111In-DOTA-mAb109单克隆抗体探针的制备及其分子显像的研究

以具有肿瘤靶向的新型单克隆抗体mAb109, 借助其表面的氨基偶联双功能螯合剂获得可用于放射标记的DOTA-mAb109, 制备了¹¹¹In-DOTA-mAb109分子探针. Radio-HPLC分析结果表明, 其标记率96%, 放化纯度大于98%. 体外稳定性实验结果表明¹¹¹In-DOTA-mAb109在NaAc、PBS缓冲溶液以及5%人血清白蛋白溶液中均具有很高的稳定性. 建立 PANC-1胰腺癌裸鼠模型, 通过Nano-SPECT设备观察其在模型动物体内的代谢情况: 在静脉注射18.5 MBq ¹¹¹In-DOTA-mAb109探针分别于24 h, 48 h, 72 h进行SPECT/CT的显像, 随着时间的延长, 其在肿瘤组织表现出代谢摄取的增高. 通过断层显像, 进一步分析, 可见从特点层面观察到肿瘤组织具有明显的放射性摄取. 上述研究结果表明, ¹¹¹In-DOTA-mAb109分子探针有望发展成为一种具有肿瘤靶向性的新型分子探针.     

124I原位标记有机黑色素纳米粒子的制备及初步分子影像研究

探索了有机黑色素纳米粒子对一种目前最有潜力的新型PET成像核素的原位标记方法，制备出新型多功能纳米探针，并进行初步的分子影像研究.以自然存在的黑色素（Melanin）为原料，利用超声破碎法制备超微粒径（5.5 nm）黑色素纳米粒子（MNPs），并使用两端具有氨基的PEG₃₅₀₀对其表面进行修饰，获得具有较好水分散性和氨基活性基团的新型PEG-MNP纳米载体.采用动态光散射（DLS）、透射电镜（TEM）、红外光谱（FTIR）以及核磁氢谱（¹H NMR）对纳米粒子进行充分形貌表征.而后使用溴代琥珀酰亚胺（NBS）作为氧化剂进行长半衰期核素¹²⁴I的原位标记，获得了相应的具有PET成像功能的¹²⁴I-PEG-MNP纳米载体.而后使用游离¹²⁴I、¹²⁴I-PEG-MNP分别进行正常昆明小鼠Micro-PET成像对比研究，同时构建胰腺癌荷瘤鼠模型BxPC3，并进行¹²⁴I-PEG-MNP肿瘤成像研究.结果显示，长半衰期核素¹²⁴I对PEG-MNP的标记率可达99%以上，且体外稳定性良好.Micro-PET图像显示，¹²⁴I-PEG-MNP在小鼠体内未见脱标现象，体内放射性分布与游离¹²⁴I成像差异明显.通过基于选定甲状腺及肝脏感兴趣区（Region of Interest，ROI）的半定量分析表明，经过¹²⁴I标记后的PEG-MNP纳米粒子，与原有¹²⁴I的代谢学行为具有显著的统计学差异（P<0.001）.同时，¹²⁴I-PEG-MNP利用自身的实体瘤高通透性和滞留效应（EPR）在肿瘤部位有明显的富集，并在肿瘤部位滞留超过48 h.上述研究表明，有机纳米粒子PEG-MNP具备标记单质长半衰期核素的能力，并可用于肿瘤模型PET显像，为其进一步构建长循环多模态成像探针提供实验依据.     

靶向髓过氧化酶的双模态探针分子的合成与表征

5-羟色胺(5-HT)对动脉粥样硬化斑块中巨噬细胞分泌的髓过氧化酶(MPO)具有靶向功能,通过酯化反应将5-HT接枝到两亲型聚合物聚衣康酸接枝聚乙二醇接枝十二胺(PIA-g-PEG-g-DDA)上,制备了具有靶向功能的两亲型聚合物(5-HT-g-PIA-g-PEG-g-DDA).采用配体交换法,将超顺磁性氧化铁纳米粒子(SPION)包覆在该聚合物上制备具有磁性的纳米粒子(5-HT-g-PIA-g-PEG-g-DDA@SPION),通过静电力结合使其与碳点(CDs)结合,制备具有荧光成像和核磁造影成像的双模态探针的纳米粒子.采用动态光散射(DLS)及透射电子显微镜(TEM)分析了其粒径和形貌.采用荧光光谱仪与振动样品磁强计(VSM)测试证明该纳米粒子具备双模态成像功能.共聚焦成像(CLSM)的测试结果表明,该纳米试剂对动脉粥样硬化斑块中的巨噬细胞具有靶向性,MTT法的测试结果表明该探针分子具有良好的生物相容性.该双模态探针具有靶向性好、分辨率高及使用便捷的特点,是一种性能优异的双模态检测纳米试剂.     

