Lijian Liu

A Facile One‐Pot Construction of Supramolecular Polymer Micelles from α‐Cyclodextrin and Poly(ε‐caprolactone)

Weak interactions such as hydrogen bonds, ionic bonds, hydrophobic interactions, and p–p interactions govern the structural conformation of all biological macromolecules, for example the double helix of DNA and cell membranes formed by lipids. In the past few decades, chemists have made significant progress in rationalizing the fundamental rules of these interactions and have developed various self-assembling polymer systems including polymer micelles from amphiphilic block copolymers. Recently, block-copolymerfree strategies were developed to construct supramolecular polymer micelles (SMPMs) through the noncovalent interaction between a hydrophilic polymer host and a hydrophobic polymer guest. However, the fabrication of SMPMs still poses a tremendous challenge as it involves the multistep synthesis of carefully designed polymer hosts and guests; thus a more convenient method to construct SMPMs needs to be developed. Cyclodextrins (CDs) are an ideal species for the development of new self-assembling systems. The cone-shaped cavities of CDs can act as hosts for a great variety of macromolecular guests containing multiple binding sites to form polyrotaxanes, with the inclusion driven by the geometric compatibility and hydrophobic interactions between the CDs and the polymers. Various cyclodextrin/poly(ecaprolactone) (CD/PCL) based polyrotaxanes have been reported. These pioneering studies have provided a wealth of new insights into these CD-containing systems, but, from the standpoint of potential applications, a great challenge still exists as a result of the insolubility of polyrotaxanes in most solvents, especially water, because of the strong intermolecular hydrogen bonds that are formed between CDs. These bonds may be weakened by either physical or chemical methods, such as those already applied to cellulose. We report here an entirely new approach for the construction of SMPMs in which a-CD and PCL are used as building blocks. These species initially self-assemble in THF/ H2O to form an amphiphilic complex of PCL, only part of which is threaded through the a-CDs. Removal of the THF results in a second assembly process in which the supramolecular polymer amphiphiles form SMPMs (Figure 1). The second step occurs as the section of PCL threaded through the

A tough double network hydrogel for cartilage tissue engineering

To develop hydrogels with high mechanical strength for cell encapsulation and three-dimensional culture is a critical challenge for cartilage tissue engineering. In this study, novel double network (DN) hydrogels were fabricated and phosphate buffer solution (PBS) was used as the solvent to facilitate cell encapsulation. The tough DN hydrogels were prepared through a two-step photopolymerization using neutral oligo(2,2-dimethyltrimethylene carbonate)-poly(ethylene glycol)-oligo(2,2-dimethyltrimethylene carbonate)-diacrylate (DPD-DA) chains for the first network and methacrylated hyaluronic acid (HA-GMA) chains for the second network. The fracture stress values of the optimized and cell-laden DN hydrogels were 8.38 ± 0.67 MPa and 6.28 ± 1.26 MPa, respectively, which showed comparable mechanical strength with natural articular cartilage tissue. The live/dead cell viability assay of cell-laden DN hydrogels demonstrated the tough DN hydrogels have comparable cytocompatibility with PEG hydrogels. After long-term culture, cartilage-specific extra cellular matrix accumulated in these DN hydrogels. The results indicated the potential of the novel DN hydrogels as cartilage tissue engineering scaffolds.

Preparation and characterization of a biodegradable hydrogel containing oligo(2,2-dimethyltrimethylene carbonate) moieties with tunable properties

A series of biodegradable hydrogels based on oligo(2,2-dimethyltrimethylene carbonate)-block-poly(ethylene glycol)-block-oligo(2,2-dimethyltrimethylene carbonate) diacrylate (DPD-DA) precursor with varied length of hydrophilic poly(ethylene glycol) (PEG) segment and hydrophobic oligo(2,2-dimethyltrimethylene carbonate) (ODTC) segment were prepared by photopolymerization. Hydrophobic interaction was found to affect the properties of the hydrogel. The elastic modulus and toughness of the hydrogel could be tuned by altering the lengths of the hydrophobic ODTC segment as well as the hydrophilic PEG segment. In a monolayer culture, the number of swine cartilage chondrocytes (SCCs) attached to the hydrogel surface increased along with an increase in the length of ODTC segment in the precursor. SCCs cultured on the surface of hydrogel and photo-encapsulated in the hydrogel demonstrated comparable cytocompatibility with the widely recognized PEG hydrogel.

