氟尿嘧啶-聚酰胺-胺复合物的制备及大鼠体内药代动力学

合成并表征了聚酰胺-胺（PAMAM）G5.0树枝状聚合物,平衡透析法制备氟尿嘧啶-聚酰胺-胺复合物（5-Fu-PAMAM）,研究PAMAM对5-Fu的结合能力;高效液相色谱法研究大鼠经口给予5-Fu混悬液和5-Fu-PAMAM复合物的药代动力学。结果显示,当5-Fu与PAMAM G5.0的物质的量比在250附近达到最大结合,制备的复合物粒径为（30.2±4.9)nm。大鼠经口给予复合物组的K_a,c_max均较混悬液组有显著增加（P<0.01）,AUC_0-∞是混悬液组的1.37倍。研究表明PAMAM能显著增加5-Fu的口服吸收,提高5-Fu制剂的生物利用度。     

Micro- and nanocarrier-mediated lung targeting

Importance of the field: Drug delivery to lungs appears to be an attractive proposition on account of the large surface area of the alveolar region; it provides tremendous opportunities to improve drug therapies both systemically and locally using new drug delivery systems. Administration of drugs directly to the lungs is the most appropriate route in the treatment of asthma and other pulmonary diseases such as tuberculosis, chronic obstructive pulmonary disease and lung cancer.

Areas covered in this review: This review focuses on the utilization of nano- and microcarriers such as microspheres, nanoparticles, liposomes, niosomes and dendrimers for targeted delivery of bioactive molecules to lungs.

What the reader will gain: This review sheds light on the current status of nano- and microcarrier-mediated lung targeting of bioactive compounds.

Take home message: The literature review shows that carriers could supplement sustained drug delivery to the lungs, extended duration of action, reduced therapeutic dose, improved patient compliance, and reduced adverse effects of highly toxic drugs. There is still a need to identify more specific receptors that are present exclusively in the lungs. The identification of such receptors may also facilitate drug targeting to further specific parts of the lungs, such as bronchioles and alveoli.     

Drug delivery using multifunctional dendrimers and hyperbranched polymers

Importance of the field: The review presents the design strategy and synthesis of multifunctional dendrimers and hyperbranched polymers with the objective to develop effective drug delivery systems.

Areas covered in this review: Well-characterized, commercially available dendritic polymers were subjected to functionalization for preparing drug delivery systems of low toxicity, high loading capacity, ability to target specific cells and transport through their membranes. This has been achieved by surface targeting ligands, which render the carriers specific to certain cells and polyethylene glycol groups, securing water solubility, stability and prolonged circulation. Moreover, transport agents facilitate transport through cell membranes while fluorescent probes detect their intracellular localization. A common feature of surface groups is multivalency, which considerably enhances their binding strength with complementary cell receptors. To these properties, one should also add the property of attaining high loading of active ingredients coupled with controlled and/or triggered release.

What the reader will gain: Readers will be exposed to the strategy of synthesizing multifunctional polymers, aimed at the development of effective drug delivery systems.

Take home message: Multifunctional systems upgrade the therapeutic potential of drugs and, in certain cases, may even lead to the application of new bioactive compounds that would otherwise not be feasible.     

Erratum

Abstract

Nanomaterials such as carbon nanotubes (CNTs) and nanoparticles have received enormous attention in analytical areas for their potential applications as new tools for biotechnology and life sciences. Most of these possible applications involve the use of CNTs and related materials as vehicles for drug delivery and/or gene therapy. In this study, we introduce a methodology to evaluate the interactions between CNTs/dendrimers nanoconjugates and phospholipid biomembrane models, using the Langmuir film balance technique. Our main goal was to elucidate the action of engineered nanomaterials in cell membranes, at the molecular level, using a membrane model system. The penetration of single-walled carbon nanotubes (SWCNTs)/polyamidoamine dendrimer nanocomplexes into dipalmitoylphosphatidylcholine monolayers was pronounced, as revealed by adsorption kinetics and surface pressure measurements. These findings suggest that SWCNTs were able to interact even at high surface pressure values, ～30 mN/m. Therefore, the results confirm that the presence of the nanomaterial affects the packing of the synthetic membranes. We believe the methodology introduced here may be of great importance for further nanotoxicity studies.     

Dendrimer-based targeted intravitreal therapy for sustained attenuation of neuroinflammation in retinal degeneration

Retinal neuroinflammation, mediated by activated microglia, plays a key role in the pathogenesis of photoreceptor and retinal pigment epithelial cell loss in age-related macular degeneration and retinitis pigmentosa. Targeted drug therapy for attenuation of neuroinflammation in the retina was explored using hydroxyl-terminated polyamidoamine (PAMAM) dendrimer-drug conjugate nanodevices. We show that, upon intravitreal administration, PAMAM dendrimers selectively localize within activated outer retinal microglia in two rat models of retinal degeneration, but not in the retina of healthy controls. This pathology-dependent biodistribution was exploited for drug delivery, by covalently conjugating fluocinolone acetonide to the dendrimer. The conjugate released the drug in a sustained manner over 90 days. In vivo efficacy was assessed using the Royal College of Surgeons (RCS) rat retinal degeneration model over a four-week period when peak retinal degeneration occurs. One intravitreal injection of 1 μg of FA conjugated to 7 μg of the dendrimer was able to arrest retinal degeneration, preserve photoreceptor outer nuclear cell counts, and attenuate activated microglia, for an entire month. These studies suggest that PAMAM dendrimers (with no targeting ligands) have an intrinsic ability to selectively localize in activated microglia, and can deliver drugs inside these cells for a sustained period for the treatment of retinal neuroinflammation.     

