交联高分子网络平衡溶胀化的溶剂依赖性和温度依赖性

用链长分布不同的活性聚苯乙烯子聚物与二乙烯基苯进行阴离子嵌段共聚,合成了一系列两相模型交联网络。以作者等提出的方法测定了所合成网络的结构非均一因子Z。实验测定的网络结构非均一因子Z与交联前聚苯乙烯活性链的分子量分布宽度指数d之间有平行的相应变化规律,表明所给予的非均一因子Z的物理意义是合理的。同时说明,子聚物链长分布较宽时,在网络的高交联区中除了二乙烯基苯外,还有一些对溶胀无贡献的子聚物以悬挂链的形式存在。     

性质可比自微乳处方的制备、筛选及其对白藜芦醇增溶能力的研究

目的 通过制备一系列不同油相组成的自微乳处方,从中筛选出能形成相近粒径、表面电荷和均一性微乳的可比处方,进一步考察其对白藜芦醇的增溶能力.方法 分别以中链脂肪酸甘油酯、长链脂肪酸甘油酯和非甘油三脂肪酸酯为油相,通过伪三元相图法确定微乳区,并利用纳米粒度电位分析仪测定所得微乳的粒径、多分散性和Zeta电位,从中筛选出性质可比自微乳处方;通过HPLC测定自微乳及稀释后微乳对白藜芦醇的增溶能力.结果 通过筛选,选择了4种自微乳处方,其中油相为MCT(60%)或蓖麻油(40%)的微乳处方,粒径为140 nm左右;油相为MCT(40%)或油酸乙酯(40%)的微乳处方,粒径为60 nm左右.所得自微乳处方对白藜芦醇的增溶能力达到其水溶解度的8000倍左右.结论 本研究获得了一系列具有可比性的自微乳处方:当组分相同时,所得微乳粒径及分散性差别较大;当组分不同时,所得微乳粒径及分散性相近,可以用于考察微乳性质对药物生物利用度的影响.     

Inactivated infectious bronchitis virus vaccine encapsulated in chitosan nanoparticles induces mucosal immune responses and effective protection against challenge

Avian infectious bronchitis virus (IBV) is one of the most important viral diseases of poultry. The mucosa of upper respiratory tract, specially the trachea, is the primary replication site for this virus. However, conventional inactivate IBV vaccines usually elicit reduced mucosal immune responses and local protection. Thus, an inactivated IBV vaccine containing BR-I genotype strain encapsulated in chitosan nanoparticles (IBV-CS) was produced by ionic gelation method to be administered by oculo-nasal route to chickens. IBV-CS vaccine administered alone resulted in markedly mucosal immune responses, characterized by high levels of anti-IBV IgA isotype antibodies and IFNγ gene expression at 1dpi. The association of live attenuated Massachusetts IBV and IBV-CS vaccine also induced strong mucosal immune responses, though a switch from IgA isotype to IgG was observed, and IFNγ gene expression peak was late (at 5 dpi). Efficacy of IBV-CS was evaluated by tracheal ciliostasis analysis, histopathology examination, and viral load determination in the trachea and kidney. The results indicated that IBV-CS vaccine administered alone or associated with a live attenuated heterologous vaccine induced both humoral and cell-mediated immune responses at the primary site of viral replication, and provided an effective protection against IBV infection at local (trachea) and systemic (kidney) sites.     

Interfacial properties and micellization of triblock poly(ethylene glycol)-poly(ε-caprolactone)-polyethyleneimine copolymers

This study aimed to explore the link between block copolymers’ interfacial properties and nanoscale carrier formation and found out the influence of length ratio on these characters to optimize drug delivery system. A library of diblock copolymers of PEG-PCL and triblock copolymers with additional PEI (PEG-PCL-PEI) were synthesized. Subsequently, a systematic isothermal investigation was performed to explore molecular arrangements of copolymers at air/water interface. Then, structural properties and drug encapsulation in self-assembly were investigated with DLS, SLS and TEM. We found the additional hydrogen bond in the PEG-PCL-PEI contributes to film stability upon the hydrophobic interaction compared with PEG-PCL. PEG-PCL-PEI assemble into smaller micelle-like (such as PEG-PCL4006-PEI) or particle-like structure (such as PEG-PCL8636-PEI) determined by their hydrophilic and hydrophobic block ratio. The distinct structural architectures of copolymer are consistent between interface and self-assembly. Despite the disparity of constituent ratio, we discovered the arrangement of both chains guarantees balanced hydrophilic–hydrophobic ratio in self-assembly to form stable construction. Meanwhile, the structural differences were found to have significant influence on model drugs incorporation including docetaxel and siRNA. Taken together, these findings indicate the correlation between molecular arrangement and self-assembly and inspire us to tune block compositions to achieve desired nanostructure and drug loading.     

