智能纳米水凝胶的刺激响应性研究进展

智能纳米水凝胶在药物输送与可控释放、医学诊断、生物传感器、微反应器、催化剂载体等方面有良好的应用前景。结合本课题组近年来的研究成果,分别介绍了具有温度刺激响应性、pH刺激响应性、光刺激响应性、磁场刺激响应性、分子识别刺激响应性和多重刺激响应性智能纳米水凝胶的研究进展。另外,对这几种智能纳米水凝胶目前存在的问题和今后的发展方向提出了一些粗浅的看法。     

刺激响应型聚合物前药

前药(prodrug)是一类经过生物体内转化后才具有药理作用的化合物。与传统纳米药物输送系统相比具有载药率确定、稳定性高、爆释现象小等优点。但是,前药本身也面临着可控性,特异性释药不足而引起效果不佳等问题。因此,能够靶向病灶部位并能够针对病灶部位进行特异性释药的刺激敏感型前药受到广泛研究。本文以国内外学者及本课题组的研究成果为基础,以肿瘤部位特殊的生理环境为背景,综述了近年来pH敏感、温敏、氧化还原敏感、酶敏感等生物刺激响应型抗肿瘤聚合物前药的研究进展。     

刺激响应型生物医用聚合物纳米粒子研究进展

近十几年来, 纳米科学的发展极大地推动了纳米材料在生物医用领域的应用. 聚合物纳米粒子由于其独特的性能在药物传递、医学成像等医用领域备受关注. 其中, 刺激响应型聚合物纳米粒子是一类可以在外界信号刺激下(包括pH、温度、磁场、光等)发生结构、形状、性能改变的纳米粒子. 利用这种刺激响应性可调节纳米粒子的某种宏观行为, 故而刺激响应型聚合物纳米粒子也被称为智能纳米粒子. 因为其特有的“智能性”, 刺激响应型聚合物纳米粒子的研究已成为当前生物材料领域的研究热点. 本文综述了几类重要的生物医用刺激响应型聚合物纳米粒子, 侧重介绍双重及多重刺激响应型聚合物纳米粒子的制备及其生物医学应用.     

基于含苯硼酸聚合物的双响应性胶束

分别合成了苯硼酸修饰的嵌段聚合物聚乙二醇-b-聚(天冬氨酸-co-天冬酰氨基苯硼酸)[PEG-b-P(Asp-co-AspPBA)]和含有二硫键及多元二醇的小分子3,3'-二硫代二[1,2(S)-丙二醇](DTBPD). 以DTBPD为小分子交联剂, 通过二醇单元与苯硼酸之间的共价酯化作用, 诱导PEG-b-P(Asp-co-AspPBA)自组装形成以苯硼酸环酯为核、 PEG为壳的交联胶束. 利用核磁共振氢谱和激光光散射对胶束的结构进行了表征, 并分别测定了该胶束在葡萄糖和氧化-还原试剂二硫苏糖醇(DTT)刺激下的响应行为. 结果表明, DTBPD可与聚合物链上的苯硼酸形成苯硼酸环酯, 通过交联作用诱导聚合物形成胶束. 交联度不同时, 胶束对于外界刺激(葡萄糖和DTT的响应行为也不同: 随着DTT和葡萄糖浓度的增加, 交联度高的胶束只发生响应性溶胀, 交联度低的胶束则先溶胀, 之后溶胀程度较大的部分胶束则发生解体, 导致胶束的平均粒径减小.     

双刺激响应型纳米载药系统的构建及性能

采用聚乙二醇单甲醚(mPEG)为亲水段,聚赖氨酸(PzLL)为疏水段,通过二硫键和碳氮双键串联桥连合成了两嵌段共聚物(mPEG-CN-SS-PzLL),其中的二硫键具有还原敏感性,碳氮双键具有pH酸敏感性。通过红外光谱和核磁共振谱等手段测试分析了产物的化学结构。将聚合物通过透析法自组装制备得到双刺激响应型纳米载药粒子。结果表明:该纳米载药粒子的药物包封率较高,达到52%。该载药系统在还原环境或酸性环境下具有良好的体外释药性能。     

