Xiao-Ding Xu

Fabrication of Supramolecular Hydrogels for Drug Delivery and Stem Cell Encapsulation

Supramolecular hydrogels self-assembled by alpha-cyclodextrin and methoxypolyethylene glycol-poly(caprolactone)-(dodecanedioic acid)-poly(caprolactone)-methoxypolyethylene glycol (MPEG-PCL-MPEG) triblock polymers were prepared and characterized in vitro and in vivo. The sustained release of dextran-fluorescein isothiocyanate (FITC) from the hydrogels lasted for more than 1 month, which indicated that the hydrogels were promising for controlled drug delivery. ECV304 cells and marrow mesenchymal stem cells (MSC) were encapsulated and cultured in the hydrogels, during which the morphologies of the cells could be kept. The in vitro cell viability studies and the in vivo histological studies demonstrated that the hydrogels were non-cytotoxic and biocompatible, which indicated that the hydrogels prepared were promising candidates as injectable scaffolds for tissue engineering applications.

Strategies to improve the response rate of thermosensitive PNIPAAm hydrogels

Poly(N-isopropylacrylamide) (PNIPAAm) hydrogel is one of the most extensively studied thermosensitive hydrogels, it displays a lower critical solution temperature (LCST) at around 33 °C in aqueous solution and undergoes an abrupt thermoreversible change in volume as the external temperature cycles around this critical temperature. The fast response rate of hydrogels is critically important in some applications, such as artificial organs, actuators, and on-off switches. In this article, we review different strategies, including physical and chemical strategies, for improving the response kinetics of PNIPAAm-based hydrogels. Based on the numerous strategies, the factors that are essential to achieve the fast response rate are identified.

Low Molecular Weight Polyethylenimine Grafted N-Maleated Chitosan for Gene Delivery: Properties and In Vitro Transfection Studies

To develop chitosan-based efficient gene vectors, chitosans with different molecular weights were chemically modified with low molecular weight polyethylenimine. The molecular weight and composition of polyethylenimine grafted N-maleated chitosan (NMC-g-PEI) copolymers were characterized using gel permeation chromatography (GPC) and (1)H NMR, respectively. Agarose gel electrophoresis assay showed that NMC-g-PEI had good binding ability with DNA, and the particle size of the NMC-g-PEI/DNA complexes was 200-400 nm, as determined by a Zeta sizer. The nanosized complexes observed by scanning electron microscopy (SEM) exhibited a compact and spherical morphology. The NMC-g-PEI copolymers showed low cytotoxicity and good transfection activity, comparable to PEI (25 KDa) in both 293T and HeLa cell lines, except for NMC 50K-g-PEI. The results indicated that the molecular weight of NMC-g-PEI has an important effect on cytotoxicity and transfection activity, and low molecular weight NMC-g-PEI has a good potential as efficient nonviral gene vectors.

Synthesis and properties of pH and temperature sensitive P(NIPAAm-co-DMAEMA) hydrogels

In order to investigate the influence of the continuous alkylamide sequence having pH sensitive unit on the temperature sensitivity of poly(N-isopropylacrylamide) (PNIPAAm)-based hydrogel, a monomer, N-(2-(dimethylamino) ethyl)-methacrylamide (DMAEMA), having an ethylamide group as well as an aliphatic tertiary amino group, was designed and synthesized. Hydrogels based on NIPAAm and DMAEMA were prepared via free radical polymerization. The resulted P(NIPAAm-co-DMAEMA) hydrogels were characterized in terms of maximum swelling ratio, swelling kinetics, temperature response kinetics, and effect of pH. The data obtained show that the novel hydrogels have the strong desire to respond to external temperature and pH stimuli. Importantly, because the P(NIPAAm-co-DMAEMA) hydrogels have the continuous alkylamide sequence containing isopropylamide pendant groups from PNIPAAm and ethylamide pendant groups from PDMAEMA, the incorporation of DMAEMA moiety not only provides the pH sensitivity, but also maintains the thermal properties of P(NIPAAm-co-DMAEMA) hydrogels, even as the molar percentage of DMAEMA moiety reaches 14 mol%.

Biodegradable and pH-Sensitive Hydrogels for Cell Encapsulation and Controlled Drug Release

Hydrogels with pH-sensitive poly(acrylic acid) (PAAc) chains and biodegradable acryloyl-poly(-caprolactone)-2-hydroxylethyl methacrylate (AC-PCL-HEMA) chains were designed and synthesized. The morphology of hydrogel was observed by scanning electron microscopy. The degradation of the hydrogel in the presence of Pseudomonas lipase was studied. The in vitro release of bovine serum albumin from the hydrogel was investigated. Cytotoxicity study shows that the AC-PCL-HEMA/AAc copolymer exhibits good biocompatibility. Cell adhesion and migration into the hydrogel networks were evaluated by using different cell lines. The hydrogel with a lower cross-linking density and a larger pore size exhibited a better performance for cells migration.

