多芳基取代咪唑的合成及其逆转多药耐药性研究

合成了一系列新的多芳基取代咪唑类化合物,其结构经元素分析、IR、¹HNMR和MS等确定,并采用MTT法测定了它们对由P-糖蛋白(P-gp)介导的肿瘤多药耐药性(MDR)的逆转效果.结果表明,化合物和具有很好的体外逆转MDR活性     

抗耐药性病原菌感染以及具有多药耐药逆转活性的天然产物研究进展

综述了近年来抗耐药性病原菌感染和具有多药耐药逆转活性的天然产物的研究进展,重点介绍了这类天然产物的结构特征、生理活性和部分化合物的全合成研究.     

纳米高分子材料在医用载体方面的应用

医用纳米高分子作为药物、基因传递和控释的载体,是一种新型的控释体系,它与微米粒子载体的主要区别是超微小体积,它能穿过组织间隙并被细胞吸收,可通过人体最小的毛细血管,还可通过血脑屏障,因而作为新的控释体系而被广泛研究,具有广阔的发展前景,重点论述了纳米高分子控释系统在药物和基因载体方面的最新研究进展,并对其发展前景提出了展望。     

DNA纳米结构在药物转运载体和智能载药中的应用进展

纳米材料具有荷载效率高、靶向性能好、半衰期较长等优点, 非常适于作为药物转运载体, 可有效提高药物的水溶性、稳定性和疾病治疗效果.目前, 开发具有良好生物相容性、可控靶向释放能力和精确载药位点的理想药物转运载体, 仍是该领域存在的挑战性问题和当前研究的重点.自组装DNA纳米结构是一类具有精确结构、功能多样的纳米生物材料, 具有良好的生物相容性和稳定性、较高的膜渗透性和可控靶向释放能力等优点, 是理想的药物转运载体和智能载药材料.本文总结了DNA纳米结构的发展历程、DNA纳米结构作为药物转运载体的研究现状、动态DNA纳米结构在智能载药中的应用进展, 并对其发展前景进行了展望.     

pH响应型纳米药物载体的释药机制及性能研究进展

pH响应型纳米载体因具有智能的酸敏或碱敏释药性能,已成为当前一类重要的多功能纳米载体,并得到了研究人员的广泛关注。特别是酸敏性纳米载体,可用于肿瘤弱酸微环境的药物控释,因而对药物的定点释放和癌症的靶向治疗等生物医学应用发挥了积极作用。本文综述了近年来各类pH响应型纳米载体的典型合成方法,系统地介绍了共价键、分子间作用力以及物理结构变化3种方式引发的pH响应释药机制。深入阐述了pH响应型纳米载体的载药性能、体外释药性能、体外细胞毒性、体内抗癌性能及体内分布性能,并详细列举了近年来pH响应型纳米载体的各类实验参数,进而为pH响应型纳米载体的深入研究提供了方法学的借鉴和性能参考。     

纳米药物载体结合分子靶向在肿瘤化疗中的应用

纳米技术与肿瘤治疗中的化学疗法相结合具有广阔的应用前景,应用纳米技术设计药物载体递送化疗药物已经成为当前人类攻克肿瘤研究的一个重要手段。纳米药物载体与肿瘤靶向在化疗方面的应用,能够有效改善化疗药物水溶性和稳定性,提高药物利用率和抗肿瘤活性,降低对机体正常细胞组织的毒副作用,克服多药耐药性问题,进而提高肿瘤化疗效果和促进肿瘤化疗的发展进步。本文着重综述纳米药物载体系统及其靶向策略方面的研究现状与进展,并探讨纳米技术与化疗相结合攻克肿瘤的应用前景。     

具有肿瘤多药耐药逆转作用的金雀异黄素衍生物的合成及生物活性研究

细胞膜P-糖蛋白(P-gp)介导的药物外流是肿瘤多药耐药(MDR)产生的重要机制,异黄酮类化合物可以通过抑制P-gp活性发挥MDR逆转作用.通过对P-gp抑制剂进行结构分析,以金雀异黄素为母体,在其7位、8位及4'位分别引进碱性边链,设计、合成了20个金雀异黄素衍生物(其中16个未见文献报道),并检测了其多药耐药逆转活性.结果表明,大多数目标化合物对人白血病耐药细胞株K562/A02具有不同程度的耐药逆转作用.其中目标化合物8a,8b,8d,8e逆转作用较强,逆转倍数分别为8.97,6.36,5.19和5.82.     

