Liqun Wang

Surface Functionalization of Porous Coordination Nanocages Via Click Chemistry and Their Application in Drug Delivery

The discrete coordination-driven self assemblies have received continuous attention due to their molecular architecture esthetics and applications in recognition, catalysis, storage, etc. [ 1 ] Among these self assemblies, one species that has emerged recently is the porous coordination nanocages formed between carboxylate ligands and metal clusters, which are also known as metal-organic polyhedra (MOP). [ 2 ] Due to the robust porous structure and versatile functionality, they have found applications as plasticizer, gas sponge, ion channel, coatings, and building units. [ 3 ] Presumably, the porous shell and uniform yet tunable cavity make them good candidates for drug delivery purpose. However, almost all the coordination nanocages reported so far are hydrophobic, which greatly limits their applications in aqueous condition. We hypothesize this problem can be circumvented by turning these nanocages into colloids through surface functionalization with hydrophilic polymers. In this Communication, we report a porous coordination nanocage covered with alkyne groups and its surface functionalization by grafting with azide-terminated polyethylene glycol (PEG) through “click chemistry”. In addition, its drug load and release capacity has been evaluated using an anticancer drug 5-fl uorouracil as a model. The metal-organic cuboctahedron was chosen as the prototype of nanocage in this study. [ 2a , 2c ] It is composed of 12 dicopper paddlewheel clusters and 24 isophthalate moieties, with 8 triangular and 6 square windows that are roughly 8 and 12 Å across, respectively. The internal cavity has a diameter of around 15 Å. The 5-position of isophthalate moieties would be the reaction site for surface functionalization. The Cu(I)catalyzed Huisgen cycloaddition between azide and alkyne, a so-called “click reaction”, was chosen as the synthetic tool in

Coaxial electrospinning for encapsulation and controlled release of fragile water-soluble bioactive agents

Coaxial electrospinning is a robust technique for one-step encapsulation of fragile, water-soluble bioactive agents, including growth factors, DNA and even living organisms, into core-shell nanofibers. The coaxial electrospinning process eliminates the damaging effects due to direct contact of the agents with organic solvents or harsh conditions during emulsification. The shell layer serves as a barrier to prevent the premature release of the water-soluble core contents. By varying the structure and composition of the nanofibers, it is possible to precisely modulate the release of the encapsulated agents. Promising work has been done with coaxially electrospun non-woven mats integrated with bioactive agents for use in tissue engineering, in local delivery and in wound healing, etc. This paper reviews the origins of the coaxial electrospinning method, its updated status and potential future developments for controlled release of the class of fragile, water-soluble bioactive agents.

Mild immobilization of diverse macromolecular bioactive agents onto multifunctional fibrous membranes prepared by coaxial electrospinning

Coaxial electrospinning was proved to be a facile method to produce multifunctional fibrous matrices which could essentially emulate certain features of native extracellular matrix. In order to further confer capability of immobilizing diverse macromolecular bioactive agents to the fibers, composite membranes composed of cationized gelatin-coated polycaprolactone (PCL) fibers were prepared by coaxial electrospinning. Gelatin was cationized by derivation with N,N-dimethylethylenediamine. The cationized gelatin (CG) was used as a shell material for constructing a core-shell fibrous membrane. PCL formed the core section of the core-shell fibers thereby improving the mechanical properties of nanofibrous CG hydrogel. The outer CG layer was crosslinked by exposing the membranes in glutaraldehyde vapor. The adsorption behaviors of FITC-labeled bovine serum albumin (FITC-BSA) or FITC-heparin onto the fibers were investigated. The core-shell fibers could effectively immobilize the two types of agents under mild conditions. The adsorption amount could reach about 12 microg of BSA per mg of membrane and 23 microg mg(-1) for heparin. Furthermore, vascular endothelial growth factor (VEGF) could be conveniently impregnated into the fibers through specific interactions with the adsorbed heparin in the outer CG layer. Sustained release of bioactive VEGF could be achieved for more than 15 days.

