抗肿瘤药物在金属有机骨架中的装载及体外释放

以三乙胺直接加入法制备金属-有机骨架MOF-5, 采用X射线粉末衍射(XRD), 红外光谱(IR)和热重分析(TG)对所得样品进行表征. 分别以辣椒素和5-氟尿嘧啶(5-Fluouourail, 5-FU)为模型药物, 研究了MOF-5对2种药物的载药及体外释药性能. 通过将所得样品的XRD和IR谱图与标准谱图比对确定了样品的结构. TG结果表明, 所制备的MOF-5热稳定性良好. MOF-5对辣椒素的最高载入量达0.592 g/g载体, 对5-FU的最高载入量为0.315 g/g载体, 两种载药体系的体外释药均为明显的两相模式. 体外细胞毒性实验结果表明, MOF-5具有良好的生物相容性.     

乳酸-磷酸酯共聚物为载体的高分子药物的合成及其控释研究

以5-氟尿嘧啶(5-FU)为药物模型,以乳酸-磷酸酯共聚物为高分子药物载体,合成了侧链带药的乳酸-磷酸酯共聚物药物。用¹HNMR、IR、UV谱对其结构进行了表征。测定高分子药物中5-FU的含量,研究了高分子药物的体外释药性能及共聚物组成对释药性能的影响。     

葡萄糖响应苯硼酸接枝壳聚糖盐酸盐抗肿瘤药物载体

通过分子改性向壳聚糖盐酸盐高分子链中引入苯硼酸基,合成了双亲性化合物苯硼酸接枝壳聚糖盐酸盐.细胞毒性实验表明苯硼酸接枝壳聚糖盐酸盐具有良好的细胞相容性.该双亲性化合物能够自组装成胶束聚集体,并包封疏水药物.以阿霉素为模型药物,研究了载药胶束聚集体的体外药物释放行为,结果表明,阿霉素在载药胶束聚集体内能够持续释放,且具有葡萄糖响应性.在生理p H=7.4和固体肿瘤弱酸性(p H=6.5)条件下,药物的释放速度十分缓慢,而当释放介质中有葡萄糖存在时,药物释放速度都明显加快.     

功能化纳米粒子作为药物载体的研究

将合成的含有羧基侧基官能团的己内酯类聚合物, 用溶剂挥发与超声乳化相结合的方法制备成表面可供修饰的纳米粒子. 利用扫描电镜(SEM)研究了纳米粒子在水溶液中的形态. 使用5-氟脲嘧啶(5-FU)作为模型药物制备了载药纳米粒子, 利用紫外分光光度计法、差示扫描量热法(DSC)、X射线衍射法(XRD)研究了纳米粒子的载药及释放性能. 研究表明, 载药纳米粒子可以控制5-FU的释放速率. 释放时间可持续至96 h 以上, 符合Higuchi 动力学方程.     

纳米孔硅灰石载药抗菌止血材料的研究

采用溶胶-凝胶法,以聚氧乙烯-聚氧丙烯-聚氧乙烯三嵌段共聚物(P₁₂₃)为模板剂,合成了纳米孔硅灰石(np-WT),用np-WT载盐酸万古霉素研制了一种新型的载药抗菌止血材料,并对其止血性能进行了研究。结果表明：np-WT具有排列有序的纳米孔道结构,其孔径在2 nm左右,高比表面积的np-WT能够明显地缩短体外部分凝血活酶时间(APTT)和凝血酶原时间(PT)。载药np-WT能够在磷酸缓冲溶液(PBS)中缓慢地释放药物,载药np-WT对其凝血性能没有明显的影响。载药np-WT对大肠杆菌有很好的抗菌作用,细胞毒性实验表明：载药np-WT无细胞毒性。载药np-WT具有很好的止血性能,能够阻止兔背部伤口的流血和缩短其流血时间。     