一种caspase-3靶向激活型PET分子探针的制备与表征

诱导肿瘤细胞凋亡是多种肿瘤治疗方案的作用机制之一，因此检测肿瘤细胞是否产生凋亡已成为评价肿瘤治疗疗效的一种重要指标。以caspase-3为靶点设计凋亡靶向特异性探针，通过对其表达水平进行监测可以及时评估肿瘤疗效。本研究报道了一种靶向caspase-3的正电子发射断层显像(PET)探针[¹⁸F]8。采用简便的固相合成法和点击缩合法合成多肽和前体8,利用¹⁸F-¹⁹F氟离子交换法进行放射性核素氟-18标记，得到放射化学产率16%和放射化学纯度95%的探针[¹⁸F]8。探针[¹⁸F]8在PBS和小鼠血清中具有较好的稳定性，脂水分配系数Log P为-1.69±0.01,表明探针亲水性较好。高效的合成方法以及良好的理化性质为探针应用于肿瘤凋亡模型的PET成像研究奠定了良好的基础。     

叶酸受体介导的肿瘤靶向光学成像技术

叶酸受体(FR)在肿瘤细胞中都有过度表达,而在正常组织中保守表达,利用叶酸受体与叶酸及其类似物高亲合力结合的特性,将叶酸偶联荧光探针输送到肿瘤组织,从而实现肿瘤组织的特异性靶向光学成像。本文阐述了叶酸荧光探针的结构及其用于标记肿瘤细胞的作用机制,介绍了近十年来叶酸受体介导的肿瘤靶向光学成像技术,例如有机荧光染料,染料掺杂纳米颗粒,量子点,磁性纳米微粒以及多功能纳米粒子等在肿瘤靶向成像中的研究及应用进展,指出了当前研究中的主要发展方向和仍需解决的问题。     

羟基磷灰石负载放射性18F作为分子影像纳米探针在生物医学中的应用

采用简便有效的方法,制备了生物兼容性强、放射性标记羟基磷灰石(HAp)纳米粒子的正电子发射计算机断层显像(PET)纳米探针。在合成HAp纳米粒子的过程中,放射性的~(18)F作为掺杂剂,占据HAp晶格中羟基位置,在短时间内牢固地标记到HAp上。~(18)F不仅标记在纳米粒子的表面,而且还通过强的化学键标记在纳米颗粒的内部。以达到提高标记量并防止辐射泄漏的目的。设计的高标记量的放射性纳米探针应用于动物实验并靶向到达脏器器官。     

自组装多肽探针在磁共振成像中的应用

磁共振成像(MRI)是一种强大的非侵入式生物医学诊断技术. 临床上, MRI需要借助造影剂来提高成像质量, 从而提高诊断的准确性. 由于具有优越的信号放大能力和生物相容性, 自组装多肽探针可负载特定的MRI分子, 通过酶促自组装过程实现肿瘤靶向和特异性富集, 增强肿瘤病灶区MRI信号, 从而进一步提高MRI的准确性和灵敏度. 本综述总结了近年来多肽自组装探针在不同MRI模式( ¹H MRI, ¹⁹F MRI和双自旋核MRI)下的最新进展, 并展望了这类新型探针在MRI领域的应用前景.     

基于分子信标荧光纳米探针的李斯特菌DNA均相检测方法

基于分子信标(MB)识别和荧光纳米粒子探针技术,建立了均相体系中李斯特菌目标DNA的高灵敏检测新方法.首先以羊抗人免疫球蛋白(IgG)标记的异硫氰酸荧光素(FITC)为核材料,成功制备了FITC-IgG@SiO2核壳荧光纳米粒子,有效防止了传统方法中采用单一FITC制备纳米颗粒时泄露严重的问题.随后以FITC-IgG@SiO2荧光纳米粒子和纳米金分别标记单核细胞增生李斯特菌序列特异性分子信标探针5'端和3'端,成功构建了单核细胞增生李斯特菌序列特异性分子信标荧光纳米探针.在实验优化条件下,α(令α=F/F0,F代表MB和目标DNA杂交以后的荧光强度,F0代表MB完全闭合时的荧光强度)与目标DNA浓度在1～200pmol/L浓度范围内呈良好的线性关系,检出下限为0.3pmol/L,相对标准偏差为2.6%(50pmol/L,n=11).将该方法应用于食品样品中单核细胞增生李斯特菌的检测,结果与国标法一致.     

