新型亲核NO供体Diazeniumdiolate及其靶向性控释材料

新型亲核NO供体diazeniumdiolate独特的化学结构和性质,使其成为目前NO供体研究的一个热点.要使其成为更有效的药物,它的靶向性和控释性能是当前研究的重点,减小亲核试剂(多胺)的细胞毒性和亚硝胺的生成是研究的难点.本文对增强靶向性释放所采取的三个措施(聚合物控释、特定酶代谢释放和光降解释放)的近十几年国外的研究情况进行了综述.     

基于介孔二氧化硅纳米颗粒的可控释放体系

基于介孔二氧化硅的控制释放体系具有良好的生物相容性、细胞靶向性、精准响应性控制释放和到达目标位点前有效阻止药物释放等功能特性。近年来,基于介孔二氧化硅的可控释放体系已成为众多科研工作者研究的热点。本文讨论了基于介孔二氧化硅纳米颗粒可控释放体系的特点,同时以不同的响应特性为主线,系统分析和总结了各种响应性介孔二氧化硅控释体系的开关及其控制释放机制,包括氧化还原控释系统、光控释系统、pH控释系统及生物分子相关控释系统等一系列基于介孔二氧化硅的控释系统,并对该领域未来的发展方向作了展望。     

可释放一氧化氮聚合物材料的制备及其在生物医疗器械中的应用

一氧化氮（NO）是一种很好的血小板黏附或活化的抑制剂，同时也是很有效的抗平滑肌细胞增生剂。可释放NO的聚合物材料显示出较好的抗血栓形成及抑制细胞增生的性能。本文综述了可释放NO聚合物材料的制备方法及其近年来在生物医疗器械中的应用。用来制备可释放NO聚合物材料的NO供体主要有两大类，一类是亲核NO供体N-diazeniumdiolates，另一类是S-亚硝基硫醇（RENOs）。制备可释放NO聚合物材料的方法主要有3种：（1）通过物理掺杂的方式将小分子的NO供体分散到聚合物材料中；（2）对聚合物材料的填料微粒进行化学改性，得到可释放NO的填料粒子，再将其填充到聚合物材料中；（3）通过共价键将可释放NO的基团连接到聚合物主链及侧链上。所得到的可释放NO聚合物材料在血管内传感器、体外血液循环电路和体内移植血管等生物医疗器械中有广泛的应用。     

磁性铁氧化物纳米粒子在药剂学上的应用

磁性铁氧化物纳米粒子（MIONPs）是近几十年发展起来的一种具有磁靶向性的纳米材料,其以良好的磁靶向性、小尺寸效应、生物相容性在生物医学领域具有很好的应用前景,尤其在药剂学领域的应用已经成为一个重要的研究热点。本文在总结近年来国内外有关多功能磁性铁氧化物纳米粒子研究成果的基础上,阐述了各种铁氧化物纳米粒子在药剂学领域的应用,主要是：MIONPs的智能载药靶向控释,MIONPs对特殊药物的靶向负载,MIONPs降低身体的多药耐药性（Multidrug resistance, MDR）,MIONPs加强药物治疗     

介孔硅纳米储存器在智能药物释放系统的应用

开发新型细胞微环境刺激响应性智能药物控释系统是目前材料学、药理学与临床医学研究的共同热点之一,其目的在于寻求合适的药物载体,提高药物的安全性、有效性及降低药物毒副作用。本文综述了介孔硅功能复合纳米材料在生物医药领域的应用研究进展;通过对其进行特定的化学修饰、生物修饰、物理修饰,不仅能特异性细胞识别靶向,还能针对病变细胞实现药物定点、定时、定量的“生物爆破”释放;这在药物可控释放、靶向癌症治疗、靶向基因递送等领域展示了其广阔的应用前景。同时,本文还系统地分析和总结了各种智能响应性介孔硅纳米储存器的制备方法和响应机制,包括“无机纳米塞-介孔硅”纳米智能控释系统、“有机大分子控制器-介孔硅”智能功能复合型控释系统、“分子开关控制器-介孔硅”自响应性纳米控释系统等,这为设计新型响应性介孔硅纳米储存器系统提供了借鉴与思路。     

一种两亲生物降解高分子-聚丙交酯-聚乙二醇嵌段共聚物的研究进展

PLA-PEG良好的生物相容和降解性能在生物医学领域受到了广泛关注，对其性能和应用已经有了深入的研究。就PLA-PEG这一类两亲生物降解高分子的合成、性能作一简介，并对其在组织工程，药物控释以及靶向载体等方面的应用和前景作一综述和展望。     