荧光介孔二氧化硅纳米粒子的合成及药物运输（英文）

合成了荧光介孔二氧化硅纳米粒子(MSNs-FITC),并研究了其在持续药物释放和生物示踪成像方面的应用。首先,采用一步法合成出MSNs-FITC,结合SEM、TEM、FT-IR、XRD和氮气吸附脱附等表征技术进行表征。其次,将抗癌药物阿霉素(DOX)负载到MSNs-FITC中。载药粒子的药物释放行为具有明显的pH依赖性,酸性环境加速释放速率。同时,体外细胞毒性测试表明MSNs-FITC具有良好的生物相容性。激光共聚焦扫描显微镜(CLSM)图像表明,MSNs-FITC可以进入细胞并具有剂量依赖性,流式细胞术分析(FCM)进一步证明了这一结果。     

聚乳酸-乙醇酸/纳米氧化锌复合电纺纤维装载亲疏水药物的控释及体外细胞毒性

利用静电纺丝技术制备了负载亲水性药物阿霉素(DOX)以及疏水性药物喜树碱(CPT)的复合纳米纤维. 先用巯基封端的普朗尼克(F127)修饰纳米氧化锌(FZnO), 再将FZnO负载盐酸阿霉素(DOX@FZnO), 最后将DOX@FZnO与CPT一起纺入聚乳酸-乙醇酸(PLGA)纤维中. 体外药物释放结果表明, 复合纳米纤维能够减小亲水性药物的突释, 减缓药物释放速率, 延长药物释放时间. 体外细胞活性结果表明, 双载药复合纤维比单载药复合纤维具有更强的细胞毒性, 能够有效抑制癌细胞生长.     

基于碳点多功能纳米载药体系的制备及pH响应释药性能研究

采用一步微波法成功制备了表面带氨基的荧光纳米碳点CDots, 并通过酰胺化反应将靶向基团叶酸接枝到碳点表面, 成功获得中间产物CDots-FA. 在此基础上, 通过已合成四臂端酰肼基化合物2与抗肿瘤药物阿霉素(DOX)连接, 实现在碳点表面的阿霉素药物分子的化学键合, 最终获得多功能纳米载药体系DOX-CDots-FA. 利用原子力显微镜(AFM)、高分辨透射电镜(HR-TEM)和荧光光谱仪对荧光纳米碳点CDots的性能进行表征, 并通过核磁共振、紫外-可见吸收光谱对DOX-CDots-FA结构、接枝率进行了表征. 同时对纳米载药体系DOX-CDots-FA体外药物释放行为、细胞毒性及细胞摄取成像进行了系统的研究. 结果表明, DOX-CDots-FA具有良好的pH响应性. 叶酸靶向基团能加速DOX-CDots-FA被HeLa (FR+)细胞摄取, 并表现出更强的细胞毒性. 同时细胞摄入成像实验表明, 在叶酸靶向作用下, DOX-CDots-FA通过内吞作用进入HeLa细胞, 随后阿霉素被释放出来并进入细胞核区域, 抑制细胞的生长, 从而实现靶向治疗, 降低毒副作用.     

新型2-取代氨基-5-(N-异丙基-9H-咔唑-2-基)-1,3,4-噻二唑类衍生物的合成及抗肿瘤活性

以N-异丙基-9H-咔唑为起始原料,经取代、氧化、环合、酰化4步反应合成了7个新型2-取代氨基-5-(N-异丙基-9H-咔唑-2-基)-1,3,4-噻二唑类化合物(1a～1g),其结构经~1H NMR,~(13)C NMR, MS(ESI)和元素分析表征。采用MTT法测定了1a～1g对5种肿瘤细胞的体外抗增殖活性。结果表明:1a～1g对人正常VEC细胞的抑制活性弱于5-FU。1d和1e对人白血病细胞(K562)和人结肠癌细胞(HCT-8),1e对人肺癌细胞(A549细胞),以及1g对人结肠癌细胞(HCT-8)的抑制活性(IC_(50)≤9.28μmol·L~(-1))均与5-FU相当。     

5-氟尿嘧啶的三元环类化合物的缀合物的合成及其抗肿瘤活性

基于具有三元环状结构的化合物的广泛生理活性和氟尿嘧啶的抗癌作用机制,本文设计、合成并表征了一系列新型5-氟尿嘧啶（5-FU）的三元碳环缀合物及三元氧杂环缀合物。并对5-FU 的N-1和N-3位的选择性烷基化方法进行了系统研究,发现苄氧甲酰氧甲基保护基具有稳定性高、有效保护性好、制备方便、易于脱除等特点,适宜于在本类反应中应用。测试了所合成的新型5-FU三元环缀合物的体外抗肿瘤活性,化合物7、8、12、13显示了对人食管癌细胞Ec9706不同程度的抑制活性。     