~(64)Cu-NOTA-Herceptin的设计、活性测定及肿瘤靶向分子显像研究

利用双功能螯合剂2-[(4-异硫氰基苯基)甲基]-1,4,7-三氮杂环九烷-1,4,7-三乙酸(NCS-Bz-NOTA)对Herceptin单抗表面的氨基进行修饰获得了NOTA-Herceptin,通过基质辅助激光解吸电离飞行时间质谱(MALDI-TOF)对该偶联物进行了表征.利用酶联免疫吸附测定了偶联前后Herceptin抗体效价的改变.利用新型正电子核素~(64)Cu标记,获得可用于肿瘤放射靶向精准诊疗的~(64)Cu-NOTA-Herceptin探针,其标记率为90%,放化纯度98%,比活度185 MBq/nmol.分别进行了该探针在HER2过表达胃癌细胞NCI-N87及HER2低表达胃癌细胞BGC823等肿瘤细胞中的摄取实验,测定了该探针的肿瘤特异性.建立了荷人胃癌BGC823裸鼠模型,通过微型正电子断层显像(Micro-PET)设备观察了探针在模型动物体内的代谢情况:在静脉注射7.4 MBq~(64)Cu-NOTA-Herceptin探针后,分别于4和60 h进行正电子断层显像(PET)的显像,观察到其在肿瘤部位的摄取有所富集,且随着代谢时间的延长,肝脏部位摄取得到明显降低.研究结果表明,~(64)Cu-NOTAHerceptin探针有望应用于肿瘤放射性靶向诊疗.     

Gd3+与RGD共修饰量子点用于胰腺癌细胞的荧光及MR双模态成像

结合磁共振成像(MRI)和荧光成像技术,以钆离子(Gd3+)、量子点及精氨酸(R)-甘氨酸(G)-天冬氨酸(D)(RGD)多肽等为功能单元,采用纳米载体组装技术构建了MRI弛豫率/荧光效率高和靶向性强的Gd3+与RGD共修饰的量子点双模态纳米探针(QDs@Gd3+-RGD),并将其用于胰腺癌细胞的双模态成像.实验结果表明,QDs@Gd3+-RGD双模态纳米探针具有较高的弛豫率,且能对胰腺癌patu8988细胞进行荧光和T1-weighted MR成像.     

二氧化碳和丙烯直接合成甲基丙烯酸的NiPMo/TiO2催化剂的研究

用溶胶-凝胶法以磷钼酸(MPA)的镍盐溶液水解钛酸四丁酯制备了NiPMo/TiO2催化剂.使用ICP、 XRD、 TG-DTA、 IR、 TPD-MS和微反应技术研究了催化剂的化学组成、热稳定性、化学吸附性质和催化反应性能.杂多钼酸盐与TiO2通过O2-在TiO2表面发生了键合.在623 K下,杂多阴离子仍保持原有的Keggin结构.CO2在Lewis酸位Ni(Ⅱ)和Lewis碱位Ni-O-Mo的桥氧协同作用下生成CO2卧式吸附态Ni(Ⅱ)←O-(CO)←(O--Ni).丙烯有多种吸附态在催化剂上吸附.在563 K、 1 MPa和空速1500 h-1的反应条件下,丙烯的摩尔转化率为3.2%,产物MAA选择性为95%.     

Synthesis of 1-benzyloxypyrazin-2(1H)-one derivatives

Different approaches for the synthesis of 1-benzyloxypyrazin-2(1H)-one derivatives from simple amino acids have been investigated. A library of 33 precursors for the preparation of N-hydroxy pyrazinones was obtained in moderate to good yields.     

Toward new camptothecins. Part 6: Synthesis of crucial ketones and their use in Friedländer reaction

In the context of the preparation of camptothecin and luotonin A analogs, the synthesis of some key keto-precursors and their use in Friedländer condensation are described. This paper also focuses on the stability of these keto intermediates and emphasizes the major differences between indolizinones and pyrroloquinazolinones series. Noteworthy is also the report of some original structures isolated as by-products of some experiments.     