Design of a Cellular‐Uptake‐Shielding “Plug and Play” Template for Photo Controllable Drug Release

Polymeric drug delivery systems have been widely used for controlled drug release. [ 1–5 ] To enhance the antitumor effi ciency of antineoplastic drugs, a traditional way is to introduce a target ligand into the polymer to promote the drug endocytosis of tumor cells. [ 6–11 ] Furthermore, stimulus-responsive polymers such as pH-sensitive, light-sensitive, or temperaturesensitive polymers have been also used to trigger the drug release at tumor sites to improve the cure effect. [ 12–17 ] However, both methods cannot inhibit normal cells endocytosing antineoplastic drugs and this limitation might cause fatal damage to normal tissues. New drug delivery systems that can evade normal tissues will be critically important to reduce the side effect of antineoplastic drug in normal tissues. Here, we designed a novel light-responsive “plug and play” (PnP) polyanionic template as drug delivery system, which can inhibit the endocytosis of antineoplastic drug for normal tissues. The drug loaded on the polyanionic template is repelled by cells and will not be uptaken by normal tissues during blood circulation, whereas upon irradiation of UV light at the target site, such as tumor tissues, the loaded drug can be released quickly from the template and thereafter be endocytosed by tumor cells. Importantly, as a PnP polymeric template, antineoplastic drug and additional functional moieties such as target ligand can be simultaneously loaded and unloaded onto the template. The polyanionic template consists of polyacrylic acid (PAA) and azobenzene (Azo). The loading and unloading process is driven by the photo-switchable host-guest interaction between α -cyclodextrin ( α -CD) and Azo. Azobenzene, having trans and cis forms, can be reversibly transformed to each other upon photo-irradiation. [ 18–21 ] Driven by hydrophobic and van der Waals interactions, trans -azobenzene could be well recognized by α -CD. On the other hand, once trans -azobenzene transforms to cis form, α -CD cannot include the bulky cis -azobenzene anymore because of the mismatch between the host and guest. [ 22–27 ]

Encapsulation of an Adamantane-Doxorubicin Prodrug in pH-Responsive Polysaccharide Capsules for Controlled Release

Supramolecular microcapsules (SMCs) with the drug-loaded wall layers for pH-controlled drug delivery were designed and prepared. By using layer-by-layer (LbL) technique, the SMCs were constructed based on the self-assembly between polyaldenhyde dextran-graft-adamantane (PAD-g-AD) and carboxymethyl dextran-graft-β-CD (CMD-g-β-CD) on CaCO(3) particles via host-guest interaction. Simultaneously, adamantine-modified doxorubicin (AD-Dox) was also loaded on the LbL wall via host-guest interaction. The in vitro drug release study was carried out at different pHs. Because the AD groups were linked with PAD (PAD-g-AD) or Dox (AD-Dox) by pH-cleavable hydrazone bonds, AD moieties can be removed under the weak acidic condition, leading to destruction of SMCs and release of Dox. The pH-controlled drug release can enhance the uptake by tumor cells and thus achieve improved cancer therapy efficiency.

Peptide Hydrogel as an Intraocular Drug Delivery System for Inhibition of Postoperative Scarring Formation

A biocompatible hydrogel self-assembled from a peptide comprised of a peptide backbone containing Arg-Gly-Asp (RGD) sequence and a hydrophobic N-fluorenyl-9-methoxycarbonyl (FMOC) tail was designed and prepared to load antiproliferative model drug (5-fluorouracil, 5-Fu). After administering this 5-Fu-loaded peptide hydrogel in the filtering surgery of rabbit eyes, because of the sustained release of 5-Fu from the hydrogel to inhibit the scleral flap fibrosis efficiently, the pathology and immunohistochemistry demonstrate that the filtration fistula is patent without postoperative scarring formation, resulting in the significantly low intraocular pressure (IOP) of the rabbit eyes within postoperative 28 days. In a comparison with the conventional 5-Fu exposure, the strategy demonstrated here presents several advantages including providing convenience and preventing the toxicity of 5-Fu to the surrounding ocular tissues efficiently, suggesting a feasibility of this peptide hydrogel as a potential implanted drug delivery system for the inhibition of postoperative scarring formation.

Biological Glucose Metabolism Regulated Peptide Self-Assembly as a Simple Visual Biosensor for Glucose Detection

A glucose oxidase (GOx)-mediated glucose metabolism was in vitro mimicked and employed to regulate the self-assembly of peptide-based building blocks. In this new stimuli-responsive self-assembly system, two peptide-based building blocks, respectively, having aspartic acid (gelator 1) and lysine (gelator 2) residues were designed and prepared. When adding glucose and GOx to the aqueous solution of gelator 1 or the self-assembled fibrillar hydrogel of gelator 2 to construct glucose metabolism system, the metabolic product (gluconic acid) can trigger the protonation of the peptide molecules and induce the phase transitions of gelators 1 (sol-gel) and 2 (gel-sol). Because this glucose metabolism regulated peptide self-assembly is built on the oxidation of glucose, it can be used as a simple visual biosensor for glucose detection.

pH responsive micelle self-assembled from a new amphiphilic peptide as anti-tumor drug carrier.

An acid-responsive amphiphilic peptide that contains KKGRGDS sequence in hydrophilic head and VVVVVV sequence in hydrophobic tail was designed and prepared. In neutral or basic medium, this amphiphilic peptide can self-assemble into micelles through hydrogen bonding and hydrophobic interactions. If changing the solution pH to an acidic environment, the electrostatic repulsion interaction among the ionized lysine (K) residues will prevent the self-assembly of the amphiphilic peptide, leading to the dissociation of micelles. The anti-tumor drug of doxorubicin (DOX) was chosen and loaded into the self-assembled micelles of the amphiphilic peptide to investigate the influence of external pH change on the drug release behavior. As expected, the micelles show a sustained DOX release in neutral medium (pH 7.0) but fast release behavior in acidic medium (pH 5.0). When incubating these DOX-loaded micelles with HeLa and COS7 cells, due to the over-expression of integrins on cancer cells, the micelles can efficiently use the tumor-targeting function of RGD sequence to deliver the drug into HeLa cells. Combined with the low cytotoxicity of the amphiphilic peptide against both HeLa and COS7 cells, the amphiphilic peptide reported in this work may be promising in clinical application for targeted drug delivery.