Enzymatically cross-linked hyaluronic acid/graphene oxide nanocomposite hydrogel with pH-responsive release.

Hyaluronic acid (HA) is made up of repeating disaccharide units (β-1,4-d-glucuronic acid and β-1,3-N-acetyl-d-glucosamine) and is a major constituent of the extracellular matrix. HA and its derivatives which possess excellent biocompatibility and physiochemical properties have been studied in drug delivery and tissue engineering applications. Tyramine-based HA hydrogel with good compatibility to cell and tissue has been reported recently. However, inferior mechanical property may limit the biomedical application of the HA hydrogel. In this study, HA/graphene oxide (GO) nanocomposite (NC) hydrogel was prepared through a horseradish peroxidase catalyzed in situ cross-linking process. As compared with pure HA hydrogels, incorporation of GO to the HA matrix could significantly enhance the mechanical properties (storage moduli 1800 Pa) of the hydrogel and prolong the release of rhodamine B (RB) as the model drug from the hydrogel (33 h) as well. In addition, due to the multiple interactions between GO and RB, the NC hydrogels showed excellent pH-responsive release behavior. The release of RB from the NC hydrogel was prolonged at low pH (pH 4.0) in the presence of GO, which could be attributed to the enhanced interactions between GO and HA as well as with RB. In situ three-dimensional encapsulation of mouse embryonic fibroblasts (BALB 3T3 cells) in the NC hydrogels and cytotoxicity results indicated the cytocompatibility of both the enzymatic cross-linking process and HA/GO NC hydrogels (cell viability 90.6 ± 4.25%). The enzymatically catalyzed fabrication of NC hydrogels proved to be an easy and mild approach, and had great potential in the construction of both tissue engineering scaffolds and stimuli-responsive drug release matrices.

Highly Efficient Drug Delivery Nanosystem via L‐Phenylalanine Triggering Based on Supramolecular Polymer Micelles

An intelligent drug delivery nanosystem has been developed based on biodegradable supramolecular polymer micelles (SMPMs). The drug release can be triggered from SMPMs responsively by a bioactive agent, L-phenylalanine in a controlled fashion. The SMPMs are constructed from ethylcellulose-graft-poly(ε-caprolactone) (EC-g-PCL) and α-cyclodextrin (α-CD) derivate via host-guest and hydrophobic interactions. It has been found that these SMPMs have disassembled rapidly in response to an additional L-phenylalanine, due to great affinity discrepancy to α-CD between L-phenylalanine and PCL. Experiments have been carried out on trigger-controlled in vitro drug release of the SMPMs loaded with a model porphyrin based photosensitizer THPP. The result shows that the SMPMs released over 85% THPP in 6 h, which is two orders magnitudes faster than that of control. Also investigated is the photodynamic therapy (PDT) of THPP-loaded SMPMs with and without L-phenylalanine on MCF-7 carcinoma cell line. An effective trigger-concentration dependent lethal effect has been found showing promise in clinical photodynamic therapy.

Biopolymer-based supramolecular micelles from β-cyclodextrin and methylcellulose

Supramolecular polymer micelles (SMPMs) were constructed from natural and natural-derived polymers: β-cyclodextrin (β-CD)/maleic anhydride modified β-cyclodextrin (MAh-β-CD) and methylcellulose (MC) in aqueous solution by one-pot self-assembly procedure, in which, β-CD and MAh-β-CD inclusion complexes were used as the hydrophilic shell and the free MC as the core. The shapes of the SMPMs were regular spheres with diameters of 25±5 nm. The critical micelle concentrations, calculated from steady-state fluorescence emission spectra, were around 15.13 and 20.89 mg/L for MC/β-CD and MC/MAh-β-CD SMPMs, respectively. The in vitro drug release behaviors of the micelles were studied using prednisone acetate as a model drug, and the results showed that the MC/MAh-β-CD micelle had a drug-enrichment core and excellent drug released behaviors with a sustaining release time of 700 h.

