Youhua Tao

Spatial and temporal control of the alkyne–azide cycloaddition by photoinitiated Cu(II) reduction

The click reaction paradigm is focused on the development and implementation of reactions that are simple to perform while being robust and providing exquisite control of the reaction and its products. Arguably the most prolific and powerful of these reactions, the copper-catalysed alkyne-azide reaction (CuAAC) is highly efficient and ubiquitous in an ever increasing number of synthetic methodologies and applications, including bioconjugation, labelling, surface functionalization, dendrimer synthesis, polymer synthesis and polymer modification. Unfortunately, as the Cu(I) catalyst is typically generated by the chemical reduction of Cu(II) to Cu(I), or added as a Cu(I) salt, temporal and spatial control of the CuAAC reaction is not readily achieved. Here, we demonstrate catalysis of the CuAAC reaction via the photochemical reduction of Cu(II) to Cu(I), affording comprehensive spatial and temporal control of the CuAAC reaction using standard photolithographic techniques. Results reveal the diverse capability of this technique in small molecule synthesis, patterned material fabrication and patterned chemical modification.

Cross-linked micelles of graftlike block copolymer bearing biodegradable ε-caprolactone branches: a novel delivery carrier for paclitaxel

The poor stability of micellar drug delivery system in vivo due to large volume dilution often leads to premature drug release with low therapeutic efficacy. In this study, shell cross-linked micelles of graftlike block copolymer bearing biodegradable e-caprolactone branches (PMAA-b-PFM) were prepared to be used as a novel carrier for paclitaxel (PTX). PTX was successfully encapsulated into the hydrophobic cores of the cross-linked micelles using the dialysis method. The resultant PTX-loaded cross-linked micelles were about 99 nm in diameter with spherical shape and high encapsulation efficiency. The PTX-loaded cross-linked micelles had smaller sizes and better stability as compared to the non-cross-linked controls. Fluorescence microscopy and flow cytometry studies showed that PTX-loaded cross-linked micelles had excellent cellular uptake ability by bone marrow derived macrophages and human glioma U87 cells. Cellular uptake of cross-linked micelles was found to be higher than non-cross-linked controls due to smaller size. In vitro cytotoxicity studies also revealed that the PTX-loaded cross-linked micelles exhibit high anti-cancer activity to U87 cells. These results suggested that cross-linked PMAA-b-PFM micelles could be a potential vehicle for delivering hydrophobic chemotherapeutic drugs to tumors.

Nano-formulation of paclitaxel by vitamin E succinate functionalized pluronic micelles for enhanced encapsulation, stability and cytotoxicity.

Vitamin E succinate (TOS) modified pluronic micelles (PF-TOS micelles) were prepared to be used as a vehicle for paclitaxel (PTX). The average size of resultant PTX-loaded PF-TOS micelles (PF-TOS-PTX-micelles) was about 58 nm. PF-TOS-PTX-micelles showed enhanced encapsulation efficiency and better stability as compared to the non-modified controls. Fluorescence microscopy and high performance liquid chromatography studies showed that PTX-loaded PF-TOS micelles had excellent cellular uptake ability by human glioma U87 cells. Cytotoxicity assay revealed that PTX-loaded PF-TOS micelles demonstrated higher anti-cancer activity to U87 cells than that of the non-modified PF micelles. Pharmacokinetic studies indicated the longer systemic circulation time and slower plasma elimination rate in PTX-loaded PF-TOS micelles than that of the non-modified controls. In vivo tissue distribution studies showed that PTX-loaded PF-TOS micelles were preferably accumulated in spleen and liver. Taken together, the results evidently indicated that PF-TOS micelles improve the hydrophobic chemotherapeutic drugs delivery by means of efficient encapsulation and stabilization for anti-tumor therapy.

