选择性作用于肿瘤的锰-dpa修饰的硅纳米颗粒

磁共振成像是临床上常用的无侵入性肿瘤早期诊断手段.锰作为人体必须的微量元素之一,具有较好的生物化学效应,顺磁性锰配合物已成为非钆基造影剂发展新方向.我们近期研究发现二吡啶甲基胺类配体锰配合物可以抑制肿瘤细胞增殖,说明这类锰配合物保留了锰离子的识别特征,可以以相同的途径进行转运.由于锰离子通过转铁蛋白运输进入线粒体内,而转铁蛋白在肿瘤细胞含量高于正常细胞,因此经转铁蛋白转运的锰配合物对肿瘤细胞的识别能力高于正常细胞,具有一定的靶向性.降低造影剂的用量来降低其对生物体的毒性已成为人们研究造影剂的共识,而把造影剂制备成纳米级成为降低其用量和降低其毒性的一个重要手段.为增加纳米粒子对肿瘤细胞的靶向性,我们设计、制备了一种水溶性Mn(Ⅱ)-dpa(dpa=二吡啶甲基胺)修饰硅纳米粒子.红外光谱、紫外光谱数据显示表面修饰的二吡啶甲基胺配体锰配合物的存在,ICP测试结果表明锰离子的含量为3.25%.透射电镜数据显示Mn(Ⅱ)-dpa修饰的硅纳米粒子粒径在60～70nm.这种水溶性纳米粒子经腹腔注射后能选择性作用于肿瘤细胞,34～120min内显著提高大鼠体内腋下肝癌的磁共振成像度.进一步体外实验表明Mn(Ⅱ)-dpa修饰的硅纳米粒子能促进钙离子引起的线粒体肿胀.肿瘤细胞线粒体对钙离子的吸收能力大于正常细胞,能调节线粒体钙离子吸收的Mn(Ⅱ)-dpa修饰的硅纳米粒子可能通过细胞内钙信号相关的线粒体途径选择性聚集于肿瘤细胞,成为主动肿瘤靶向性磁共振成像造影剂.研究结果说明具有一定肿瘤靶向性的(Mn(Ⅱ)-dpa)配合物修饰的硅纳米粒子可成为研制肿瘤靶向性诊断剂的新途径.     

具有肿瘤荧光成像性能的核壳纳米过氧化氢酶模拟物

运用微波法在硅核壳荧光材料的表面修饰了2-(二吡啶甲胺基)丙酸的锰配合物,获得具有荧光性能的锰-硅核壳纳米结构复合物,运用IR,UV,TEM等方法表征了纳米复合物的结构。H2O2岐化实验显示锰-硅核壳纳米复合物具有较好的过氧化氢酶模拟特性,是一种新的纳米过氧化氢酶模拟物。体外细胞荧光成像研究表明2-(二吡啶甲胺基)丙酸修饰的纳米球不能进入肿瘤细胞内,而锰-硅核壳纳米复合物能进入肿瘤细胞内,具备良好的肿瘤靶向性,显著提高肿瘤荧光成像效果,可作为新型的肿瘤成像剂。     

双核锰配合物[Mn2(Adpa)2Cl4]的合成、与线粒体和癌细胞的作用

本文以N-烯丙基二吡啶甲基胺为配体,合成了一个新的锰配合物.晶体结构显示其为双核锰(Ⅱ,Ⅱ)配合物.用MTT法研究了双核锰配合物体外与线粒体作用和对肿瘤细胞生长的抑制作用.实验结果表明双核锰(Ⅱ,Ⅱ)配合物对癌细胞ECA-109有较强的抑制作用,且化合物能抑制过量钙离子引起的线粒体肿胀.     

N-取代二吡啶甲基胺锌配合物的合成、与DNA作用和抗肿瘤活性

本文以N-烯丙基二吡啶甲基胺(Aldpa)和2,2-二(2-吡啶甲胺基)丙酸(Adpa)为配体,合成了2个锌配合物,并运用IR,UV,ES-MS等方法进行了表征.X-衍射晶体结构表明[(Adpa)Zn(CHCOO)]配合物中锌(Ⅱ)离子采取五配位三角双锥构型.紫外和荧光光谱滴定研究结果显示[(Adpa)Zn(CHCOO)]与ctDNA作用强于[(Aldpa)ZnCl2].用MTT法研究了配合物体外对肿瘤细胞生长的抑制作用.实验结果表明与ctDNA作用强的锌配合物抗肿瘤活性较好,二吡啶甲基胺氮原子上的取代基影响相应锌(Ⅱ)配合物的抗肿瘤活性.     