可控释放一氧化碳的纳米材料及其生物医学应用

一氧化碳（CO）是一种内源性气体信使分子,具有广泛而复杂的生理学功能.CO分子的生理学效应与其浓度、位置和作用时间密切相关.而现有的一氧化碳供体普遍存在着稳定性较差,剂量难以把控,缺乏靶向性以及对正常细胞和组织器官具有潜在的毒副作用等问题,限制了其进一步的应用.随着纳米科学技术的迅速发展,国内外研究者们构建出一系列能够实现可控释放CO的多功能纳米材料,并将其用于生物医学领域.结合纳米材料自身独特的性能优势,分类介绍了多种内源性/外源性刺激响应型CO控释纳米材料,并概述了可控释放CO的纳米药物在抑制炎症反应、抗菌和肿瘤治疗等生物医学领域的应用,最后对CO控释纳米材料在生物医学领域面临的挑战和发展前景进行了总结和讨论.     

聚乳酸组织工程支架材料

综述了生物活性因子固定化的聚乳酸-聚氨基酸衍生物共聚物和通过亲-疏水性设计的众多聚乳酸-聚氧化乙烯（PLA-PEO）共聚物的研究进展。展现了其在组织工程材料,药物控释体系和其他生物医用材料中的广泛应用前景。     

基于透明质酸构筑的药物递送载体及其应用

传统纳米药物控释载体主要通过细胞胞吞作用实现药物递送,其主要过程为被动靶向机制,因此会影响纳米载体在肿瘤组织的富集和治疗效果。近年来生物大分子透明质酸因其优异的水溶性、生物相容性、可降解性和肿瘤靶向性备受科研工作者青睐,已被广泛用于药物控释载体的构筑中,并成为靶向肿瘤治疗纳米载体领域的研究热点。本文根据透明质酸基纳米载体治疗机制的不同,从透明质酸基纳米载体在化疗、光热治疗、光动力治疗以及联合治疗的应用方面对其性能进行了总结和评述,并在此基础上展望了未来透明质酸基纳米治疗载体的研究方向和发展趋势。     

两亲聚合物胶束自组装包药研究进展

两亲聚合物胶束具有突出的理化性能和独特功能,能够在溶液中自组形成具有核壳结构的聚合物胶束,同时实现药物的负载。自组装包药技术能够缓解我国药物辅料缺乏的现状,符合目前药物辅料发展的新趋势。通过自组装形成的聚合物胶束在药物控释、药物靶向载体、药物制剂开发、新型药物辅料等方面具有广阔的应用前景。本文综述了两亲聚合物胶束自组装包载药物的原理以及方法,重点介绍了三类两亲聚合物在自组装包药方面的最新研究成果和发展趋势。本文还对载药胶束在药物释放方面的应用进行了概述。     

2-Hydroxy-5-nitrobenzyl as a diazeniumdiolate protecting group: application in NO-releasing polymers with enhanced biocompatibility

The 2-hydroxy-5-nitrobenzyl group is shown to be an effective protecting group for diazeniumdiolates. O(2)-(2-hydroxy-5-nitrobenzyl)-substituted diazeniumdiolates display enhanced thermal stability, but efficiently release nitric oxide (NO) in pH 7.4 aqueous solutions. A lipophilic analogue incorporated into hydrophobic polymers shows NO surface flux rates comparable to that of the natural endothelium. Importantly, these polymer formulations also show significantly enhanced biocompatibility in vivo with use of a porcine implant model.     

Bis-diazeniumdiolates of dialkyldiamines: enhanced nitric oxide loading of parent diamines

[reaction: see text] The synthesis and characterization of a series of symmetric bis-dialkyldiamine-based diazeniumdiolates, RN[N(O)NO(-)Na(+)](CH(2))(x)()N[N(O)NO(-)Na(+)]R', are reported. Preparation of corresponding intramolecular diazeniumdiolates of the form RN[N(O)NO](-)(CH(2))(x)()NH(2)(+)R' with alkyl groups > (CH(2))(4)CH(3) have been shown previously to lack stability. In contrast, sodium-stabilized bis-diazeniumdiolates of such lipophilic species can be readily formed when these same diamines are reacted with NO in basic media. The resulting compounds release 4 mol of NO per mole of original diamine. This approach enables the synthesis of more lipophilic NO donors than previously possible.     