Development of sucrose stearate-based nanoemulsions and optimisation through γ-cyclodextrin

Nanoemulsions aimed at dermal drug delivery are usually stabilised by natural lecithins. However, lecithin has a high tendency towards self-aggregation and is prone to chemical degradation. Therefore, the aim of this study was to develop nanoemulsions with improved structure and long-term stability by employing a natural sucrose ester mixture as sole surfactant. A thorough comparison between the novel sucrose stearate-based nanoemulsions and corresponding lecithin-based nanoemulsions revealed that the sucrose ester is superior in terms of emulsifying efficiency, droplet formation as well as physical and chemical stability. The novel formulations exhibited a remarkably homogeneous structure in cryo TEM investigations, as opposed to the variable structure observed for lecithin-based systems. The in vitro skin permeation rates of lipophilic drugs from sucrose stearate nanoemulsions were comparable to those obtained with their lecithin-based counterparts. Furthermore, it was observed that addition of γ-cyclodextrin led to enhanced skin permeation of the steroidal drug fludrocortisone acetate from 9.99 ± 0.46 to 55.10 ± 3.67 μg cm⁻² after 24 h in the case of sucrose stearate-based systems and from 9.98 ± 0.64 to 98.62 ± 24.89 μg cm⁻² after 24 h in the case of lecithin-based systems. This enhancement effect was significantly stronger in formulations based on lecithin (P < 0.05), which indicates that synergistic mechanisms between the surfactant and the cyclodextrin are involved. Cryo TEM images suggest that the cyclodextrin is incorporated into the interfacial film, which might alter drug release rates and improve the droplet microstructure.     

The influence of chitosan content in cationic chitosan/PLGA nanoparticles on the delivery efficiency of antisense 2′-O-methyl-RNA directed against telomerase in lung cancer cells

Tailorable cationic chitosan/PLGA nanoparticles (CPNP) were used for the delivery of an antisense 2′-O-methyl-RNA (2OMR) directed against RNA template of human telomerase. Here, we describe the influence of the chitosan content on binding efficiency, complex stability, uptake in different human lung cell types and finally demonstrate the efficacy of this nanoplex system.CPNPs were prepared by the emulsion-solvent evaporation method using different amounts of chitosan and purified by preparative size exclusion chromatography. The characterization by photon correlation spectroscopy and zeta potential measurements showed a small increase in size and an increase of zeta potential with increasing amounts of chitosan. Binding efficiency and complex stability with 2OMR was high in water and correlated well with the chitosan content of particles but was weak in physiologically relevant media (PBS and RPMI cell culture medium). However, flow cytometry analysis showed that the uptake of 2OMR into A549 lung cancer cells was considerably higher in combination with nanoparticles and dependent on the amount of chitosan when compared to 2OMR alone. Confocal laser scanning microscopy revealed that the uptake into A549 cells is mediated via complexes of 2OMR and chitosan/PLGA nanoparticles despite the weak binding in cell culture medium. The nanoparticles were well tolerated and efficient in inhibiting telomerase activity.     

SLN for topical application in skin diseases—Characterization of drug–carrier and carrier–target interactions

The modes of drug–particle interactions considerably influence drug delivery by nanoparticulate carrier systems and drug penetration into the skin. The exact mechanism of the drug loading and its release are still ambiguous. Therefore, the loading process, the interaction of the agent and the lipid matrix of solid lipid nanoparticles (SLNs) as well as the uptake of the loaded agent by skin lipids were analysed by electron spin resonance (ESR) and parelectric spectroscopy (PS) using spin probes (TEMPO, TEMPOL, and CAT-1) as model drugs differing in their lipophilicity. The spin probes were closely attached to the particles lipid surface (TEMPO) or located in the layers of the surfactant (CAT-1), respectively. Furthermore, two distinct sub-compartments on the SLN were found. To simulate the processes at the phase boundary SLN dispersion/skin, skin lipid mixtures were prepared and the transfer process of the spin labels was followed by ESR tomography. Transfer rates were related to the lipophilicity of the spin probe, the lipid mixture and the applied pharmaceutical formulation, SLN dispersion and aqueous solution, respectively. In particular, SLN accelerated in particular the distribution of the lipophilic agents.     

