Jieli Wu

Multifunctional pH-sensitive superparamagnetic iron-oxide nanocomposites for targeted drug delivery and MR imaging.

A multifunctional pH-sensitive superparamagnetic iron-oxide (SPIO) nanocomposite system was developed for simultaneous tumor magnetic resonance imaging (MRI) and therapy. Small-size SPIO nanoparticles were chemically bonded with antitumor drug doxorubicin (DOX) and biocompatible poly(ethylene glycol) (PEG) through pH-sensitive acylhydrazone linkages, resulting in the formation of SPIO nanocomposites with magnetic targeting and pH-sensitive properties. These DOX-conjugated SPIO nanocomposites exhibited not only good stability in aqueous solution but also high saturation magnetizations. Under an acidic environment, the DOX was quickly released from the SPIO nanocomposites due to the cleavage of pH-sensitive acylhydrazone linkages. With the help of magnetic field, the DOX-conjugated SPIO nanocomposites showed high cellular uptake, indicating their magnetic targeting property. Comparing to free DOX, the DOX-conjugated SPIO nanocomposites showed better antitumor effect under magnetic field. At the same time, the relaxivity value of these SPIO nanocomposites was higher than 146s(-1)mM(-1) Fe, leading to ~4 times enhancement compared to that of free SPIO nanoparticles. As a negative contrast agent, these SPIO nanocomposites illustrated high resolution in MRI diagnosis of tumor-bearing mice. All of these results confirm that these pH-sensitive SPIO nanocomposites are promising hybrid materials for synergistic MRI diagnosis and tumor therapy.

A supramolecular approach to the preparation of charge-tunable dendritic polycations for efficient gene delivery

A facile supramolecular approach for the preparation of charge-tunable dendritic polycations, by a combination of the multi-functionality of dendritic polymers with the dynamic-tunable ability of supramolecular polymers, has been developed. It provides a new strategy for designing and developing efficient gene vectors via noncovalent interactions.

Biodegradable Hyperbranched Polyglycerol with Ester Linkages for Drug Delivery

Biodegradable hyperbranched polyglycerols (dHPGs) were synthesized through oxyanionic initiating hybrid polymerization of glycerol and glycidyl methacrylate. Due to the introduction of ester linkages into the hyperbranched polyglycerol backbone, dHPGs showed good biodegradability and low cytotoxicity. Benefiting from the existence of terminal hydroxyls and methacryloyl groups, both the anticancer drug methotrexate (MTX) and fluorescent probe Rhodamine-123 could be conjugated onto the surface of dHPGs easily. The resultant MTX-conjugated polymers (dHPG-MTXs) exhibited an amphiphilic character, resulting in the formation of micelles in an aqueous solution. The release of MTX from micelles was significantly faster at mildly acidic pH of 5.0 compared to physiological pH of 7.4. dHPG-MTX micelles could be efficiently internalized by cancer cells. MTT assay against cancer cells showed dHPG-MTXs micelles had high anticancer efficacy. On the basis of their good biodegradability and low cytotoxicity, dHPGs provide an opportunity to design excellent drug delivery systems.

Role of Branching Architecture on the Glass Transition of Hyperbranched Polyethers

The influence of branching architecture on the glass transition of hyperbranched polyethers has been investigated. For amorphous samples, the glass transition temperature (T(g)) first increases with the degree of branching (DB), passes through a maximum, and then decreases sharply. An attempt is made to explain this by the competition between the junction density and the free volume of terminal units. For the crystalline samples, the crystallization of polymer chains makes the relationship of DB and T(g) more complicated. By the introduction of branching architecture, the crystallization ability of the branched polymer is weakened gradually. When the samples are isothermally crystallized for a long time, the T(g) of polyethers decreases monotonically with DB.

Design and synthesis of cationic drug carriers based on hyperbranched poly(amine-ester)s.

Novel cationic drug carriers based on hyperbranched poly(amine-ester)s were successfully prepared through proton-transfer polymerization. Both vinyl and epoxy groups of commercially available glycidyl methacrylate monomer could be polymerized through oxyanionic initiation of triethanolamine in the presence of potassium hydride catalysis. By changing the molar ratios of triethanolamine/glycidyl methacrylate or potassium hydride/triethanolamine, we obtained a series of hyperbranched poly(amine-ester)s. The generation of highly branched poly(amine-ester)s was confirmed by (13)C DEPT-135 NMR and 2D NMR techniques, and their degrees of branching were found to be 0.47 to 0.68. The structure and properties of hyperbranched poly(amine-ester)s were analyzed by dynamic light scattering, gel permeation chromatography, Fourier transformed infrared, differential scanning calorimeter, and zeta-potential measurements. Methyl tetrazolium (MTT) assay suggested that the cell viability after 48 h incubation with hyperbranched poly(amine-ester) concentrations up to 1 mg/mL remained nearly 100% compared with the untreated cells. The high cellular uptake of these cationic polymers was confirmed by flow cytometry and confocal laser scanning microscopy. Furthermore, conjugation of a model hydrophobic anticancer drug chlorambucil to hyperbranched poly(amine-ester)s inhibited the proliferation of MCF-7 breast cancer cells. MTT assay indicated that the chlorambucil dose required for 50% cellular growth inhibition against MCF-7 cells was 120 microg/mL. All of these results show that hyperbranched poly(amine-ester)s are promising materials for drug delivery.

