姜黄素前药的研究进展

近年来,天然产物姜黄素因其显著的抗肿瘤等多种生物活性引起广泛关注.然而姜黄素水溶性差、化学结构不稳定、生物利用度低,限制了其在临床上的进一步应用.用小分子或大分子载体对姜黄素的酚羟基进行修饰制备得到的姜黄素前药能较好地解决姜黄素上述的缺点,也是改善姜黄素成药性的有效策略.综述了近年来国内外姜黄素前药的研究进展.     

石墨烯纳米载药体系的制备及对肿瘤细胞的杀伤作用

通过聚乙二醇(PEG)及分支型聚乙烯亚胺(bPEI)对纳米氧化石墨烯(NGO)修饰作为大分子载药基底的载药平台,增加了NGO的水溶性及其对蛋白的吸附作用,随后分别负载抗癌药物顺铂(CDDP)和低温乙醇法分离提纯的肿瘤患者血清形成能够特异性富集于鼻咽癌细胞的大分子石墨烯纳米载药体系。通过紫外-可见光谱和傅里叶变换红外光谱表征结果证实NGO-PEG-bPEI-CDDP载药体系制备成功,NGO-PEG-bPEI对CDDP的载药率为34.6%。聚丙烯酰胺凝胶电泳(SDS-PAGE)表明对NGO-PEG-bPEI-CDDP-Antibody大分子纳米载药体系中特异性抗体蛋白的强烈吸附作用,该纳米复合物能够特异性地富集在肿瘤细胞部位,对人鼻咽癌细胞(CNE-1)细胞系的识别极其敏感。细胞毒性实验(MTT)检测实验结果表明:在相同剂量(质量浓度)、相同作用时间的情况下,NGO-PEG-bPEI-CDDP-Antibody大分子纳米石墨烯载药体系兼具对人口腔鳞癌细胞(KB)、CNE-1杀伤作用和避免正常细胞的额外损伤。NGO-PEG-bPEI-CDDP-Antibody纳米载药体系不仅能够通过特异性识别将药物富集于病灶区降低正常细胞损害,还能够有效杀伤癌细胞,降低化疗药物使用剂量,是一种很有前景的大分子纳米载药体系。     

壳聚糖基载药纳米微粒制备研究进展

有关可生物降解多糖类纳米微粒用作给药载体的研究，近年颇受重视。简要评述了壳聚糖基载药纳米微粒的制备方法，包括共价交联、离子诱导、沉淀析出、大分子复合和自组装方法及其研究进展。     

大分子引发剂用于合成嵌段液晶共聚物的新进展

前有多种制备嵌段液晶共聚物的方法，采用大分子引发剂合成嵌段液晶共聚物，方法简单且易于实施，越来越受到人们的青睐。综述了由大分子引发剂合成嵌段液晶共聚物方面取得的新进展。     

肽类树枝状大分子:自组装胶束及药物释放研究

本文以三代聚谷氨酸肽类树枝状分子(G3-Glu)为大分子引发剂,引发N-羧基-L-苯丙氨酸-环内酸酐(NCA-Phe)的开环聚合反应,制备聚谷氨酸树枝状大分子-聚苯丙氨酸嵌段共聚物.嵌段共聚物通过自组装形成以聚苯丙氨酸链段为核,聚谷氨酸树枝状大分子为壳的胶束.将抗肿瘤药物阿霉素负载到高分子胶束中,研究其药物释放性能及体外抗肿瘤效果.结果表明,共聚物胶束具有良好的生物相容性.载药胶束具有药物缓释效果,药物持续释放时间可达60h.载药胶束的体外抗肿瘤实验表明其对肝癌细胞HepG2具有很好的杀灭效果,共培养48h后对癌细胞的杀死率可高达75%.     

水凝胶纳米粒及其在生物医药领域的应用

作为环境响应性和纳米控释给药系统，水凝胶纳米粒主要用于毒副作用大、生物半衰期短、易被生物酶降解的多肽类、蛋白质等生物大分子药物的给药，在生物医药领域具有越来越广阔的应用前景。本文主要综述了水凝胶纳米粒的分类、制备方法及其在生物医药领域的应用。     

立体选择活性自由基聚合进展

尽管人工大分子的合成已经取得了长足发展,特别是在多种活性自由基聚合技术出现后,合成大分子的分子量和拓扑结构得到了良好控制,但如果以结构精确、高度功能化的生物大分子为模型来看,就会发现人工大分子的完全裁制合成仍是一个重大挑战。本文首先简述了合成大分子与生物大分子的结构差异,以及合成大分子在活性聚合领域和立体选择聚合领域各自已经取得的进展,在此基础上,专门介绍了近年来同时对合成大分子的分子量、立体结构和区域规整性进行控制的尝试,特别是在立体选择活性自由基聚合领域的进展。     

生物相容性分离介质在样品前处理中的应用

生物样品基体复杂,蛋白质等生物大分子的干扰给样品前处理带来很大的困难.近年来,生物相容性分离介质在样品前处理中的应用特别引人注目.本文综述了生物相容性分离介质及其在固相萃取、固相微萃取、微透析样品前处理中应用的进展.     