多聚赖氨酸淀粉纳米颗粒基因载体的研制及应用

以可溶性淀粉为原料, 利用反向微乳液法, 加入交联剂三氯氧磷, 制备了直径为50 nm左右带负电荷的交联淀粉纳米颗粒. 以该纳米颗粒为内核, 经多聚赖氨酸修饰, 得到了多聚赖氨酸淀粉纳米颗粒(PLL-StNP). 对PLL-StNP进行了颗粒粒度、稳定性和电性的表征, 并通过颗粒的体外细胞毒性检测、颗粒与DNA结合能力及细胞转染等方面的分析, 发现多聚赖氨酸淀粉纳米颗粒(PLL-StNP)有可能作为基因载体, 在此基础上发展了多聚赖氨酸淀粉纳米颗粒基因载体的构建与基因转染技术. 作为非病毒基因载体, 赖氨酸淀粉纳米颗粒具有基因装载量大、转染率高、细胞毒性低以及可生物降解等优点.     

微纳米粒子的形貌调控及其对药物/基因传递体系的影响

超分子组装体由于具有适合的微纳米尺寸、可控的结构和良好的生物相容性等特点,极大地促进了药物/基因传递体系的发展。拓扑结构(如形貌、尺寸)是影响药物/基因传递体系的重要因素,这方面研究正成为这一领域的研究热点。本文综述了调控组装体形貌的主要手段,包括聚合物链结构与组成、组装条件、外界刺激及聚合诱导的组装体形貌,初步探讨了微观形貌对药物/基因传递体系的影响,并对这一领域进行了展望。     

A pH‐Responsive Carrier System that Generates NO Bubbles to Trigger Drug Release and Reverse P‐Glycoprotein‐Mediated Multidrug Resistance

Multidrug resistance (MDR) resulting from the overexpression of drug transporters such as P‐glycoprotein (Pgp) increases the efflux of drugs and thereby limits the effectiveness of chemotherapy. To address this issue, this work develops an injectable hollow microsphere (HM) system that carries the anticancer agent irinotecan (CPT‐11) and a NO‐releasing donor (NONOate). Upon injection of this system into acidic tumor tissue, environmental protons infiltrate the shell of the HMs and react with their encapsulated NONOate to form NO bubbles that trigger localized drug release and serve as a Pgp‐mediated MDR reversal agent. The site‐specific drug release and the NO‐reduced Pgp‐mediated transport can cause the intracellular accumulation of the drug at a concentration that exceeds the cell‐killing threshold, eventually inducing its antitumor activity. These results reveal that this pH‐responsive HM carrier system provides a potentially effective method for treating cancers that develop MDR.     

Recent Advances in Understanding the Mechanisms of Elemene in Reversing Drug Resistance in Tumor Cells: A Review

Malignant tumors are life-threatening, and chemotherapy is one of the common treatment methods. However, there are often many factors that contribute to the failure of chemotherapy. The multidrug resistance of cancer cells during chemotherapy has been reported, since tumor cells’ sensitivity decreases over time. To overcome these problems, extensive studies have been conducted to reverse drug resistance in tumor cells. Elemene, an extract of the natural drug Curcuma wenyujin, has been found to reverse drug resistance and sensitize cancer cells to chemotherapy. Mechanisms by which elemene reverses tumor resistance include inhibiting the efflux of ATP binding cassette subfamily B member 1(ABCB1) transporter, reducing the transmission of exosomes, inducing apoptosis and autophagy, regulating the expression of key genes and proteins in various signaling pathways, blocking the cell cycle, inhibiting stemness, epithelial–mesenchymal transition, and so on. In this paper, the mechanisms of elemene’s reversal of drug resistance are comprehensively reviewed.     

