Gangsheng Tong

Oxime Linkage: A Robust Tool for the Design of pH-Sensitive Polymeric Drug Carriers

Oxime bonds dispersed in the backbones of the synthetic polymers, while young in the current spectrum of the biomedical application, are rapidly extending into their own niche. In the present work, oxime linkages were confirmed to be a robust tool for the design of pH-sensitive polymeric drug delivery systems. The triblock copolymer (PEG-OPCL-PEG) consisting of hydrophilic poly(ethylene glycol) (PEG) and hydrophobic oxime-tethered polycaprolactone (OPCL) was successfully prepared by aminooxy terminals of OPCL ligating with aldehyde-terminated PEG (PEG-CHO). Owing to its amphiphilic architecture, PEG-OPCL-PEG self-assembled into the micelles in aqueous media, validated by the measurement of critical micelle concentration (CMC). The MTT assay showed that PEG-OPCL-PEG exhibited low cytotoxicity against NIH/3T3 normal cells. Doxorubicin (DOX) as a model drug was encapsulated into the PEG-OPCL-PEG micelles. Drug release study revealed that the DOX release from micelles was significantly accelerated at mildly acid pH of 5.0 compared to physiological pH of 7.4, suggesting the pH-responsive feature of the drug delivery systems with oxime linkages. Flow cytometry and confocal laser scanning microscopy (CLSM) measurements indicated that these DOX-loaded micelles were easily internalized by living cells. MTT assay against HeLa cancer cells showed DOX-loaded PEG-OPCL-PEG micelles had a high anticancer efficacy. All of these results demonstrate that these polymeric micelles self-assembled from oxime-tethered block copolymers are promising carriers for the pH-triggered intracellular delivery of hydrophobic anticancer drugs.

Real-time monitoring of anticancer drug release with highly fluorescent star-conjugated copolymer as a drug carrier.

Chemotherapy is one of the major systemic treatments for cancer, in which the drug release kinetics is a key factor for drug delivery. In the present work, a versatile fluorescence-based real-time monitoring system for intracellular drug release has been developed. First, two kinds of star-conjugated copolymers with different connections (e.g., pH-responsive acylhydrazone and stable ether) between a hyperbranched conjugated polymer (HCP) core and many linear poly(ethylene glycol) (PEG) arms were synthesized. Owing to the amphiphilic three-dimensional architecture, the star-conjugated copolymers could self-assemble into multimicelle aggregates from unimolecular micelles with excellent emission performance in the aqueous medium. When doxorubicin (DOX) as a model drug was encapsulated into copolymer micelles, the emission of star-conjugated copolymer and DOX was quenched. In vitro biological studies revealed that fluorescent intensities of both star-conjugated copolymer and DOX were activated when the drug was released from copolymeric micelles, resulting in the enhanced cellular proliferation inhibition against cancer cells. Importantly, pH-responsive feature of the star-conjugated copolymer with acylhydrazone linkage exhibited accelerated DOX release at a mildly acidic environment, because of the fast breakage of acylhydrazone in endosome or lysosome of tumor cells. Such fluorescent star-conjugated copolymers may open up new perspectives to real-time study of drug release kinetics of polymeric drug delivery systems for cancer therapy.

Amorphous carbon dots with high two-photon fluorescence for cellular imaging passivated by hyperbranched poly(amino amine)

Amorphous carbon dots (C-Dots) with high two-photon fluorescence were prepared by using citric acid (CA) as the carbon source and hyperbranched poly(amino amine) (HPAA) as the surface passivation agent through a facile hydrothermal approach. The C-Dots with an average diameter about 10 nm were readily dispersed in water. They exhibited excellent fluorescence properties and excitation-dependent fluorescence behavior with the corresponding quantum yield (QY) of 17.1% in aqueous solution. Interestingly, the C-Dots emitted bright fluorescence even in the solid state with a QY of 16.3%, which is the highest value obtained for carbon-based nanomaterials. Using the MTT assay, the C-Dots showed low cytotoxicity against L929 normal cells. Furthermore, they were easily internalized by HeLa cells and presented high quality one- and two-photon cellular imaging, suggesting significant potential for application in biological imaging.

