Dehai Liang

Multi-responsive nanogels containing motifs of ortho ester, oligo(ethylene glycol) and disulfide linkage as carriers of hydrophobic anti-cancer drugs

A family of multi-responsive nanogels with different compositions and crosslinking degrees have been prepared by the miniemulsion copolymerization of monomethyl oligo(ethylene glycol) acrylate (OEGA) and an ortho ester-containing acrylic monomer, 2-(5,5-dimethyl-1,3-dioxan-2-yloxy) ethyl acrylate (DMDEA), with bis(2-acryloyloxyethyl) disulfide (BADS) as a crosslinker. These nanogels are thermoresponsive and labile in the weakly acidic or reductive environments. The thermoresponsive behaviors, acid-triggered hydrolysis, and reduction-induced degradation of these nanogels were studied by means of dynamic light scattering (DLS), transmission electron microscopy (TEM) and atomic force microscopy (AFM). The results indicate that the volume phase transition temperature (VPTT), thermally induced deswelling ratio, and acid-triggered swelling ratio of the nanogels are closely relevant to their compositions and crosslinking degrees. Although these nanogels could be reductively disrupted by dithiothreitol (DTT), single polymer chains with sizes smaller than 20 nm were not detected by DLS. This is probably due to the existence of some unbreakable linkages formed by chain transfer to the disulfide bond during the radical polymerization. These nanogels are capable of encapsulating hydrophobic compounds. The loading capability of the nanogels for Nile Red (NR), paclitaxel (PTX), and doxorubicin (DOX), and the release behaviors of the drug-loaded nanogels were investigated by UV-vis spectrometry and HPLC. As expected, drug release can be greatly accelerated by a cooperative effect of both acid-triggered hydrolysis and DTT-induced degradation. Finally, the PTX-loaded nanogels exhibit a concentration-dependent toxicity to MCF-7 cells while the intact unloaded nanogels are non-toxic, thereby they may be used as potential carriers for hydrophobic anticancer drugs.

In vitro non-viral gene delivery with nanofibrous scaffolds

Extracellular and intracellular barriers typically prevent non-viral gene vectors from having an effective transfection efficiency. Formulation of a gene delivery vehicle that can overcome the barriers is a key step for successful tissue regeneration. We have developed a novel core-shelled DNA nanoparticle by invoking solvent-induced condensation of plasmid DNA (β-galactosidase or GFP) in a solvent mixture [94% N,N-dimethylformamide (DMF) + 6% 1× TE buffer] and subsequent encapsulation of the condensed DNA globule in a triblock copolymer, polylactide-poly(ethylene glycol)-polylactide (L8E78L8), in the same solvent environment. The polylactide shell protects the encapsulated DNA from degradation during electrospinning of a mixture of encapsulated DNA nanoparticles and biodegradable PLGA (a random copolymer of lactide and glycolide) to form a nanofibrous non-woven scaffold using the same solution mixture. The bioactive plasmid DNA can then be released in an intact form from the scaffold with a controlled release rate and transfect cells in vitro.

pH‐Responsive Size‐Tunable Self‐Assembled DNA Dendrimers

Putting the DNA in dendrimers: a strategy to swiftly prepare DNA dendrimers based solely on DNA self-assembly is presented. This technique produces highly pure DNA dendrimers with an excellent yield of high generation dendrimers. The incorporation of molecular motors (i-motifs) into the DNA dendrimers allows for a change in size (up to 30%) in response to changing pH values.

Active control of surface properties and aggregation behavior in amino acid-based Gemini surfactant systems

Two types of Gemini surfactants containing a disulfide bond in the spacer, sodium dilauroyl cystine (SDLC) and sodium didecamino cystine (SDDC), were synthesized, and their surface properties and aggregation behavior in aqueous solution were studied by means of surface tension measurements, dynamic light scattering (DLS), transmission electron microscopy (TEM), and fluorescence. During the transition of the Gemini surfactants to their corresponding monomers through the reduction of disulfide bonds, the surface tensions of their aqueous solutions, as well as their aggregation behavior, changed greatly. The reduction of SDLC and SDDC led to disruption of the vesicle, and the oxidation of corresponding monomers to Gemini surfactants led to vesicle re-formation. These results demonstrated the control of surface properties and aggregation behavior by the reversible transition between the Gemini surfactant and its monomer via reduction/oxidation reactions.

Endowing catanionic surfactant vesicles with dual responsive abilities via a noncovalent strategy: introduction of a responser, sodium cholate†

A noncovalent strategy is proposed for endowing responseless catanionic surfactant (a mixture of cationic and anionic surfactants) aggregates with responsive abilities by addition of a responser. In this strategy, the composition of catanionic surfactant can be carefully selected to render aggregates sensitive to added responsers, and the responsers can be chosen from plenty of commercialized candidates, which bear responsive groups and will be noncovalently incorporated into the aggregates. In this paper, we report an illustrative example for the strategy: dual-responsive vesicles are realized by simply adding a responser, SC (sodium cholate), to a stimuli-inert DEAB/SDS (dodecyl triethyl ammonium bromide/sodium dodecyl sulfate) vesicular aqueous solution at a low responser/surfactant molar ratio of 0.045. The resultant DEAB/SDS/SC aggregates undergo reversible transitions between vesicles and micelles in response to temperature or pH variations. Possible mechanisms for these responsive behaviors are speculated, where the temperature-responsive hydroxyl groups and pH-responsive carboxylate group of SC are thought to be crucial. This responsive ability-endowing noncovalent strategy shows potential as a general, versatile, and economical method for fabricating stimuli-responsive self-assemblies.