“Click” Synthesis of a Bipolar Dendrimer as a Host Material for Electrophosphorescent Devices

A new solution‐processable bipolar dendrimer with carbazole units as hole‐transporting units and oxadiazole units as electron‐transporting units was efficiently synthesized based on a convergent approach by alternation of a Cu‐catalyzed azide/alkyne cycloaddition reaction and Williamson ether synthesis. The orthogonal chemistry completely avoided protection and activation of the focal points in the process of dendrimer synthesis. The dendrimer showed a wide bandgap and good thermal stability. Electrophosphorescent devices with the configuration ITO/PEDOT:PSS/bipolar dendrimer:Ir(ppy)₃/TPBI/LiF/Al were fabricated. The devices showed a maximum current efficiency of 16.8 cd · A^?1, a maximum power efficiency of 4.22 lm · W^?1 and an external quantum efficiency of 5.7%.

     

“Tree‐Shaped” Copolymers Based on Poly(ethylene glycol) and Atactic or Isotactic Polylactides: Synthesis and Characterization

“Tree‐shaped” copolymers constituted by an m‐PEG trunk and poly(L ‐lactide) or poly(D ,L ‐lactide) branches were obtained. The m‐PEG was functionalized at the terminal chain with two (G1) and four (G2) hydroxyl groups, then reacted with Al(CH₃)₃ to produce aluminum alkoxide species, active as initiators in the ROP of L‐ or D ,L‐ lactide. Copolymers were characterized by ¹H and ¹³C NMR, GPC and DSC, and compared with analogous linear copolymers. Characterization of a low‐molecular‐weight G1 copolymer confirmed the architecture. GPC curves showed monomodal and narrow molecular weight distribution for all the samples, while the melting points of the copolymers seemed more correlated to the architecture than to the composition.

     

StarburstTM Polyamidoamine Dendrimers介导的绿色荧光蛋白基因在小鼠体内的表达分布及对恶性疟DNA 疫苗ES312免疫原性的影响

目的研究StarburstTM Polyamidoamine(PAMAM)dendrimers介导绿色荧光蛋白基因在小鼠体内的表达分布及对恶性疟DNA疫苗ES312免疫原性的影响.方法经股四头肌给小鼠注射StarburstTM PAMAM dendrimers与绿色荧光蛋白基因或恶性疟DNA疫苗ES312的复合物.通过流式细胞术、Western blot和间接免疫荧光方法检测绿色荧光蛋白的表达分布和表达量.用ELISA方法检测恶性疟DNA疫苗ES312的免疫原性.结果在注射StarburstTMPAMAM dendrimers/DNA复合物后2 h～7 d内,StarburstTM PAMAM dendrimers携带的绿色荧光蛋白基因的表达在小鼠的心、肝、脾、肺、肾、脑、肌肉中均能被检测到,在肾总蛋白中所占百分比最高,且各器官管腔内皮细胞中的绿色荧光蛋白表达量较高.小鼠的脑和肾中,在StarburstTM PAMAM dendrimers的存在下,绿色荧光蛋白基因的表达量明显高于裸DNA的表达量.经StarburstTM PAMAM dendrimers携带的恶性疟DNA疫苗ES312诱导的抗体反应水平明显高于单纯裸DNA疫苗所诱导的抗体水平.结论StarburstTM PAMAM dendrimers作为一种低抗原性、非病毒的新型DNA载体,能够明显提高裸DNA在体内的表达水平,诱导产生很强的体液免疫反应.但是,StarburstTM PAMAMdendrimers/DNA复合物在各组织器官中的广泛分布,尤其是透过血脑屏障的能力,已超出疫苗载体的适用范围.作为DNA疫苗载体,要对现有StarburstTM PAMAM dendrimers分子的结构做进一步的修饰.     

具有内皮祖细胞捕获功能的聚氨酯的合成与研究

以聚碳酸酯二元醇(PCDL)为软段,1,6-六亚甲基二异氰酸酯(HDI)为硬段,二羟甲基丙酸(bis-MPA)为扩链剂合成了一种侧 链含有羧基官能团的聚碳酸酯型聚氨酯材料。将氨基封端的四代树枝状聚酯大分子共价接枝到聚氨酯的侧链上,脱除树枝状分子表 面缩酮保护基后得到了一种新型的侧链树枝化多羟基聚氨酯材料。此聚合物能有效黏附CD133抗体,黏附了抗体的材料可大大提高 CD133内皮祖细胞的黏附。这一结果为通过加速血液接触材料表面内皮化来提高其血液相容性提供了可能。     

Permeability of surface-modified polyamidoamine (PAMAM) dendrimers across Caco-2 cell monolayers

Aim of this study was to prepare polyamine-conjugated PAMAM dendrimers and study their permeability across Caco-2 cell monolayers. Polyamines, namely, arginine and ornithine were conjugated to the amine terminals of the G4 PAMAM dendrimers by Fmoc synthesis. The apical-to-basolateral (AB) and basolateral-to-apical (BA) apparent permeability coefficients (P_app) for the PAMAM dendrimers increased by conjugating the dendrimers with both of the polyamines. The enhancement in permeability was dependent on the dendrimer concentration and duration of incubation. The correlation between monolayer permeability and the decrease in transepithelial electrical resistance (TEER) with both the PAMAM dendrimers and the polyamine-conjugated dendrimers suggests that paracellular transport is one of the mechanisms of transport across the epithelial cells. Cytotoxicity of the polyamine-conjugated dendrimers was evaluated in Caco-2 cells by MTT (methylthiazoletetrazolium) assay. Arginine-conjugated dendrimers were slightly more toxic than PAMAM dendrimer as well as ornithine-conjugated dendrimers. Though investigations on the possible involvement of other transport mechanisms are in progress, results of the present study suggest the potential of dendrimer–polyamine conjugates as drug carriers to increase the oral absorption of drugs.