Synthesis and characterization of temperature responsive graft copolymers of dextran with poly(N-isopropylacrylamide)

Abstract Poly (N-isopropylacrylamide) (PNIPAAm) was grafted to dextran using ceric ion as redox initiator. The graft copolymers formed temperature responsive materials and can be used to construct polymeric micelles as drug carriers for colon-site specifically delivery. The chemical structure of the graft copolymers was characterized by FTIR, 1H- and 13C-NMR spectroscopy. The influence of reaction conditions on the grafting parameters was investigated. It was found that the percentage of homopolymer formation (H%), the grafting efficiency (GE%) and the grafting (G%) of the copolymers increased with increasing the amount of the ceric catalyst used. Extension of the duration of graft reaction increased GE% and G% of the copolymers, suggesting that G% of the copolymers could be readily manipulated by changing copolymerization duration. Higher grafting temperature was in favor of increasing GE% and G%, however, when the reaction temperature was above the LCST of the copolymers, GE% and G% decreased. The optical transmittance of the copolymers in the aqueous solution was examined by UV–Vis instrument. The result showed that the phase transition of the graft copolymer in aqueous solution moved slightly to higher temperature when G% of the graft copolymers decreased. The results of atomic force microscopy and dynamic light scattering measurement indicated that the graft copolymers form micelles in a spherical morphology, and for the copolymer with the G% of 33.8% formed micelles in the mean diameter of less than 30 nm in aqueous solution.

A Facile Route for Regioselective Conjugation of Organo-Soluble Polymers onto Chitosan

A facile route is described for the regioselective conjugation of organo-soluble polymers onto chitosan under very mild conditions, using SCC as intermediates. SCC could be prepared simply by mixing chitosan acidic aqueous solution with SDS. PEG or PCL were then grafted to SCC using the NHS/DCC coupling method. In addition, the polymers were found to be linked to chitosan through the hydroxyl groups of chitosan when stoichiometric SCC was used as a precursor. SDS could be removed simply by either precipitating the solution of SCC-graft-polymer in DMSO into Tris aqueous solution or dialyzing against Tris solution.

Synthesis of Hemoglobin Conjugated Polymeric Micelle: A ZnPc Carrier with Oxygen Self-Compensating Ability for Photodynamic Therapy.

Photodynamic therapy (PDT) is a promising singlet oxygen ((1)O2) mediated clinical treatment for many tumors. As the source of (1)O2, oxygen plays an important role in the curative effect of PDT. However, the facts of photochemical depletion of oxygen and the intrinsic hypoxic microenvironment of tumors remain the major challenges. In this work, a novel photosensitizer carrier with oxygen self-compensating ability was designed for PDT. It was synthesized via chemical conjugation of hemoglobin (Hb) to polymeric micelles formed by triblock copolymers of poly(ethylene glycol)-block-poly(acrylic acid)-block-polystyrene (PEG-b-PAA-b-PS). The PEG-b-PAA-b-PS and resultant micelles in aqueous solution were comprehensively characterized by means of FTIR, (1)H NMR, GPC, DLS, TEM, and fluorescence spectroscopy. The oxygen-binding capacity and antioxidative activity of the Hb conjugated micelles were evaluated via UV-vis spectroscopy. In addition, compared with the control micelles without Hb, the Hb conjugated photosensitizer carrier was able to generate more (1)O2 and exert greater photocytotoxicity on Hela cells in vitro.

Generation of nano-sized core–shell particles using a coaxial tri-capillary electrospray-template removal method

This study proposed a new strategy based on a coaxial tri-capillary electrospray-template removal process for producing nanosized polylactide-b-polyethylene glycol (PLA-PEG) particles with a core-shell structure. Microparticles with core-shell-corona structures were first fabricated by coaxial tri-capillary electrospray, and core-shell nanoparticles less than 200 nm in size were subsequently obtained by removing the PEG template from the core-shell-corona microparticles. The nanoparticle size could be modulated by adjusting the flow rate of corona fluid, and nanoparticles with an average diameter of 106±5 nm were obtained. The nanoparticles displayed excellent dispersion stability in aqueous media and very low cytotoxicity. Paclitaxel was used as a model drug to be incorporated into the core section of the nanoparticles. A drug loading content in the nanoparticles as high as 50.7±1.5 wt% with an encapsulation efficiency of greater than 70% could be achieved by simply increasing the feed rate of the drug solution. Paclitaxel exhibited sustained release from the nanoparticles for more than 40 days. The location of the paclitaxel in the nanoparticles, i.e., in the core or shell layer, did not have a significant effect on its release.