CoFe2O4自形成磁性液体场致结构化对磁化的影响

The Langevin paramagnetic theory can’t describe the relation between magnetization of ferrofluids and applied magnetic field. The structuralization of ferrofluids, which is considered the main influence factor of the magnetization, is regarded. The part of magnetization works is deposited when the structure is forming. This action influences the magnetization of ferrofluids directly or indirectly. On the base of the “compressing” model, the Langevin function that usually describes the magnetization of ferrofluid is modified, and a well-fitted curve is obtained. An equation of the relation between the equivalent volume fraction after being “compressed” and the intensity of magnetic field is discovered, which approximately describes the process of magnetization. The relation between the approximate initial susceptibility and the volume fraction can be obtained from modified formula.     

Highly regioselective Buchwald–Hartwig amination at C-2 of 2,4-dichloropyridine enabling a novel approach to 2,4-bisanilinopyridine (BAPyd) libraries

The highly regioselective Buchwald–Hartwig amination at C-2 of the cheap and readily accessible reagent, 2,4-dichloropyridine with a range of anilines and heterocyclic amines is described. This new methodology is robust and provides a facile access to 4-chloro-N-phenylpyridin-2-amines on 0.25 mol scale. These intermediates undergo a further Buchwald–Hartwig amination at higher temperature to enable rapid exploration of the chemical space at C-4 and to provide a library of 2,4-bisaminopyridines.     

KMnO4-mediated oxidative CN bond cleavage of tertiary amines: Synthesis of amides and sulfonamides

KMnO₄-mediated oxidative CN bond cleavage of tertiary amines producing secondary amine was introduced, which was trapped by electrophiles (acyl chloride and sulfonyl chloride) to form amides and sulfonamides. The reaction could take place at mild condition, tolerating a wide range of function groups and affording products in moderate to excellent yields.     

Chemistry of heterocyclic compounds at the A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences, over 50 years (Review)

The review contains a concise historical account and information on the most significant researches undertaken by the staff at the A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences on the Chemistry of Heterocyclic Compounds. Dedicated to Academician of the Russian Academy of Sciences B. A. Trofimov on his 70th jubilee. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1443–1502, October, 2008.     

A general and convenient synthesis of 4-(tosylmethyl)semicarbazones and their use in amidoalkylation of hydrogen,heteroatom, and carbon nucleophiles

A general synthesis of previously unknown semicarbazone-based α-amidoalkylating reagents, 4-(tosylmethyl)semicarbazones, has been developed. The synthesis involved three-component condensation of semicarbazones of aliphatic or aromatic aldehydes with the same or other aldehydes and p-toluenesulfinic acid. The scope and limitations of this reaction were investigated. The compounds obtained were demonstrated to be an efficient α-(4-semicarbazono)alkylating agents. They were reacted with H- (sodium borohydride), O- (sodium methylate), S- (sodium phenylthiolate), N- (pyrrolidine, sodium succinimide), P- (trialkyl phosphites), and C-nucleophiles (sodium diethyl malonate) to give the corresponding products of the tosyl group substitution, 4-substituted semicarbazones, including analogues of nitrofurazone. Among the prepared compounds tested in vitro for antibacterial and antifungal activity, three nitrofuryl-containing semicarbazones exhibited high biological activities with minimum inhibitory concentration (MIC) values of 8–32 μg/mL.     

Sulfur-directed metal-free and regiospecific methyl C(sp3)–H imidation of thioanisoles

Regiospecific and direct imidation of the methyl C(sp³)–H bond of thioanisoles is realized under mild and metal-free conditions with N-fluorobis(benzenesulfonyl)imide as an oxidant and nitrogen source. Proposed mechanism suggests that thionium ion intermediates and a Pummerer-type reaction are involved. The imidation has advantages such as high step-economy, excellent functionality tolerance, and regiospecificity, giving structurally diverse imidation products.     

Synthesis of novel chiral bidentate hydroxyalkyl-N-heterocyclic carbene ligands and their application in palladium-catalyzed Mizoroki–Heck couplings and asymmetric addition of diethylzinc to benzaldehyde

A small library of new chiral bidentate hydroxyalkyl-imidazolium salts 1 is conveniently synthesized on multi-gram scale from inexpensive and commercially available chiral pool amino acids. The corresponding carbenes, generated by deprotonation of imidazolium salts 1, in combination with palladium(II) chloride were tested in the Mizoroki–Heck coupling reaction. The most significant results in terms of yields and reactivities were achieved with low catalyst loading. The catalytic activities of these imidazolium salts were also investigated in the asymmetric addition of diethylzinc to benzaldehyde. The use of MgO nanoparticles as an additive in conjunction with these ligands played a crucial role in increasing the efficiency of these reactions.