Lamellarins as Inhibitors of P‐Glycoprotein‐Mediated Multidrug Resistance in a Human Colon Cancer Cell Line

Chemical analysis of a Didemnum sp. (CMB‐01656) collected during scientific Scuba operations off Wasp Island, New South Wales, yielded five new lamellarins A1 ( 1 ), A2 ( 2 ), A3 ( 3 ), A4 ( 4 ) and A5 ( 5 ) and eight known lamellarins C ( 6 ), E ( 7 ), K ( 8 ), M ( 9 ), S ( 10 ), T ( 11 ), X ( 12 ) and χ ( 13 ). Analysis of a second Didemnum sp. (CMB‐02127) collected during scientific trawling operations along the Northern Rottnest Shelf, Western Australia, yielded the new lamellarin A6 ( 14 ) and two known lamellarins G ( 15 ) and Z ( 16 ). Structures were assigned to 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 on the basis of detailed spectroscopic analysis with comparison to literature data and authentic samples. Access to this unique library of natural lamellarins ( 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ) provided a rare opportunity for structure–activity relationship (SAR) investigations, probing interactions between lamellarins and the ABC transporter efflux pump P‐glycoprotein (P‐gp) with a view to reversing multidrug resistance in a human colon cancer cell line (SW620 Ad300). These SAR studies, which were expanded to include the permethylated lamellarin derivative ( 17 ) and a series of lamellarin‐inspired synthetic coumarins ( 19 , 20 , 21 , 22 , 23 , 24 ) and isoquinolines ( 25 , 26 ), successfully revealed 17 as a promising new non‐cytotoxic P‐gp inhibitor pharmacophore.     

Chemical synthesis of bioactive siRNA in solution phase by using 2-(azidomethyl)benzoyl as 3′-hydroxyl group protecting group

A protecting group AZMB was introduced to ribonucleosides 3′-hydroxyl group to facilitate solution phase synthesis of siRNA. The protection and cleavage reaction were carried out in mild conditions, that is protection by acyl chloride and cleavage by triphenylphosphine. The synthesized siRNA showed good biological activity to suppress targeted superoxide dismutase gene expression.     

Self‐assembled Lipid Nanoparticles for Ratiometric Codelivery of Cisplatin and siRNA Targeting XPF to Combat Drug Resistance in Lung Cancer

DNA damage repair through the nucleotide excision repair (NER) pathway is one of the major reasons for the decreased antitumor efficacy of platinum‐based anticancer drugs that have been widely applied in the clinic. Inhibiting the intrinsic NER function may enhance the antitumor activity of cisplatin and conquer cisplatin resistance. Herein, we report the design, optimization, and application of a self‐assembled lipid nanoparticle (LNP) system to simultaneously deliver a cisplatin prodrug together with siRNA targeting endonuclease xeroderma pigmentosum group F (XPF), a crucial component in the NER pathway. The LNP is able to efficiently encapsulate both the platinum prodrug and siRNA molecules with a tuned ratio. Both platinum prodrug and XPF‐targeted siRNA are efficiently carried into cells and released; the former damages DNA and the latter specifically downregulates both mRNA and protein levels of XPF to potentiate the platinum drug, leading to enhanced expression levels of apoptosis markers and improved cytotoxicity in both cisplatin‐sensitive and ‐resistant human lung cancer cells. Our results demonstrate an effective approach to utilize a multi‐targeted nanoparticle system that can specifically silence an NER‐related gene to promote apoptosis induced by cisplatin, especially in cisplatin‐refractory tumors.     

Detection of Mutations in RNA Polymerase Beta Subunit Gene Encoding Resistance to Rifampin in Mycobacterium tuberculosis by DNA Microarray

Abstract

Rapid and efficient diagnosis is essential in the management of drug‐resistant tuberculosis. A DNA microarray technique based on differential hybridization method was described in the present study for detecting mutations in the RNA polymerase beta subunit (rpoB) gene of Mycobacterium tuberculosis (M. tuberculosis) cultures and in clinical specimens. The mutations in rpoB confer resistance to rifampin, an important first‐line antituberculosis drug. The differential hybridization approach was mainly based on the effect of a single base mismatch on the melting temperature of the hybridized DNA; therefore, any point mutation of rpoB gene resulting in the rifampin resistance can be detected efficiently. The development of the DNA microarray involves the design of dozens of oligonucleotide probes for identifying rifampin‐resistant and ‐sensitive strains. The method comprises isolating genomic DNA from the samples containing M. tuberculosis cells, amplifying rpoB gene coding sequence to produce fluorescently labelled product, and hybridization with the oligonucleotide arrays. The results demonstrated the capability of DNA microarray to provide important clinically relevant information about the rpoB gene of mycobacterial organisms. The DNA microarray offers a reliable diagnostic test for rapidly detecting multidrug resistance caused by gene mutations of mycobacteria.