Chitosan‐poly(ε‐caprolactone)‐poly(ethylene glycol) graft copolymers: Synthesis, self‐assembly, and drug release behavior

Biodegradable tri-component graft copolymers, chitosan-poly(ε-caprolactone)-poly(ethylene glycol) (CPP), were synthesized via a mild route, using sodium dodecyl sulfate-chitosan complex (SCC) as a precursor. Both PCL and PEG could be conveniently conjugated to the hydroxyl sites of chitosan without the need of tedious chemical protection/deprotection processes, thereby leaving the amino groups of chitosan intact. The self-assembly and release behavior of the copolymer micelles were investigated. Paclitaxel and rutin were used as model drugs. Spherical micelles could be formed through self-assembly of CPP in aqueous media. The micelle diameter increased with PEGylation degree and ranged from 30 to 45 nm. The incorporation of drugs into the micelles significantly raised the micelle diameter and diversified the micelle morphologies. The micelles were further subjected to glutaraldehyde treatment to prolong the release of the incorporated drugs. It was found that the crosslinking process shrunk the drug-loaded micelles. In addition, the micelles were endowed with self-luminescent properties after crosslinked with glutaraldehyde. By increasing crosslinking density, the release duration of the model drugs could be prolonged.

Triggered disassembly of hierarchically assembled onion-like micelles into the pristine core-shell micelles via a small change in pH.

The size and surface property of nanomaterial-based delivery systems administered intravenously play important roles in their cell uptake and in vivo distribution. Both of them should be capable of self-evolution in order to achieve efficient targeting performance. A facile strategy was proposed to manipulate both the size and surface property of polymeric micelles. It was found that the hierarchical assembly between trimethylated chitosan-g-poly(ε-caprolactone) (TMC-PCL) micelles and carboxyethyl chitosan-g-poly(ethylene glycol) (CEC-PEG) could produce onion-like micelles with enlarged size and PEGylated surface. The onion-like micelles could withstand the ionic strength of plasma and competitive exchange with BSA, and abruptly disassemble into the pristine TMC-PCL micelles via a small change in pH. By varying the degree of carboxyethylation, the disassembly pH could be modulated to the range of the tumoral microclimate pH. In contrast with TMC-PCL micelles, which displayed high cytotoxicity and endocytic ability towards C6 glioma cells, the onion-like micelles were cell-friendly and internalized by the cells at a very low level. Doxorubicin was used as a model chemotherapeutic agent and incorporated within TMC-PCL micelles. Dox release from both TMC-PCL micelles and the onion-like micelles was very slow under normal physiological conditions and displayed excellent pH sensitivity. Cell viability of Dox-loaded micelles was also investigated.

Novel complex hydrogels based on N-carboxyethyl chitosan and quaternized chitosan and their controlled in vitro protein release property

A novel pH-responsive hydrogel (CHC) composed of N-carboxyethyl chitosan (CEC) and N-[(2-hydroxy-3-trimethylammonium) propyl] chitosan chloride (HTCC) was synthesized by the redox polymerization technique. Turbidimetric titrations were used to determine the stoichiometric ratio of these two chitosan derivatives. The hydrogel was characterized by FT-IR, thermal gravimetric analysis (TGA), X-ray diffractometry (XRD), and scanning electron microscopy (SEM). The dynamic transport of water showed that the hydrogel reached equilibrium within 48h. The swelling ratio of CHC hydrogel depended significantly on the pH of the buffer solution. The performance of the CHC as a matrix for the controlled release of BSA was investigated. It was found that the release behavior was determined by pH value of the medium as well as the intermolecular interaction between BSA and the hydrogels.