Pharmaceutical Applications of Ionic Liquids: A Personal Account

Ionic liquids (ILs) have been extensively used in drug formulation and delivery as designer solvents and other components because of their inherent tunability and useful physicochemical and biopharmaceutical properties. ILs can be used to manage some of the operational and functional challenges of drug delivery, including drug solubility, permeability, formulation instability, and in vivo systemic toxicity, that are associated with conventional organic solvents/agents. Furthermore, ILs have been recognized as potential solvents to address the polymorphism, limited solubility, poor permeability, instability, and low bioavailability of crystalline drugs. In this account, we discuss the technological progress and strategies toward designing biocompatible ILs and explore potential biomedical applications, namely the solubilization of small and macromolecular drugs, the creation of active pharmaceutical ingredients, and the delivery of pharmaceuticals.     

Insight into the Inhibition of Drug‐Resistant Mutants of the Receptor Tyrosine Kinase EGFR

Targeting acquired drug resistance represents the major challenge in the treatment of EGFR‐driven non‐small‐cell lung cancer (NSCLC). Herein, we describe the structure‐based design, synthesis, and biological evaluation of a novel class of covalent EGFR inhibitors that exhibit excellent inhibition of EGFR‐mutant drug‐resistant cells. Protein X‐ray crystallography combined with detailed kinetic studies led to a deeper understanding of the mode of inhibition of EGFR‐T790M and provided insight into the key principles for effective inhibition of the recently discovered tertiary mutation at EGFR‐C797S.     

Hybrid Drugs—A Strategy for Overcoming Anticancer Drug Resistance?

Despite enormous progress in the treatment of many malignancies, the development of cancer resistance is still an important reason for cancer chemotherapy failure. Increasing knowledge of cancers’ molecular complexity and mechanisms of their resistance to anticancer drugs, as well as extensive clinical experience, indicate that an effective fight against cancer requires a multidimensional approach. Multi-target chemotherapy may be achieved using drugs combination, co-delivery of medicines, or designing hybrid drugs. Hybrid drugs simultaneously targeting many points of signaling networks and various structures within a cancer cell have been extensively explored in recent years. The single hybrid agent can modulate multiple targets involved in cancer cell proliferation, possesses a simpler pharmacokinetic profile to reduce the possibility of drug interactions occurrence, and facilitates the process of drug development. Moreover, a single medication is expected to enhance patient compliance due to a less complicated treatment regimen, as well as a diminished number of adverse reactions and toxicity in comparison to a combination of drugs. As a consequence, many efforts have been made to design hybrid molecules of different chemical structures and functions as a means to circumvent drug resistance. The enormous number of studies in this field encouraged us to review the available literature and present selected research results highlighting the possible role of hybrid drugs in overcoming cancer drug resistance.     

Recent Aspects of Pharmaceutical Application of Cyclodextrins

Because of the multi-functional characteristics and bioadaptability, cyclodextrin (CyD) is capable of alleviating the undesirable properties of drug molecules through the formation of inclusion complexes. This paper outlines the current application of natural and chemically modified CyDs in the various pharmaceutical formulations including peptide and protein drugs. Furthermore, potential use of CyD/drug conjugates in site-specific drug delivery is discussed.     

胆汁酸为载体的肝靶向一氧化氮释放药物的设计与合成

新型肝靶向一氧化氮释放药物对许多肝脏疾病具有较好的治疗作用. 以胆酸和熊去氧胆酸作为药物的载体, 以氨基酸作为联接子, 以氨基酸的α羧基模拟胆酸或熊去氧胆酸分子24位羧基的负电性, 最大限度地保持胆酸或熊去氧胆酸的结构特征, 通过酰胺键将载体与一氧化氮供体硝酸酯偶联, 设计并合成了一系列新型肝靶向一氧化氮释放偶合物, 其结构经元素分析, IR, 1H NMR和MS光谱分析确证. 利用四氯化碳及对乙酰氨基酚所致小鼠急性肝损伤模型研究化合物对小鼠急性肝损伤的修复作用.     