Reaction of nitric oxide at the beta-carbon of enamines. A new method of preparing compounds containing the diazeniumdiolate functional group

The reaction of nitric oxide (NO) with enamines has been investigated. Unlike previously reported reactions of NO as a free radical with alkenes, the electrophilic addition of NO to the beta-carbon of enamines results in the formation of compounds containing the diazeniumdiolate functional group (-[N(O)NO](-)). This reaction between NO and enamines has been shown to be quite general and a variety of enamine-derived diazeniumdiolates have been isolated and characterized. While enamines derived from aldehydes and ketones whose structures allow for sequential multiple electrophilic additions tended to undergo overreaction leading to unstable products, it has been shown that this complication may be overcome by suitable choice of reaction solvent. The products obtained may exist as zwitterionic iminium salts or as neutral species depending upon the structure of the parent enamine. The diazeniumdiolate derived from 1-(N-morpholino)cyclohexene is unique among the new compounds in that it spontaneously releases NO upon dissolution in buffered aqueous solution at pH 7.4 and 37 degrees C. While the total quantity of NO released by this material (ca. 7% of the theoretical 2 moles) is apparently limited by a competing reaction in which it hydrolyzes to an alpha-diazeniumdiolated carbonyl compound and the parent amine, this feature may prove to be of great value in the development of multiaction pharmaceuticals based upon this new type of NO-releasing compound. Reports of enzymatic (oxidative) release of NO from previously known carbon-bound diazeniumdiolates also suggest that analogues of these compounds may be useful as pharmaceutical agents. This new method of introducing the relatively rarely studied diazeniumdiolate functional group into organic compounds should lead to further research into its chemical and biological properties.     

可释放一氧化氮纳米材料的研究进展

一氧化氮(NO)是一种内源性双原子分子,在许多生理学和病理学过程中起了关键的调节作用,包括血管平滑肌松弛、免疫反应、神经传递、呼吸作用、细胞凋亡等。NO的生理调节作用在很大程度上依赖于NO释放的位置、时间以及剂量。开发出能够储存NO并且在指定的地点和时间释放需求量的NO的纳米运输平台是非常重要的研究课题。此篇综述,主要介绍近期我们课题组和其他研究人员在NO控制释放以及生物学应用的研究进展。本文首先概述了几类具有应用前景的外源性NO供体,如偶氮二醇烯、亚硝基硫醇、硝基苯和金属亚硝酰化合物。然后,重点讨论了结合NO供体和纳米平台在控制释放NO和生物医学的潜在应用。     

Controlled photochemical release of nitric oxide from O2-benzyl-substituted diazeniumdiolates

An investigation of potential photosensitive protecting groups for diazeniumdiolates (R2N-N(O)=NO-) has been initiated, and here the effect of meta electron-donating groups on the photochemistry of O2-benzyl-substituted diazeniumdiolates (R2N-N(O)=NOCH2Ar) is reported. Photolysis of the parent benzyl derivative (Ar = Ph) results almost exclusively in undesired photochemistry-the formation of nitrosamine and an oxynitrene intermediate with very little, if any, photorelease of the diazeniumdiolate. We have been able to use meta substitution to tune the photochemistry of these benzylic systems. The desired diazeniumdiolate photorelease has been shown to become more substantial with stronger pi-donating meta substituents. This effect has been verified by direct observation of the photoreleased diazeniumdiolate with 1H NMR spectroscopy and by NO quantification measurements conducted in high- and low-pH solutions. In addition, the observed rates of NO release are consistent with that expected for normal thermal decomposition of the diazeniumdiolate in aqueous solutions and also show the same pH dependence.     

Dendrimers as a scaffold for nitric oxide release

The preparation and characterization of nitric oxide (NO)-releasing dendrimer conjugates are reported. Generation 3 and 5 polypropylenimine dendrimers (DAB-Am-16 and DAB-Am-64) were modified at the exterior to impart different amine functionalities. The ability to store NO on a dendritic scaffold using N-diazeniumdiolate NO donors was examined via the reaction of primary amine, secondary amine, and amide functionalities with high pressures of NO (5 atm). The secondary amine dendrimer conjugates exhibited a high storage capacity for NO (up to 5.6 micromol NO/mg), greatly increasing the "payload" of released NO over existing macromolecular NO donors. The mechanism of diazeniumdiolate decomposition was proton initiated, generating NO spontaneously under physiological conditions (pH 7.4, 37 degrees C). The NO release durations (>16 h) observed for the secondary amine dendrimers were significantly longer compared to small molecule alkyl secondary amine diazeniumdiolates, thus illustrating a dendritic effect on NO release kinetics. The multivalent exterior of dendrimers allows for the future combination of NO donors and other functionalities on a single molecular scaffold, enabling diverse utility as NO storage/delivery systems.     