Transgene regulation system responding to Rho associated coiled-coil kinase (ROCK) activation

Recently, we have proposed a new system of gene regulation called ‘drug or gene delivery system responding to cellular signals’ (D-RECS). In this system, transgene expression is activated in response to intracellular target protein kinases or proteases for safe, cell-specific gene delivery by using peptide-polymer conjugates. Here we applied this system to an intracellular Rho-associated coiled-coil kinase (ROCK) signal, which is activated abnormally in cardiovascular diseases. A ROCK responsive polymer consisting of neutral polymers in main chain and cationic ROCK substrate peptides in side chains was prepared and could form the complex with plasmid DNA. The complex was transferred into NIH3T3 cells with or without L-α-lysophosphatidic acid (LPA) that increases ROCK activity. At an N/P ratio of 2.0, a significant increase of the gene expression was identified in LPA-treated NIH3T3 cells, but was disappeared in NIH3T3 cells treated with ROCK specific inhibitor, Y-27632. These results suggest that the ROCK responsive polymer can regulate gene expression in response to ROCK activity.     

Bioresponsive immune-booster-based prodrug nanogel for cancer immunotherapy

The combination of chemotherapy and immunotherapy motivates a potent immune system by triggering immunogenic cell death (ICD), showing great potential in inhibiting tumor growth and improving the immunosuppressive tumor microenvironment (ITM). However, the therapeutic effectiveness has been restricted by inferior drug bioavailability. Herein, we reported a universal bioresponsive doxorubicin (DOX)-based nanogel to achieve tumor-specific co-delivery of drugs. DOX-based mannose nanogels (DM NGs) was designed and choosed as an example to elucidate the mechanism of combined chemo-immunotherapy. As expected, the DM NGs exhibited prominent micellar stability, selective drug release and prolonged survival time, benefited from the enhanced tumor permeability and prolonged blood circulation. We discovered that the DOX delivered by DM NGs could induce powerful anti-tumor immune response facilitated by promoting ICD. Meanwhile, the released mannose from DM NGs was proved as a powerful and synergetic treatment for breast cancer in vitro and in vivo, via damaging the glucose metabolism in glycolysis and the tricarboxylic acid cycle. Overall, the regulation of tumor microenvironment with DOX-based nanogel is expected to be an effectual candidate strategy to overcome the current limitations of ICD-based immunotherapy, offering a paradigm for the exploitation of immunomodulatory nanomedicines.     

Natural exosome-like nanovesicles from edible tea flowers suppress metastatic breast cancer via ROS generation and microbiota modulation

Although several artificial nanotherapeutics have been approved for practical treatment of metastatic breast cancer, their inefficient therapeutic outcomes, serious adverse effects, and high cost of mass production remain crucial challenges. Herein, we developed an alternative strategy to specifically trigger apoptosis of breast tumors and inhibit their lung metastasis by using natural nanovehicles from tea flowers (TFENs). These nanovehicles had desirable particle sizes (131 nm), exosome-like morphology, and negative zeta potentials. Furthermore, TFENs were found to contain large amounts of polyphenols, flavonoids, functional proteins, and lipids. Cell experiments revealed that TFENs showed strong cytotoxicities against cancer cells due to the stimulation of reactive oxygen species (ROS) amplification. The increased intracellular ROS amounts could not only trigger mitochondrial damage, but also arrest cell cycle, resulting in the in vitro anti-proliferation, anti-migration, and anti-invasion activities against breast cancer cells. Further mice investigations demonstrated that TFENs after intravenous (i.v.) injection or oral administration could accumulate in breast tumors and lung metastatic sites, inhibit the growth and metastasis of breast cancer, and modulate gut microbiota. This study brings new insights to the green production of natural exosome-like nanoplatform for the inhibition of breast cancer and its lung metastasis via i.v. and oral routes.