含磺胺嘧啶基团的葡聚糖钆配合物的研究

将具有肿瘤靶向性的磺胺嘧啶(SD)、二乙三胺五乙酸(DTPA)与葡聚糖(dextran)大分子侧链羟基偶联,合成葡聚糖大分子配体(SD-Dextran-DTPA),再与金属钆离子Gd3+配合,从而制备肿瘤靶向性葡聚糖大分子钆配合物(SD-Dextran-DTPA-Gd).对所合成的配体及钆配合物进行FTIR、UV和1H-NMR等结构表征,测试了配体及钆配合物在水溶液中的粒径分布和zeta电位、钆配合物的体外弛豫率、细胞摄取与T1加权磁共振成像性能.与小分子钆-二乙三胺五乙酸(Gd-DTPA)相比,SD-Dextran-DTPA-Gd具有较高的弛豫率,对肺癌细胞系H460、乳腺癌细胞系MDA-MB-231和T40D均有较好的亲和性,可被肿瘤细胞较好地摄取,并能获得较好的肿瘤细胞磁共振成像.     

基于双靶向黑色素纳米粒的肿瘤深穿透光声成像

通过1-(3-二甲基氨基丙基)-3-乙基碳二亚胺和N-羟基丁二酰亚胺反应将透明质酸(hyaluronic acid,HA)和4-羧丁基三苯基溴化膦((4-carboxybutyl) triphenylphosphonium bromide,TPP)分子连接到聚乙二醇-氨基(PEG-NH₂)修饰过的黑色素纳米颗粒(melanin nanoparticles,MNP)表面,设计合成了一种具有双靶向能力的黑色素纳米颗粒(MNP-TPP-HA),赋予了黑色素的双靶向能力。体外三维(3D)多细胞肿瘤球荧光成像和活体肿瘤光声成像实验表明MNP-TPP-HA具有优异的肿瘤靶向穿透能力。     

基于双靶向黑色素纳米粒的肿瘤深穿透光声成像

通过1‐(3‐二甲基氨基丙基)‐3‐乙基碳二亚胺和N‐羟基丁二酰亚胺反应将透明质酸(hyaluronic acid,HA)和4‐羧丁基三苯基溴化膦((4‐carboxybutyl) triphenylphosphonium bromide,TPP)分子连接到聚乙二醇-氨基(PEG‐NH₂)修饰过的黑色素纳米颗粒(melanin nanoparticles,MNP)表面,设计合成了一种具有双靶向能力的黑色素纳米颗粒(MNP‐TPP‐HA),赋予了黑色素的双靶向能力。体外三维(3D)多细胞肿瘤球荧光成像和活体肿瘤光声成像实验表明MNP‐TPP‐HA具有优异的肿瘤靶向穿透能力。     

Cr(Ⅲ)-取代磷钨杂多配合物对4-甲基吡啶的电催化氧化作用

利用Cr(Ⅲ)-取代磷钨杂多配合物PW11O39CrⅢ(H2O)4-的内球电子转移特性,通过与反应活性中心CrⅢ(H2O)第六配位水分子的交换反应,将4-甲基吡啶分子络合修饰到该活性中心上进行阳极催化氧化.可见吸收光谱证实4-甲基吡啶和CrⅢ(H2O)中心进行配体交换反应生成PW11O39CrⅢ(NC6H7)4-;而循环伏安和恒电位电解实验结果表明,修饰在Cr(Ⅲ)活性中心上的4-甲基吡啶分子每一步都经历2电子氧化,依次生成吡啶-4-甲醇,吡啶-4-甲醛和吡啶-4-甲酸.由此提出了一个关于这类反应的分子内电催化模板机制,为过渡金属取代杂多配合物作为间接氧化电催化剂的应用开辟了一条新途径.     

Cu(ClO4)2诱导的N-苯基二吡啶甲基胺的邻位苯甲基化及其溴桥联铜配合物的形成

N-苯基二吡啶甲基胺和苯甲基溴在Cu(ClO4)2存在的条件下反应导致N-苯基二吡啶甲基胺的邻位苯甲基化和一个新的溴桥联的双核铜配合物的形成。实验结果显示阴离子显著影响反应的选择性,CuCl2和Cu(NO3)2不能提高N-苯基二吡啶甲基胺邻位苯甲基化的选择性。NMR和元素分析数据证实N-苯基二吡啶甲基胺邻位苯甲基化产物的形成。X-射线晶体结构数据表明溴桥联的双核铜配合物中铜原子被3个N原子,1个配位溴离子和1个μ2-桥联的溴结合形成扭曲的三角双锥的构型。研究结果表明Cu(ClO4)2可作为N-苯基二吡啶甲基胺邻位烷基化反应的催化剂。研究结果有助于设计新的选择性苯甲基化催化剂。     