Chemistry of the diazeniumdiolates. 2. Kinetics and mechanism of dissociation to nitric oxide in aqueous solution

Diazeniumdiolate ions of structure R(2)N[N(O)NO](-) (1) are of pharmacological interest because they spontaneously generate the natural bioregulatory species, nitric oxide (NO), when dissolved in aqueous media. Here we report the kinetic details for four representative reactivity patterns: (a) straightforward dissociation of the otherwise unfunctionalized diethylamine derivative 2 (anion 1, where R = Et) to diethylamine and NO; (b) results for the zwitterionic piperazin-1-yl analogue 4, for which the protonation state of the neighboring basic amine site is an important determinant of dissociation rate; (c) data for 5, a diazeniumdiolate derived from the polyamine spermine, whose complex rate equation can include terms for a variety of medium effects; and (d) the outcome for triamine 6 (R = CH(2)CH(2)NH(3)(+)), the most stable structure 1 ion identified to date. All of these dissociations are acid-catalyzed, with equilibrium protonation of the substrate preceding release of NO. Specific rate constants and pK(a) values for 2-6 have been determined from pH/rate profiles. Additionally, a hypsochromic shift (from approximately 250 to approximately 230 nm) was observed on acidifying these ions, allowing determination of a separate pK(a) for each substrate. For 6, the pK(a) value obtained kinetically was 2-3 pK(a) units higher than the value obtained from the spectral shift. Comparison of the ultraviolet spectra for 6 at various pH values with those for O- and N-alkylated diazeniumdiolates suggests that protonation at the R(2)N nitrogen initiates dissociation to NO at physiological pH, with a second protonation (at oxygen) accounting for both the spectral change and the enhanced dissociation rate at pH <4. Our results help to explain the previously noted variability in dissociation rate of 5, whose half-life we found to increase by an order of magnitude when its concentration was raised from near-zero to 1 mM, and provide mechanistic insight into the factors that govern dissociation rates among diazeniumdiolates of importance as pharmacologic progenitors of NO.     

Preparation and reactivity of O2-sulfonated diazeniumdiolates

We report the facile preparation of O2-sulfonated diazeniumdiolates and mechanistic investigation of their reactions with representative nucleophiles. This new class of compounds extends the range of O2-substituted diazeniumdiolates available for potential applications in research and medicine.     

O2-(N-hydroxy(methoxy)-2-ethanesulfonamido) protected diazen-1-ium-1,2-diolates: nitric oxide release via a base-induced β-elimination cleavage

O(2)-(Ethanesulfohydroxamic acid) and O(2)-(N-methoxy-2-ethanesulfonylamido) diazen-1-ium-1,2-diolates (4-7), a novel type of O(2)-(protected) diazeniumdiolate, were synthesized using a key thioacetate oxidation reaction. Nitric oxide release studies showed that O(2)-(N-methoxy-2-ethanesulfonylamido) diazeniumdiolates 5 and 7 released NO in a nonphysiological alkaline buffer, in the presence of bases such as the basic natural amino acids Arg and His, or the non-nucleophilic organic base DBU in PBS at pH 7.4, via a β-elimination cleavage reaction.     

The secondary amine/nitric oxide complex ion R(2)N[N(O)NO](-) as nucleophile and leaving group in S9N)Ar reactions

Ions of structure R(2)N[N(O)NO](-) and their alkylation products have seen increasing use as nitric oxide (NO)-generating agents for biomedical research applications. Here we show that such diazeniumdiolate anions can readily displace halide from a variety of electrophilic aza- or nitroaromatic substrates to form O(2)-arylated derivatives of structure R(2)N-N(O)=N-OAr. The site of arylation and the cis arrangement of the oxygens were confirmed by X-ray crystallography. Displacement by various nucleophiles showed R(2)N[N(O)NO](-) to be a reasonably good leaving group, with rate constants for displacement by hydroxide, methoxide, and isopropylamine that were between those of chloride and fluoride in the S(N)Ar reactions we surveyed. The Meisenheimer intermediate could be spectrally observed. These O(2)-aryl diazeniumdiolates proved capable of reacting with the nucleophilic sulfur of the HIV-1 p7 nucleocapsid protein's zinc finger assembly to eject the zinc, disrupting a structural motif critical to viral replication and suggesting possible utility in the drug discovery realm.