Brain-targeting gene delivery using a rabies virus glycoprotein peptide modulated hollow liposome: bio-behavioral study

In this study, a novel hollow liposome modified with a rabies virus glycoprotein peptide (RVG-liposome) was designed and synthesized for siRNA delivery to the brain. The resultant RVG-liposome was about 91 nm in diameter with a regular globular shape and hollow structure. siRNA was successfully encapsulated into the hollow cores of the RVG-liposome, achieving ∼75% entrapment efficacy while maintaining the nanodimensions of the RVG-liposome. The siRNA-loaded RVG-liposome can be effectively internalized and subsequently releases siRNA in bone marrow macrophages. With siRNA loading, the RVG-liposome mediated effective siRNA delivery and resulted in high transfection efficiency in U87 cells. MTT assay demonstrated that neither the RVG-liposomes themselves nor siRNA-loaded RVG-liposome showed cytotoxicity, even at high concentrations. Moreover, in vivo live imaging and fresh frozen sections showed that the RVG-liposome has the ability to cross the blood–brain barrier (BBB) and was preferably accumulated in the brain. Such a hollow RVG-liposome holds great promise as a non-viral vector for efficient and brain-targeting gene delivery.

New bio-renewable polyester with rich side amino groups from L-lysine via controlled ring-opening polymerization

Lysine, a renewable resource from biomass fermentation, was simply converted to its corresponding α-hydroxyl acids and then cyclized to give the pure O-carboxyanhydride (OCA) monomer. Ring-opening polymerization of the resulting monomer was carried out using dimethylaminopyridine (DMAP) as a catalyst in CH2Cl2 at room temperature, and gave well-defined lysine-derived polyesters bearing pendant carbobenzyloxy (Cbz)-protected amino groups with number average molecular weight of up to 45 kg mol−1 in narrow polydispersity. 1H NMR, GPC, and MALDI-TOF MS measurements of the products clearly indicated the controlled/living character of the polymerization. Moreover, amino-functionalized polyesters were readily prepared by the removal of the Cbz protecting group, and the integrity of the polyester backbone was confirmed by 1H NMR. These amino-functionalized polyesters showed a tunable glass transition temperature and exhibited excellent cell compatibility, suggesting their potential to be used as novel materials in biomedical applications.

Reduction-responsive gold-nanoparticle-conjugated Pluronic micelles: an effective anti-cancer drug delivery system

In this study, gold-nanoparticle-crosslinked Pluronic micelles were synthesized and used as a carrier for paclitaxel (PTX). The resultant PTX-loaded gold-nanoparticle-crosslinked Pluronic micelles were about 69 nm in diameter. Physical stability and in vivo pharmacokinetic studies revealed that these micelles were more stable as compared to the non-cross-linked controls. Fluorescence microscopy and flow cytometry analyses showed that PTX-loaded cross-linked micelles had excellent cellular uptake ability by human glioma U87 cells. The cleavage of disulfide bridge linkages under glutathione stimulus resulted in destruction of micelles and induced rapid drug release. In vitro cytotoxicity studies revealed that these cross-linked micelles exhibited high anti-cancer activity against glutathione monoester pre-treated U87 cells compared to non-pretreated cells. Cytoarchitecture studies demonstrated a similar cytoskeleton pattern before and after cross-linked micelles loaded into bone marrow derived macrophages. In vivo fresh frozen sections showed that cross-linked micelles were preferably accumulated in spleen and liver. These results indicated that gold-nanoparticle-crosslinked Pluronic micelles can be used as potential anti-cancer drug carriers for intelligent drug delivery.