(聚酰胺-胺)-水杨醛席夫碱树枝状大分子钯配合物的合成、表征及催化性能

首先通过发散法合成出1.0G～5.0G聚酰胺-胺树枝状大分子PAMAM;然后利用氨基与醛的脱水缩合反应,用水杨醛对大分子进行修饰合成出(聚酰胺-胺)-水杨醛席夫碱树枝状大分子配体PAMAMSA;再通过PAMAMSA与氯钯酸锂在甲醇中反应制得一系列钯配合物PAMAMSA-Pd.用红外光谱、核磁共振谱、热重-差热法对所合成的材料结构组成进行了表征与确证.研究了在纯水介质中PAMAMSA-Pd作为催化剂前躯体对碘代苯及其衍生物与丙烯酸Heck交叉偶联反应的催化性能,并比较了钯配合物和PdCl2的催化活性,结果表明树枝状大分子催化剂显示出良好的催化活性,其中1.0G PAMAMSA-Pd和5.0G PAMAMSA-Pd的活性较高.     

水溶性大分子调控碳酸钙结晶的研究进展

结合本课题组的工作综述了水溶性大分子调控碳酸钙合成的研究进展.通过分析生物大分子、合成大分子以及大分子/表面活性剂混合体系对碳酸钙结晶习性的影响,讨论了水溶性大分子对碳酸钙形貌和晶型的调控机理.大分子调控碳酸钙合成的研究不仅为人们制备不同形貌、尺寸和晶型的碳酸钙开拓了思路,也为满足不同的工业需求提供了理论指导.     

含丙磺舒高分子药物的合成与表征

非甾体抗炎药丙磺舒以酯键连接到甲基丙烯酸2-羟乙酯上得含丙磺舒单体HP，HP在偶氮二异丁腈引发下均聚、与甲基丙烯酸甲酯共聚合成了含丙磺舒的高分子药物，产物结构经IR，1HNMR和GPC表征。     

Synthesis and structural analysis of polyester prodrugs of norfloxacin

Two-, three- and four-arm, star-shaped poly(epsilon-caprolactone) and poly(D,L-lactide) homopolymers, and copolymers of epsilon-caprolactone with D,L-lactide were synthesized via ring-opening polymerization of cyclic esters in the presence of glycerol, penthaerythritol and poly(ethylene glycol) as initiators and stannous octoate as a catalyst. Thus obtained oligomers were successfully used in the synthesis of novel macromolecular prodrugs of norfloxacin. The structures of the polymers and prodrugs were elucidated by means of MALDI-TOF MS, NMR and IR studies.     

Macromolecular Pt(IV) Prodrugs from Poly(organo)phosphazenes

The preparation of novel macromolecular prodrugs via the conjugation of two platinum(IV) complexes to suitably functionalized poly(organo)phosphazenes is presented. The inorganic/organic polymers provide carriers with controlled dimensions due to the use of living cationic polymerization and allow the preparation of conjugates with excellent aqueous solubility but long‐term hydrolytic degradability. The macromolecular Pt(IV) prodrugs are designed to undergo intracellular reduction and simultaneous release from the macromolecular carrier to present the active Pt(II) drug derivatives. In vitro investigations show a significantly enhanced intracellular uptake of Pt for the macromolecular prodrugs when compared to small molecule Pt complexes, which is also reflected in an increase in cytotoxicity. Interestingly, drug‐resistant sublines also show a significantly smaller resistance against the conjugates compared to clinically established platinum drugs, indicating that an alternative uptake route of the Pt(IV) conjugates might also be able to overcome acquired resistance against Pt(II) drugs. In vivo studies of a selected conjugate show improved tumor shrinkage compared to the respective Pt(IV) complex.

     

Hydroxypropylcellulose-aceclofenac conjugates: high covalent loading design, structure characterization, nano-assemblies and thermal kinetics

This article presents synthesis of novel macromolecular prodrugs of aceclofenac (an anti-inflammatory drug) onto hydroxypropylcellulose (HPC). The HPC-aceclofenac conjugates were prepared using an acylating agent 1,1′-carbonyldiimidazole (CDI) under homogenous reaction conditions. Aceclofenac was first activated by using CDI to form its N-acylimidazole. The N-acylimidazole of aceclofenac was then reacted with HPC polymer at 80 °C for 24 h. Highly pure prodrugs of aceclofenac were synthesized with a wide range of moderate to high degree of substitution (DS 0.41–2.12) as calculated by ¹H NMR spectroscopy. The UV spectroscopic analysis has also revealed that the active drug aceclofenac was found in different conjugates from 28 to 67 mg/100 mg of HPC-aceclofenac conjugates which are in good agreement with DS calculated by ¹H NMR spectroscopy. The gel permeation chromatography showed unimodal absorption that indicates no significant degradation in polymer chains during the reaction. The macromolecular prodrugs of aceclofenac were characterized using different spectroscopic and chromatographic techniques. The thermal analysis has revealed that HPC-aceclofenac conjugates (prodrugs) are 92 and 96 °C more stable than pure aceclofenac regarding their initial (Tdi) and maximum degradation temperatures (Tdm), respectively. The activation energy (Ea) and frequency factor (Z) of the degradation reactions were evaluated using Friedman, Broido and Chang methods. Degradation followed first order (n) kinetics. Transmission electron microscopy has revealed the formation of sponge like nano aggregates with population size distribution of around 80–150 nm.     