Studies of Ionic Current Rectification Using Polyethyleneimines Coated Glass Nanopipettes

The modification of glass nanopipettes with polyethyleneimines (PEIs) has been successfully achieved by a relatively simple method, and the smallest tip opening is around 3 nm. Thus, in a much wider range of glass pipettes with radii from several nanometers to a few micrometers, the ion current rectification (ICR) phenomenon has been observed. The influences of different KCl concentrations, pH values, and tip radii on the ICR are investigated in detail. The sizes of PEIs have been determined by dynamic light scattering, and the effect of the sizes of PEIs for the modification, especially for a few nanometer-pipettes in radii, is also discussed. These findings systemically confirm and complement the theoretical model and provide a platform for possible selectively molecular detection and mimic biological ion channels.

Characterizing DNA Condensation and Conformational Changes in Organic Solvents

Organic solvents offer a new approach to formulate DNA into novel structures suitable for gene delivery. In this study, we examined the in situ behavior of DNA in N, N-dimethylformamide (DMF) at low concentration via laser light scattering (LLS), TEM, UV absorbance and Zeta potential analysis. Results revealed that, in DMF, a 21bp oligonucleotide remained intact, while calf thymus DNA and supercoiled plasmid DNA were condensed and denatured. During condensation and denaturation, the size was decreased by a factor of 8–10, with calf thymus DNA forming spherical globules while plasmid DNA exhibited a toroid-like conformation. In the condensed state, DNA molecules were still able to release the counterions to be negatively charged, indicating that the condensation was mainly driven by the excluded volume interactions. The condensation induced by DMF was reversible for plasmid DNA but not for calf thymus DNA. When plasmid DNA was removed from DMF and resuspended in an aqueous solution, the DNA was quickly regained a double stranded configuration. These findings provide further insight into the behavior and condensation mechanism of DNA in an organic solvent and may aid in developing more efficient non-viral gene delivery systems.

Behaviors of liposomes in a thermo-responsive poly(N-isopropylacrylamide) hydrogel

Liposome-embedded hydrogels have been widely used for controlled drug release. In this work, by embedding egg phosphatidylcholine (EPC) liposome into a poly(N-isopropylacrylamide) (PNIPAm) hydrogel via chemical cross-linking, we systemically studied the physical interactions between the liposome and hydrogel matrix, as well as the release mechanism of the encapsulated content in the liposome at varying temperatures. It was found that the confinement of the network and the hydrophobic interactions between the liposome and PNIPAm determined the integrity of the liposome and, more importantly, the release profile of the encapsulated content, such as calcein. This liposome-embedded stimuli-responsive system is suitable for the delivery of mixed drugs with different release profiles, and easily achieves on-demand release.

Reduction-degradable linear cationic polymers as gene carriers prepared by Cu(I)-catalyzed azide-alkyne cycloaddition.

Linear reduction-degradable cationic polymers with different secondary amine densities (S2 and S3) and their nonreducible counterparts (C2 and C3) were synthesized by Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) step-growth polymerization of the dialkyne-oligoamine monomers and the diazide monomers. These polymers were studied with a goal of developing a set of new gene carriers. The buffering capacity and DNA binding ability of these polymers were evaluated by acid-base titration, gel retardation, and ethidium bromide (EB) exclusion assay. The polymers with lower amine density exhibit a weaker DNA-binding ability but a stronger buffering capacity in the range of pH 5.1 and 7.4. Particle size and zeta-potential measurements demonstrate that the polymers with higher amine density condense pDNA to form polyplexes with smaller sizes, while the disulfide bond in the backbone shows a negative effect on the condensing capability of the polymers, resulting in the formation of polyplexes with large size and nearly neutral surface. The reduction-sensitive polyplexes formed by polymer S2 or S3 can be disrupted by dithiothreitol (DTT) to release free DNA, which has been proven by the combination of gel retardation, EB exclusion assay, particles sizing, and zeta potential measurements. Cell viability measurements by MTT assay demonstrate that the reduction-degradable polymers (S2 and S3) have little cytotoxicity while the nonreducible polymers (C2 and C3) show obvious cytotoxicity, in particular, at high N/P ratios. In vitro transfection efficiencies of these polymers were evaluated using EGFP and luciferase plasmids as the reporter genes. Polymers S3 and S2 show much higher efficiencies than the nonreducible polymers C3 and C2 in the absence of 10% serum; unexpectedly, the lowest transfection efficiency has been observed for polymer S3 in the presence of serum.

The self-aggregation behaviour of amphotericin B-loaded polyrotaxane-based triblock copolymers and their hemolytic evaluation

As part of our continuing research work, studies toward the self-aggregation behaviour of amphiphilic triblock copolymers containing β-CD-Pluronic F127 polyrotaxane as a central block and hydrophilic brush-like PPEGMA as flanking blocks in aqueous solution were conducted by using dynamic and static light scattering (DLS and SLS) analyses and transmission electron microscopy (TEM). These self-aggregates are characterized by a unique random coil structure. Their hydrodynamic radius (Rh) and radius of gyration (Rg) decrease as the number of the entrapped β-CD molecules increases, while the core of the random coils becomes looser due to the increase of the rigidity and steric hindrance of the brush-like polymer chains. Interestingly, it was observed that the morphology of the aggregates changes greatly after loading amphotericin B (AmB). According to the DLS/SLS and TEM results, it was speculated that a solid sphere is formed, and that the density of spheres increases as the number of entrapped β-CDs increases. For these self-aggregates, as the number of entrapped β-CDs increases, their drug-loading content (DLC) and drug-loading efficiency (DLE) for AmB increases, while their hemolytic activity against rabbit erythrocytes decreases. It appears that the multiple hydrogen-bonding interactions between AmB and the entrapped β-CDs make a significant contribution to the morphology change of the self-aggregates and their high loading capability for AmB.