Paclitaxel-loaded tocopheryl succinate-conjugated chitosan oligosaccharide nanoparticles for synergistic chemotherapy

Although countless work on the synthesis, encapsulation and toxicity of paclitaxel-loaded nanoparticles (NPs) has been reported, there have been few reports on the development of the nano-carrier materials of the paclitaxel (PTX) delivery system with therapeutic effects. In this study, we synthesized PTX-loaded tocopheryl succinate-conjugated chitosan oligosaccharide (CSO–TOS) NPs for synergistic chemotherapy. The resultant PTX-loaded CSO–TOS NPs were about 116 nm in diameter with spherical shape and high encapsulation efficiency. Fluorescence microscopy and flow cytometry studies showed that PTX-loaded CSO–TOS NPs had excellent cellular uptake ability by human glioma U87 cells. In vitro cytotoxicity studies revealed that the PTX-loaded CSO–TOS NPs were more potent than free PTX. The therapeutic effects of carrier materials were also studied and a synergistic effect between TOS and PTX was achieved. Cytoarchitecture studies demonstrated a similar cytoskeleton pattern before and after PTX-NPs were loaded into bone marrow derived macrophages. In vivo pharmacokinetic results indicated that the PTX-loaded CSO–TOS NPs had a longer systemic circulation time and slower plasma elimination rate than those of Taxol®. These results suggested that CSO–TOS could be a potential vehicle for delivering hydrophobic chemotherapeutic drugs to tumors.

Nucleobase-Mediated Stereospecific Radical Polymerization and Combination with RAFT Polymerization for Simultaneous Control of Molecular Weight and Tacticity

A highly soluble thymine-based compound (1-octyl thymine), having an array of hydrogen bonding sites with an ADA sequence (A and D: proton acceptor and donor sites, respectively), was used to mediate the stereospecific radical polymerization of an acrylamide monomer [N-(6-acetamidopyridin-2-yl)acrylamide] possessing the complementary DAD sequence. The thymine derivative interacted with the monomer via the selective 1:1 and strong triple hydrogen-bonding interaction (K = 1.1 × 10(3) in CHCl(3) at 20 °C) and mediated the syndiospecific radical polymerization of the monomer to give syndiotactic rich polymers up to r = 84% in CH(2)Cl(2) at -78 °C. A combination with the RAFT polymerization enabled simultaneous control of the molecular weight (M(W)/M(n) ≈ 1.5) and tacticity (r = 73% and 76% at 60 and 20 °C, respectively) of the resulting polymers. Furthermore, the stereoblock polymerization was achieved upon the addition of the thymine-based mediator during the RAFT polymerization to give the atactic-syndiotactic stereoblock polymers with controlled molecular weights.

pH-Sensitive Micelles Based on Double-Hydrophilic Poly(methylacrylic acid)-Poly(ethylene glycol)-Poly(methylacrylic acid) Triblock Copolymer

AbstractpH-sensitive micelles with hydrophilic core and hydrophilic corona were fabricated by self-assembling of triblock copolymer of poly(methylacrylic acid)-poly(ethylene glycol)-poly(methylacrylic acid) at lower solution pH. Transmission electron microscopy and laser light scattering studies showed micelles were in nano-scale with narrow size distribution. Solution pH value and the micelles concentration strongly influenced the hydrodynamic radius of the spherical micelles (48–310 nm). A possible mechanism for the formation of micelles was proposed. The obtained polymeric micelle should be useful for biomedical materials such as carrier of hydrophilic drug.

Targeted delivery of nano-PTX to the brain tumor-associated macrophages

Nanoparticles containing mixed lipid monolayer shell, biodegradable polymer core and rabies virus glycoprotein (RVG) peptide as brain targeting ligand, were developed for brain targeted delivery of paclitaxel (PTX) to treat malignant glioma. RVG conjugated PTX loaded NPs (RVG-PTX-NPs) had the desirable size (~140 nm), narrow size distribution and spherical shape. RVG-PTX-NPs showed poor uptake by neurons and selective targeting to the brain tumor associated macrophages (TAMs) with controlled release and tumor specific toxicity. In vivo studies revealed that RVG-PTX-NPs were significant to cross the blood-brain barrier (BBB) and had specific targeting to the brain. Most importantly, RVG-PTX-NPs showed effectiveness for anti-glioma therapy on human glioma of mice model. We concluded that RVG-PTX-NPs provided an effective approach for brain-TAMs targeted delivery for the treatment of glioma.