Polymeric prodrugs of mitomycin C

Poly-[N-(2-hydroxyethyl)-L-glutamine] (PHEG) prodrugs of the cytotoxic agent Mitomycin C were synthesized using peptidyl spacers to link the drug to the polymeric carrier. The influence on the length and detailed structure of the oligopeptide on the rate of drug release was investigated in buffer, in the presence of lysosomal enzymes (tritosomes, cathepsin B and D) and metalloprotease type IV collagenase. It was observed that tetra- and hexapeptide based conjugates generally release Mitomycin C (MMC) more effectively than tripeptide derivatives. The gly-phe-ala-leu conjugate released MMC very rapidly both in presence of lysosomal enzymes and collagenase IV. Only in the presence of the aspartic protease cathepsin D, the gly-phe-leu-gly-phe-leu derivative turned out to be a better substrate. In vivo studies against C26 solid tumour bearing mice suggest that PHEG-spacer-MMC conjugates act as prodrugs of MMC: antitumour efficacy of the macromolecular prodrugs was better than free MMC both in inhibition of tumour growth and increasing survival.     

Macromolecular prodrugs. V. Simultaneous determination of high-molecular-weight dextran metronidazole monosuccinate ester prodrugs and the hydrolysis products metronidazole and the corresponding monosuccinate ester on nucleosil diol

A high-performance size-exclusion chromatography procedure using Nucleosil Diol has been developed which provides the simultaneous determination of macromolecular dextran metronidazole monosuccinate ester prodrugs and the hydrolysis products metronidazole and metronidazole monosuccinate. Various factors influencing the chromatographic behaviour of the compounds are discussed. Baseline separation of the three substances was achieved within 8 min by using a 0.05 M phosphate buffer pH 7.5 eluent at a flow-rate of 2 ml min-1. The detection limit at 320 nm for a conjugate with a degree of substitution of 4.61 was found to be 3.5 micrograms ml-1.     

Design,characterization and enhanced bioavailability of hydroxypropylcellulose-naproxen conjugates

Polysaccharides are beneficially used as drug carriers via prodrug formation and offer a mechanism for better effectiveness and delivery of the drug. The unique geometry of hydroxypropylcellulose (HPC), a polysaccharide, allows the attachment of drug molecules with a higher degree of substitution because the hydroxyls groups are projected outside the HPC chains. Therefore HPC-Naproxen conjugates, i.e., macromolecular prodrugs, were synthesized using a powerful acylation reagent carbonyldiimadazole (CDI) in N,N' dimethylacetamide (DMAc) solvent. The reactions were carried out at 80 °C under stirring for 24 h and inert environment. This reaction strategy appeared efficient to obtain a high degree of drug substitution (DS = 0.88–1.40) on the polymer parent chain as calculated by UV–visible spectrophotometry after hydrolysis of the samples. The method provides high efficacy as product yields were high (77–81%). Macromolecular prodrugs (MPDs) with different DS of naproxen designed were found soluble in organic solvents.     

丙磺舒药物键合两亲共聚物的制备

丙磺舒药物键合两亲共聚物的制备;丙磺舒; 两亲共聚物; 高分子药物     

Synthese de polymeres a proprietes pharmacologiques. Introduction de sequences peptidiques au sein de la chaine macromoleculaire

The introduction of peptidic sequences into polymers with pharmacological properties may increase the biocompatibility of the macromolecular prodrug. The synthesis of polypeptides from N-carboxyanhydrides bearing the active principles defines this objective. The l-lysine blocked as copper complex reacts with steroidic chloroformates (cholesterol-testosterone). After deblocking of the complex and treatment by phosgene, the corresponding N-carboxyanhydrides are obtained. Polymerization and copolymerization (with glycine N-carboxyanhydride) give oligopeptides bearing steroidic backbone as side-group. The low molecular weight of the synthesized compounds, the limited water solubility and the presence of secondary products limit the development of the method. Pharmacological tests are being undertaken to study delayed effects due to slow release of the steroid, to compare the biocompatibility of such prodrugs.     

Synthesis of macromolecular prodrugs of procaine, histamine and isoniazid

The attachment of various drugs bearing -NH2 groups to poly-alpha,beta-aspartic acid as a biodegradable carrier afforded in good yields macromolecular prodrugs which were characterized with respect to composition and drug load by spectroscopic and analytical methods. N-Ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) in an aqueous medium proved to be useful in the attachment reaction. Isoniazid, procaine and histamine were covalently coupled as pendant groups onto poly-alpha,beta-aspartic acid via an amide bond. In principle, controlled release of the aforementioned drugs can be achieved by biodegradation of the polymer or by cleavage of covalently bound polymer-drug conjugates.