Construction and application of pH-triggered cleavable hyperbranched polyacylhydrazone for drug delivery

Polymeric drug carriers with high stability during long circulation and triggered degradation after drug release are particularly interesting in drug delivery. Here, a novel pH-triggered backbone-cleavable hyperbranched polyacylhydrazone (HPAH) was successfully prepared through a simple polycondensation of 2,3-butanedione and 1-(2-aminoethyl) piperazine tri-propionylhydrazine. The experimental results showed that the degree of branching (DB) of HPAH was 0.60, and the weight-average molecular weight (Mw) of end-capped HPAH was 4.0 × 103 with a polydipersity index (PDI) of 1.6. 2D DOSY NMR degradation experiments demonstrated that HPAH was stable in neutral conditions while cleavable in acidic environments. Owing to the existence of numerous acylhydrazine terminals, the anticancer drug doxorubicin (DOX) was conjugated to hydrophilic HPAH. The obtained HPAH-DOX conjugate could self-assemble into polymeric micelles with an average diameter of 20 nm, which were stable under physiological pH but cleavable after endocytosis. Cell viability of HPAH, monomers, and degradation products was maintained above 70% over the culture periods, even when the concentration was up to 3 mg mL−1 according to methyl tetrazolium (MTT) assay in NIH/3T3 cell line. Both flow cytometry and confocal laser scanning microscopy (CLSM) confirmed the high cellular uptake of HPAH-DOX. Anti-cancer effect was evaluated in HeLa cell line, and the DOX dose required for 50% cellular growth inhibition was found to be 3.5 μg mL−1 by MTT assay.

Design and synthesis of thermo-responsive hyperbranched poly(amine-ester)s as acid-sensitive drug carriers

Novel thermo-responsive hyperbranched poly(amine-ester)s were designed and synthesized successfully in one-pot through proton-transfer polymerization of triethanolamine, trimethylolpropane, and glycidyl methacrylate with potassium hydride as a catalyst. The structure of the obtained polymers was confirmed by nuclear magnetic resonance, gel permeation chromatography, Fourier transformed infrared spectroscopy, and differential scanning calorimetery techniques. Thermal induced phase transition behaviors of hyperbranched poly(amine-ester)s were investigated by dynamic light scattering measurements, and the results indicated that these polymers had a tunable lower critical solution temperature (LCST) ranging from 37 to 57 °C. In vitro evaluation suggested that hyperbranched poly(amine-ester)s exhibited low cell cytotoxicity and efficient cell internalization against COS-7 cells. Moreover, doxorubicin (DOX) as a model drug was encapsulated into hyperbranched poly(amine-ester)s in aqueous solution above the LCST. In vitro release studies revealed that the loaded DOX displayed acid-triggered (pH ≈ 5.0) drug release behaviors. The DOX-loaded delivery system was investigated for proliferation inhibition of a Hela human cervical carcinoma cell line, and the DOX dose required for 50% cellular growth inhibition (IC50) was found to be 1.1 μg mL−1. All of these results suggest that thermo-responsive hyperbranched poly(amine-ester)s can be used to construct promising drug delivery systems for cancer therapy.

Synthesis, Characterization, and in Vitro Evaluation of Long-Chain Hyperbranched Poly(ethylene glycol) as Drug Carrier

A series of novel long-chain hyperbranched poly(ethylene glycol)s (LHPEGs) with biodegradable connections were designed and synthesized in one pot through proton-transfer polymerization using PEG and commercial glycidyl methacrylate as monomers and potassium hydride as catalyst. The LHPEGs were hydrolyzed at neutral pH resulting in the decrease of molecular weights. In vitro evaluation demonstrated that LHPEGs were biocompatible and displayed negligible hemolytic activity. The efficient cellular uptake of LHPEGs was confirmed by flow cytometry and confocal laser scanning microscopy. Moreover, conjugation of a model hydrophobic anticancer drug methotrexate to LHPEGs inhibited the proliferation of a human cervical carcinoma Hela cell line. MTT assay indicated that the conjugated methotrexate dose required for 50% cellular growth inhibition against Hela cells was 20 μg/mL. By combining the advantages of long-chain hyperbranched structure and PEG, LHPEG provides a promising drug carrier for therapeutic fields.

Hybrid Polymerization of Vinyl and Hetero-Ring Groups of Glycidyl Methacrylate Resulting in Thermoresponsive Hyperbranched Polymers Displaying a Wide Range of Lower Critical Solution Temperatures

Hybrid polymerization of glycidyl methacrylate (GMA) with potassium hydride (KH) and various oligo(ethylene glycol)s as the initiating system, in which both vinyl polymerization and ring-opening polymerization occur simultaneously, generates hyperbranched poly(ether-ester)s. The reaction process has been followed by an in situ nuclear magnetic resonance technique. The experimental results indicate that both the vinyl and epoxy groups of GMA undergo polymerization, with the reactivity of the latter being much higher than that of the former. Interestingly, the resulting hyperbranched polymers exhibit a sharp phase transition in water at the lower critical solution temperature (LCST). Significantly, the LCST values can be accurately controlled from 0 to 100 degrees C by changing the hydrophilic/hydrophobic balance of GMA and various oligo(ethylene glycol)s or by modification of the precursor polymer through acetylation. This novel stimuli-responsive hyperbranched polymer is a promising candidate for a new generation of commercially viable thermoresponsive polymers following on from the widely used poly(N-isopropylacrylamide) (PNIPAM).

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.