Synthesis and characterization of fluorescent oligo(3,4,5-triethoxycarbonyl-2-pyrazoline)

Pseudopeptide oligomers as newly developing fluorescent macromolecules are of significant importance and fairly attractive in bioimaging of living cells. We report that a type of efficient fluorescent pseudopeptide oligo(3,4,5-triethoxycarbonyl-2-pyrazoline) is prepared by the novel cyclo-polycondensation of 3,4,5-triethoxycarbonyl-2-pyrazoline that is a weakly-fluorescent chromophore. The pseudopeptide oligomer exhibits a strong red-shift and remarkable fluorescence enhancement compared with the monomer 2-pyrazoline and images living cells in good quality, even though it only consists of fewer than 70 glycine residues whereas for the famous green fluorescent protein (GFP) the amount of the various natural amino acid residues is 238. Oligo(3,4,5-triethoxycarbonyl-2-pyrazoline) is a GFP-mimetic but structurally-simplified fluorescent pseudopeptide with simple chemistry, generated from the only natural resource of glycine.

Denitrogen alkene polymerization of bisdiazo compounds by copper(II) catalysts

Bisdiazo compounds were synthesized and underwent denitrogen alkene polymerization (DNAP) via the formation of an sp2 carbon bond in the presence of copper(II) catalysts, affording unsaturated polymers with molecular weights in the range of 2900 to 35 400 Da. The copper-catalyzed denitrogen alkene polymerization of bisdiazo compounds allows the efficient synthesis of unsaturated polyesters.

Kinetic study of carbene polymerization of ethyl diazoacetate by palladium and rhodium catalysts

Kinetic studies of the carbene polymerization of ethyl diazoacetate (EDA) by palladium (Pd) or rhodium (Rh) catalysts were investigated by real-time Fourier transform infrared (FTIR) spectroscopy. Both (L-prolinate)RhI(1,5-cyclooctadiene) and (L-prolinate)RhI(2,5-norbornadiene) mediated EDA polymerization were proved to be first order reactions, suggesting that the formation of “Rh-carbenoid” is the rate determining step. The activation energy (11.24 kJ mol−1) of the polymerization of “carbenes” generated from EDA with (L-prolinate)RhI(1,5-cyclooctadiene) as the catalyst was calculated from kinetic data via the Arrhenius equation. On the other hand, the polymerizations of EDA catalyzed by three kinds of Pd-catalysts were revealed as zero order reactions, suggesting that the rate determining step involves the formation of an EDA–Pd transition state complex through a coordinated step. Refilling more EDA to the (bis(acetonitrile)dichloropalladium)-mediated carbene polymerization system did not change the reaction order. The rate constant increases gradually with the increase of the dosage of the catalyst and decreases with the cycle-index, which proves the formation of “EDA–Pd transition state complex” and the propagating species with Pd–C bonds at the end of the polymer chain.

Host-guest chemistry of cyclodextrin carbamates and cellulose derivatives in aqueous solution.

Supramolecular polymer micelles were prepared on basis of the inclusion complexation between cyclodextrin carbamates and cellulose derivatives in aqueous media. Cyclodextrin carbamates were synthesized by microwave-assisted method from cyclodextrin and urea. The urea modified cyclodextrin shows the higher yield than the physical mixture of urea/cyclodextrin in the micellization with cellulose derivatives. The supramolecular structure of the core-shell micelles was demonstrated by (1)H NMR spectra, TEM images, and fluorescence spectra. The drug release behavior of the supramolecular polymer micelles was evaluated using prednisone acetate as a model drug. The drug loaded micelles showed steady and long time drug release behavior. With these properties, the supramolecular polymer micelles are attractive as drug carriers for pharmaceutical applications.