Mn(Ⅲ,Ⅲ)配合物及含酚配体[N4O3]3--Ru(bPy)3模型化合物的性能研究

为了对绿色植物光系统Ⅱ给体部分进行模拟,合成了1个新的高价双核配合物[Mn2(Ⅲ,Ⅲ)L(μ-OAc)2]*PF6 (2a),其中H3L为2,6-二{[(2-羟基-5-叔丁基苄基)(吡啶-2-亚甲基)胺基]亚甲基}-4-甲基苯酚.与目前的PSⅡ模型化合物[Mn2(Ⅱ,Ⅱ)-(bpmp)(μ-OAc)2]*ClO4 (1) [Hbpmp 2,6-二{[N,N-二(吡啶-2-亚甲基)胺基]亚甲基}-4-甲基苯酚]相比,配合物2a中增加了2个酚羟基及2个叔丁基,由此带来的改进使新模型更接近于自然界四核锰簇(OEC)的真实结构.在此基础上,我们将该配体通过酰胺键与[Ru(bPy)3]2+相连设计了光诱导电子转移模型化合物2b.其中[Ru(bPy)3]2+具有良好的光电性能,用于模拟PSⅡ中酶P680.通过紫外可见、红外、荧光发射光谱及电化学对化合物进行了光、电性能研究,结果表明配合物2b具有良好的光物理性质,而且2b中Ru3+/Ru2+的氧化还原电位比Phenol+/Phenol和Mn(Ⅲ,Ⅳ)/Mn(Ⅲ,Ⅲ)的高,说明2b配位金属Mn后可满足自然界PSⅡ电子转移的基本要求,是用来模拟PSⅡ给体部分较理想的模型.     

Targeting cancer cells through iron(III) complexes of di(picolyl)amine modified silica core-shell nanospheres

In this report, we aim at optimizing the approach of delivering and imaging cancer cell targeting using anti-proliferative nanoparticle complex. Rhodamine B isothiocyanate doped silica-coated (RBITC-SiO?) were prepared by microemulsion method. Fe(III) complex of di(picolyl)amine was conjugated on to the surface RBITC-SiO? to produce final nanosphere (RBITC-SiO? @dpa-Fe) with an average hydrodynamic diameter of 74 nm. The Fe(III)-di(picolyl)amine complex modified nanospheres displayed enhanced HeLa cells uptake in vitro suggesting selective cancer cell payload delivery. RBITC-SiO? @dpa-Fe also showed reduced off-target cytotoxicity. The conjugate of dpa-Fe(III) complex and fluorescence core-shell nanoparticles RBITC-SiO? represents a class of novel multi-functional nanoparticles that combines the advantages of active cancer-targeting through Fe(III) complex mediated intracellular drug delivery and compatibility with fluorescence imaging.     

Anticancer activity, attenuation on the absorption of calcium in mitochondria, and catalase activity for manganese complexes of N-substituted di(picolyl)amine

In order to find multifunction anticancer complexes, three Mn(II) complexes of N-substituted di(2-pyridylmethyl)amine were characterized and used as agents to interfere with the functions of mitochondria and the metabolite of O(2) in cancer cells. It was found that carboxylate-bridged dimanganese(II) systems are good models of catalase and exhibit good inhibition of the proliferation of U251 and HeLa cells. The inhibiting activity of these manganese(II) complexes on the tumor cells in vitro was related to their disproportionating H(2)O(2) activity. The reaction of carboxylate-bridged dimanganese Mn(II) complex with H(2)O(2) forms a stable Mn(III)-(μ-O)(2)-Mn(IV) complex. Extensive experimental results show that chloride-bridged dimanganese(II) complexes could inhibit the swelling of calcium(II) overloaded mitochondria, and carboxylate-bridged manganese(II) complexes enhance the swelling of calcium(II) overloaded mitochondria. These results indicate that the interactions between Mn(II) complexes of N-substituted di(picolyl)amine and mitochondria are influenced by the structure and conformation of the complexes. Mn(II) complexes of N-substituted di(picolyl)amine could be developed as multifunctional anticancer complexes to interfere with the absorption of calcium(II) in mitochondria and the metabolite of O(2) through the H(2)O(2) or ROS involved signaling induced apoptosis of cancer cells.     