Aptamer-Functionalized and Backbone Redox-Responsive Hyperbranched Polymer for Targeted Drug Delivery in Cancer Therapy

A novel type of backbone redox-responsive hyperbranched poly(2-((2-(acryloyloxy)ethyl)disulfanyl)ethyl 4-cyano-4-(((propylthio)carbonothioyl)-thio)-pentanoate-co-poly(ethylene glycol) methacrylate) (HPAEG) has been designed and prepared successfully via the combination of reversible addition-fragmentation chain-transfer (RAFT) polymerization and self-condensing vinyl polymerization (SCVP). Owing to the existence of surface vinyl groups, HPAEG could be efficiently functionalized by DNA aptamer AS1411 via Michael addition reaction to obtain an active tumor targeting drug delivery carrier (HPAEG-AS1411). The amphiphilic HPAEG-AS1411 could form nanoparticles by macromolecular self-assembly strategy. Cell Counting Kit-8 (CCK-8) assay illustrated that HPAEG-AS1411 nanoparticles had low cytotoxicity to normal cell line. Flow cytometry and confocal laser scanning microscopy (CLSM) results demonstrated that HPAEG-AS1411 nanoparticles could be internalized into tumor cells via aptamer-mediated endocytosis. Compared with pure HPAEG nanoparticles, HPAEG-AS1411 nanoparticles displayed enhanced tumor cell uptake. When the HPAEG-AS1411 nanoparticles loaded with anticancer drug doxorubicin (DOX) were internalized into tumor cells, the disulfide bonds in the backbone of HPAEG-AS1411 were cleaved by glutathione (GSH) in the cytoplasm, so that DOX was released rapidly. Therefore, DOX-loaded HPAEG-AS1411 nanoparticles exhibited a high tumor cellular proliferation inhibition rate and low cytotoxicity to normal cells. This aptamer-functionalized and backbone redox-responsive hyperbranched polymer provides a promising platform for targeted drug delivery in cancer therapy.

Temperature-induced emission enhancement of star conjugated copolymers with poly(2-(dimethylamino)ethyl methacrylate) coronas for detection of bacteria.

A facile strategy for temperature-induced emission enhancement of star conjugated copolymers has been developed for biodetection. The star copolymers (HCP-star-PDMAEMAs) with different poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) chain lengths were synthesized from the hyperbranched conjugated polymer (HCP) macroinitiator by atom transfer radical polymerization (ATRP). The star conjugated copolymers exhibited interesting thermoresponsive phase transitions with adjustable lower critical solution temperature (LCST) depending on the pH of copolymer solution. Above the LCST, the emission of HCP-star-PDMAEMAs was enhanced greatly through restriction of intermolecular aggregation of conjugated polymer cores by the collapse of PDMAEMA arms. By changing the PDMAEMA length, the emission performance of HCP-star-PDMAEMAs could be readily adjusted. Correspondingly, this temperature-dependent emission enhancement of HCP-star-PDMAEMAs was successfully applied in the highly sensitive detection of bacteria. Due to the existence of a hyperbranched conjugated core and many thermo-responsive PDMAEMA arms, the detection limit of E. coli could reach 10(2) cfu mL(-1).

Protein resistant properties of polymers with different branched architecture on a gold surface

To elucidate the effect of polymeric branched architecture on the protein resistant properties, the protein adsorption behaviour of polymers with different branched architectures on a gold surface was investigated. A series of poly((S-(4-vinyl) benzyl S′-propyltrithiocarbonate)-co-(poly(ethylene glycol) methacrylate))s (poly(VBPT-co-PEGMA)s) with different branched architecture were prepared by reversible addition-fragmentation chain transfer (RAFT) copolymerization, and then grafted onto a gold surface via thiols obtained from aminolysis reaction. With the increase of polymeric branched architecture, the thiol content of poly(VBPT-co-PEGMA)s increased, resulting in the formation of a highly uniform film with high stability and multifunctionality on the gold substrate. On the other hand, incubation of the poly(VBPT-co-PEGMA)-coated surface with bovine serum albumin (BSA) and immunoglobulin (IgG) showed that the protein resistant properties of the polymer-coated surface were enhanced with the decrease of branched architecture. After surface coating with branched poly(VBPT-co-PEGMA) onto a gold surface, the adhesion and proliferation of Hela cells were inhibited efficiently. By only adjusting the branched architecture of polymers on a substrate, the high protein resistance and multifunctionality can be integrated together, realizing the optimization of nonfouling properties of polymer-coated surface.

Bioinspired synthesis of calcium carbonate hollow spheres with a nacre-type laminated microstructure.