Surface-modulated and thermoresponsive polyphosphoesternanoparticles for enhanced intracellular drug delivery

The chemical structure of end groups influenced the phase transition temperature of thermoresponsive polymers. We demonstrated a strategy for the preparation of the pH/thermo-responsive polymeric nanoparticles via subtle modification of end groups of thermoresponsive polymer segments with a carboxyl group and revealed its potential application for enhanced intracellular drug delivery. By developing a polymeric nanoparticle composed of poly(aliphatic ester) as the inner core and thermoresponsive polyphosphoester as the outer shell, we showed that end groups of thermoresponsive polyphosphoester segments modified by carboxyl groups exhibited a pH/thermo-responsive behavior due to the hydrophilic to hydrophobic transitions of the end groups in response to the pH. Moreover, by encapsulating doxorubicin into the hydrophobic core of such pH/thermo-responsive polymer nanoparticles, their intracellular delivery and cytotoxicity to wild-type and drug-resistant tumor cells were significantly enhanced through the phase-transition-dependent drug release that was triggered by endosomal/lysosomal pH. This novel strategy and the multi-responsive polymer nanoparticles achieved by the subtle chain-terminal modification of thermoresponsive polymers provide a smart platform for biomedical applications.     

Four‐fold Channel‐Nicked Human Ferritin Nanocages for Active Drug Loading and pH‐Responsive Drug Release

Human ferritins are emerging platforms for non‐toxic protein‐based drug delivery, owing to their intrinsic or acquirable targeting abilities to cancer cells and hollow cage structures for drug loading. However, reliable strategies for high‐level drug encapsulation within ferritin cavities and prompt cellular drug release are still lacking. Ferritin nanocages were developed with partially opened hydrophobic channels, which provide stable routes for spontaneous and highly accumulated loading of Fe^II‐conjugated drugs as well as pH‐responsive rapid drug release at endoplasmic pH. Multiple cancer‐related compounds, such as doxorubicin, curcumin, and quercetin, were actively and heavily loaded onto the prepared nicked ferritin. Drugs on these minimally modified ferritins were effectively delivered inside cancer cells with high toxicity.     

氘代AZD9291的合成

吲哚和2,4-二氯嘧啶经偶联反应制得3-(2-氯嘧啶-4-基)-1H-吲哚(1); 1与CD₃I 经取代反应制得3-(2-氯嘧啶-4-基)-1-(甲基-d₃)-吲哚(2); 2经两步亲核取代反应制得N′-(2-二甲基氨基乙基)-2-甲氧基-N′-甲基-N-{［4-(1-(甲基-d₃)吲哚-3-基)］嘧啶-2-基}-5-硝基苯-1,4-二胺(4); 4经还原反应后,与氯丙酰氯发生缩合反应合成了氘代AZD9291,总收率8.5%,其结构经¹H NMR, ¹³C NMR和ESI-MS表征。     

The Selectivity for Tumor Cells of Nuclear-Directed Cytotoxic RNases Is Mediated by the Nuclear/Cytoplasmic Distribution of p27KIP1

Although single targeted anti-cancer drugs are envisaged as safer treatments because they do not affect normal cells, cancer is a very complex disease to be eradicated with a single targeted drug. Alternatively, multi-targeted drugs may be more effective and the tumor cells may be less prone to develop drug resistance although these drugs may be less specific for cancer cells. We have previously developed a new strategy to endow human pancreatic ribonuclease with antitumor action by introducing in its sequence a non-classical nuclear localization signal. These engineered proteins cleave multiple species of nuclear RNA promoting apoptosis of tumor cells. Interestingly, these enzymes, on ovarian cancer cells, affect the expression of multiple genes implicated in metabolic and signaling pathways that are critic for the development of cancer. Since most of these targeted pathways are not highly relevant for non-proliferating cells, we envisioned the possibility that nuclear directed-ribonucleases were specific for tumor cells. Here, we show that these enzymes are much more cytotoxic for tumor cells in vitro. Although the mechanism of selectivity of NLSPE5 is not fully understood, herein we show that p27^KIP1 displays an important role on the higher resistance of non-tumor cells to these ribonucleases.