mixed-charge nanoparticles for long circulation, low reticuloendothelial system clearance, and high tumor accumulation.

Mixed-charge zwitterionic surface modification shows great potential as a simple strategy to fabricate nanoparticle (NP) surfaces that are nonfouling. Here, the in vivo fate of 16 nm mixed-charge gold nanoparticles (AuNPs) is investigated, coated with mixed quaternary ammonium and sulfonic groups. The results show that mixed-charge AuNPs have a much longer blood half-life (≈30.6 h) than do poly(ethylene glycol) (PEG, M¯w = 2000) -coated AuNPs (≈6.65 h) and they accumulate in the liver and spleen far less than do the PEGylated AuNPs. Using transmission electron microscopy, it is further confirmed that the mixed-charge AuNPs have much lower uptake and different existing states in liver Kupffer cells and spleen macrophages one month after injection compared with the PEGylated AuNPs. Moreover, these mixed-charge AuNPs do not cause appreciable toxicity at this tested dose to mice in a period of 1 month as evidenced by histological examinations. Importantly, the mixed-charge AuNPs have higher accumulation and slower clearance in tumors than do PEGylated AuNPs for times of 24-72 h. Results from this work show promise for effectively designing tumor-targeting NPs that can minimize reticuloendothelial system clearance and circulate for long periods by using a simple mixed-charge strategy.

Zwitterionic Phosphorylcholine–TPE Conjugate for pH-Responsive Drug Delivery and AIE Active Imaging

Polymeric micelles have emerged as a promising nanoplatform for cancer theranostics. Herein, we developed doxorubicin (DOX) encapsulated pH-responsive polymeric micelles for combined aggregation induced emission (AIE) imaging and chemotherapy. The novel zwitterionic copolymer poly(2-methacryloyloxyethylphosphorylcholine-co-2-(4-formylphenoxy)ethyl methacrylate) (poly(MPC-co-FPEMA)) was synthesized via RAFT polymerization and further converted to PMPC-hyd-TPE after conjugation of tetraphenylethene (TPE, a typical AIE chromophore) via acid-cleavable hydrazone bonds. The AIE activatable copolymer PMPC-hyd-TPE could self-assemble into spherical PC-hyd-TPE micelles, and DOX could be loaded through hydrophobic interactions. The zwitterionic micelles exhibited excellent physiological stability and low protein adsorption due to the stealthy phosphorylcholine (PC) shell. In addition, the cleavage of hydrophobic TPE molecules under acidic conditions could induce swelling of micelles, which was verified by size changes with time at pH 5.0. The in vitro DOX release profile also exhibited accelerated release rate with pH value decreasing from 7.4 to 5.0. Fluorescent microscopy and flow cytometry studies further demonstrated fast internalization and accumulation of drug loaded PC-hyd-TPE-DOX micelles in HepG2 cells, resulting in considerable time/dose-dependent cytotoxicity. Meanwhile, high-quality AIE imaging of PC-hyd-TPE micelles was confirmed in HepG2 cells. Notably, ex vivo imaging study exhibited efficient accumulation and drug release of PC-hyd-TPE-DOX micelles in the tumor tissue. Consequently, the multifunctional micelles with combined nonfouling surface, AIE active imaging, and pH-responsive drug delivery showed great potential as novel nanoplatforms for a new generation of cancer theranostics.

Failure Investigation at a Collapsed Deep Excavation in Very Sensitive Organic Soft Clay

AbstractCollapse of a 15.7-m-deep excavation in very sensitive organic soft clay in Hangzhou, China, is presented in this paper. The collapse of the excavation caused the break and/or inclination of the retaining walls, the wracking of the supporting system, significant sinking of a major road adjacent to the excavation site, and also the break in a water main beneath the road. After the collapse, the ground disturbance due to the collapse was investigated by cone penetration tests (CPTs) and field vane shear tests (VSTs). A simplified method, based on the CPT and VST test results, was used to evaluate the strength reduction ratio (SRR) of the in situ soils. According to the SRR values of the soils at different depths, the lower boundaries of the severely disturbed soils were determined and a possible slip failure surface passing through the bottom of the severely disturbed soils was justified. The factors of safety (FOSs) against basal heave of the excavation calculated from various methods were 1.05, 0....

The rational design of a gemcitabine prodrug with AIE-based intracellular light-up characteristics for selective suppression of pancreatic cancer cells.

An enzyme and reduction-activatable gemcitabine prodrug (TPE-GEM-RGD) with aggregation-induced emission (AIE) properties was designed for targeted and image-guided cancer therapy. TPE-GEM-RGD was successfully used for intracellular light-up imaging and glutathione (GSH)-responsive release of gemcitabine to suppress pancreatic cancer cells.