In this Article, we combine the characters of hyperbranched polymers and the concept of double-hydrophilic block copolymer (DHBC) to design a 3D crystal growth modifier, HPG-COOH. The novel modifier can efficiently control the crystallization of CaCO(3) from amorphous nanoparticles to vaterite hollow spheres by a nonclassical crystallization process. The obtained vaterite hollow spheres have a special puffy dandelion-like appearance; that is, the shell of the hollow spheres is constructed by platelet-like vaterite mesocrystals, perpendicular to the globe surface. The cross-section of the wall of a vaterite hollow sphere is similar to that of nacres in microstructure, in which platelet-like calcium carbonate mesocrystals pile up with one another. These results reveal the topology effect of the crystal growth modifier on biomineralization and the essential role of the nonclassical crystallization for constructing hierarchical microstructures.

Low Temperature and Template-Free Synthesis of Hollow Hydroxy Zinc Phosphate Nanospheres and Their Application in Drug Delivery

Hollow hydroxy zinc phosphate nanospheres (HZnPNSs) with sizes of 30-50 nm and wall thicknesses of about 7 nm were synthesized using a template-free method through wet precipitation of Zn(NO3)2·6H2O and (NH4)2HPO4 at temperatures of 0, 10, and 20 °C. The crystal structures, morphologies, sizes and pore properties, Zn/P molar ratios, and thermal stability properties of nanoparticles have been carefully examined. The methyl-thiotetrazole assay measurements proved the low cell cytotoxicity of the material. The protein adsorption of negatively charged bovine serum albumin (BSA) and positively charged lysozyme on HZnPNSs was also investigated. The results showed that HZnPNSs had high protein adsorption affinity. Furthermore, anticancer doxorubicin as a model drug was used to evaluate the entrapment efficiency and drug loading capacity of HZnPNSs, which showed high loading capacity (>16 wt %) for doxorubicin. The confocal laser scanning microscope observations showed that the drug could be efficiently delivered into cells.

Wet-chemical synthesis of Mg-doped hydroxyapatite nanoparticles by step reaction and ion exchange processes

Magnesium-doped hydroxyapatites (Mg-HAs) with different feeding molar ratios of Ca : Mg were synthesized by a wet-chemical method at 90 °C based on the step reaction and ion exchange processes. Firstly, magnesium nitrate (Mg(NO3)2·6H2O) and diammonium hydrogen phosphate ((NH4)2HPO4) with a Mg : P molar ratio of 1.67 were used as starting materials and ammonia water was used as the agent for pH adjustment. Perfect long hexagon shape plates 4-10 μm in size with 200-300 nm thickness were obtained. These particles were then used as precursors, and calcium nitrate (Ca(NO3)2·4H2O) solutions with feeding Ca : Mg molar ratios of 2.5 : 1, 5 : 1, 7.5 : 1, 10 : 1, 12.5 : 1, and 15 : 1 were added, followed by the addition of (NH4)2HPO4. The (Ca + Mg) : P molar ratio was kept at 1.67 during the reaction process. Magnesium ions in the precursor particles were substituted by calcium ions during the process of ion exchange in solution. As a result, the particle size (ranging from nano- to micro-scale), morphology, and magnesium content (1.3-4.2 wt%) in the final Mg-HAs were well controlled by the precursor particles and the original addition of different Ca : Mg molar ratios. The transmission electron microscopy (TEM) images showed the morphology changes with different Ca : Mg feeding ratios. The X-ray powder diffraction (XRD) analysis showed that the lattice disorder increased with Mg substitution in the hydroxyapatite. The (Ca + Mg) : P molar ratio, chemical properties, and thermal stability properties were investigated by inductively coupled plasma emission spectrometry (ICP), Fourier transform infrared spectroscopy (FTIR), and thermal gravimetric analysis (TGA), respectively. In addition, methyl-thiotetrazole (MTT) assay demonstrated that the Mg-HA materials exhibited quite low cytotoxicity. The formation mechanism of the Mg-HA particles could be explained by a precursor particle template and ion exchange process. The present work provides a novel approach to prepare well-controlled Mg-doped HA nanoparticles.

Facile fabrication and application of Au@MSN nanocomposites with a supramolecular star-copolymer template

Mesoporous silica nanoparticles (MSNs) with soft templates were readily fabricated using a sol–gel process under mild conditions. The soft templates were composed of an amphiphilic supramolecular star-copolymer from anionic monocarboxyl polydimethylsiloxane and cationic hyperbranched polyethyleneimine via the electrostatic interaction. Ascribed to the high accessibility of dendritic architecture for small molecules and the existence of plentiful amino groups, these supramolecular dendritic templates in MSNs could be used directly as the nanoreactors and reducing reagents for the in situ reduction of chloroauric acid (HAuCl4). The resultant Au@MSN nanocomposites showed excellent catalytic performance in a reduction reaction of 4-nitrophenol by sodium borohydride (NaBH4).