氯化钠-硫氰酸铵-溴化十六烷基三甲基铵体系浮选分离锌

研究观察到,在水溶液中Zn(Ⅱ）与硫氰酸铵、溴化十六烷基三甲基铵形成不溶于水的三元缔合物,在少量氯化钠存在下此三元合物沉淀浮于水相上层并与水分成界面清晰的两相,分相过程中Zn(Ⅱ）被定量浮选。实现了Zn(Ⅱ）与Fe(Ⅲ）、Al(Ⅲ）、Co(Ⅱ）、Ni(Ⅱ）、Mn(Ⅱ）等离子的分离,是一种无毒且更为简便、经济、快速的分离方法。     

Targeting cancer cells through Mn(II)-dpa grafted silica nanoparticles

The unique properties of paramagnetic nanoscale metal-organic frameworks provide them with high potential as key probes and vectors in the next generation of biomedical applications. To increase the nanoparticle targeting at the tumor site, the grafting of Mn(II)-dpa (dpa =di(picolyl)amines) on oxide nanoparticles (SiO₂) is proposed. The new Mn(II)-dpa-grafted silica nanoparticles can enhance the MR imaging area in cancer tissues and perturb the Ca²⁺-loaded mitochondria swelling. Experimental results indicate the cancer cells may be targeted through possible intracellular Ca²⁺ signaling mitochondria accumulating in vivo.     

Rapid Synthesis of Size-controlled Gold Nanoparticles by Complex Intramolecular Photoreduction

A rapid synthesis of size-controlled gold nanoparticles was proposed.The method is based on the sensitive intramolecular photoreduction reaction of Fe(Ⅲ)-EDTA complex in chloroacetic acid-sodium acetate buffer solution,where Fe(Ⅱ)-EDTA complex generated by photo-promotion acts as a reductant of AuCl-4 ions.Gold nanoparticles formed were stabilized by EDTA ligand or other protective agents added.As a result,well-dispersed gold nanoparticles with an average diameter range of 6.7 to 50.9 nm were obtained.According to the characterizations by the UV spectrum and TEM,the intramolecular charge transfer of the excited states of complex Fe(Ⅲ)-EDTA and the mechanism of forming gold nanoparticles were discussed in detail.     

Electrophoretic separation of gold nanoparticles according to bifunctional molecules‐induced charge and size

Gold nanospheres modified with bifunctional molecules have been separated and characterized by using agarose gel electrophoresis as well as optical spectroscopy and electron microscopy. The electrophoretic mobility of a gold nanosphere capped with 11‐mercaptoundecanoic acid (MUA) has been found to depend on the number of MUA molecules per gold nanosphere, indicating that it increases with the surface charge of the nanoparticle. The extinction spectrum of gold nanospheres capped with MUA at an MUA molecules per gold nanosphere value of 1000 and connected via 1,6‐hexanedithiol (HDT) decreases by 33% in magnitude and shifts to the red as largely as 22 nm with the increase of the molar ratio of HDT to MUA (R_HM). Gold nanospheres capped with MUA and connected via HDT have been separated successfully using gel electrophoresis and characterized by measuring reflectance spectra of discrete electrophoretic bands directly in the gel and by monitoring transmission electron microscope images of gold nanoparticles collected from the discrete bands. Electrophoretic mobility has been found to decrease substantially with the increment of HDT to MUA, indicating that the size of aggregated gold nanoparticles increases with the concentration of HDT.     

Schiff碱双核配合物的磁性及模拟甲烷单加氧酶催化性能的研究

存在于生命体中的甲烷单加氧酶是一种双金属单加氧酶,其结构及催化作用机制目前还不十分清楚．为了模拟甲烷单加氧酶的催化作用,探讨甲烷单加氧酶中两个金属离子间是否存在协同作用,本文按前文方法合成了双[N,N’-亚乙基-2,2’-(苯亚甲基)二(3,4-二甲基吡咯-5-醛缩亚胺)]合单金属配合物MH2L(1～7)及双金属配合物MnML(8-14)(结构见Scheme 1)．     

Amine-terminated dendrimers as biomimetic templates for silica nanosphere formation

In diatoms, silica synthesis occurs by use of complex posttranslationally modified peptides, termed silaffins, and highly complex biological polyamine structures. Silaffin peptides have lysine residues that are modified to long-chain polyamine moieties of N-methyl derivatives of polypropylenimine to drive silica synthesis at slightly acidic pH conditions. Using polypropylenimine (PPI) and PAMAM amine-terminated dendrimers as a biomimetic analogue of the polyamine modifications of silaffins, we have demonstrated the condensation of silica nanospheres. We have shown that the dendrimers react in an amine concentration-dependent fashion yielding silica nanospheres with a distinct size distribution reminiscent of the structures produced from both the modified and nonmodified peptides extracted from diatoms. Additionally, the templates were encapsulated by the growing nanospheres and precipitated from solution in a manner similar to that previously described for the bioactive peptides and polyamines.