刺激响应性电纺纳米纤维

采用静电纺丝法制备的、平均直径通常小于1000 nm的刺激响应性电纺纳米纤维是一种可响应外界刺激而发生物理化学性能改变的智能聚合物纤维,由它形成的纤维膜具有比表面积大、孔隙率高、对外界刺激产生响应速度快等优点,因此在诸多领域显示出诱人的应用前景,是近年来受到国内外高度关注的一种智能纳米材料。本文首先归纳了制备刺激响应性电纺纳米纤维的三种方法。然后从成纤聚合物的合成或选用、纺丝液配制、静电纺丝和后处理4个方面讨论了制备过程中影响纳米纤维尺寸、结构和刺激响应性等性能的主要因素。接下来重点述评了除电场外的其他各种刺激响应性电纺纳米纤维的设计及其构建研究进展,另外介绍了这些刺激响应性电纺纳米纤维膜在分离与纯化、药物控制释放、伤口敷料、细胞培养、传感器与检测等方面的应用研究情况。最后,就它们的未来研究方向进行了展望。     

活性氧刺激响应纳米载体

纳米载体一般是由天然高分子或人工合成高分子组成的、纳米级范畴的运输系统,具有减少药物毒性、提高药物的靶向性、增加药物有效性等优点。随着生物医学技术的进步,有研究表明,作为氧化代谢产物的活性氧(ROS)在疾病部位常常伴随着过表达的异常现象。基于此,近年来ROS刺激响应纳米载体获得了关注和发展,以不同响应机制的ROS响应基团为基础,发展了一系列的ROS响应纳米载体,实现了疾病部位ROS刺激下的药物特异性可控释放。该文聚焦于近年来常用于纳米载体的ROS响应基团,依据元素划分为两大类:硫族元素类响应基团(硫醚、缩硫酮、硒化物、二硒化物、碲化物)和其他元素类响应基团(芳香硼酸酯、过氧草酸酯、二茂铁);通过不同的设计理念将其引入纳米载体,根据ROS响应纳米载体的不同响应机制(疏水-亲水相变、断裂),探讨了载体各自的ROS响应情况、体外药物释放情况,以及在活体中的应用情况。     

刺激响应聚合物在金纳米粒子催化体系中的应用

刺激响应聚合物是近几年来研究的热点之一,这类聚合物能够感受外界刺激而发生响应,产生物理或化学性质的变化。金纳米粒子由于量子效应,具有良好的催化性质,因此有广阔的应用前景。但是在实际的应用中却常常面临易于团聚的问题,因此时常需要将其负载于载体之上。将刺激响应聚合物引入金纳米粒子催化体系之中,一方面可以发挥普通载体所能起到的分散作用,防止金纳米粒子团聚,另一方面也可实现可控催化,可以通过外界条件的改变来调控金纳米粒子的催化性能。本文综述了该体系近期的研究进展,从体系的构建方式、刺激响应类型等方面进行了论述,并对该体系的研究与应用进行了总结与展望。     

温度响应性单分子聚合物胶束

单分子聚合物胶束和传统的胶束一样具有核-壳结构,因其结构固定并具有良好的热力学稳定性而越来越受到研究者的关注。当这类胶束的核层或者壳层含有温敏性高分子的时候就可以形成具有温度响应性的单分子聚合物胶束。近年来,人们在温敏性的单分子聚合物胶束的合成与性能研究方面做了大量的工作。本文概述了具有温度响应行为的单分子聚合物胶束的类型、制备方法以及应用等方面取得的新进展,同时结合本实验室的工作,总结了基于超支化大分子的温敏性单分子聚合物胶束的相转变行为研究,并对这类胶束体系的发展进行了展望。     

刺激响应型聚合物刷的研究进展

本文综述了刺激响应型聚合物刷的研究进展,阐述了刺激响应型聚合物刷的分类、与基体表面的连接方式以及常规制备方法,介绍了离子强度、温度、pH值、光、溶剂等刺激响应型聚合物刷及其研究现状,并对相应的刺激响应机理进行了探讨。此外,本文还综述了多重刺激响应型聚合物刷的制备设计思路及其刺激响应特性,概述了聚合物刷在响应外界刺激后对基体的弯曲作用以及利用该作用进行可控三维自组装,并对刺激响应型聚合物刷的应用前景进行了展望。     

Recent advances in stimuli-responsive degradable block copolymer micelles: synthesis and controlled drug delivery applications

(Bio)degradation in response to external stimuli (stimuli-responsive degradation, SRD) is a desired property in constructing novel nanostructured materials. For polymer-based multifunctional drug delivery applications, the degradation enables fast and controlled release of encapsulated therapeutic drugs from delivery vehicles in targeted cells. It also ensures the clearance of the empty device after drugs are delivered to the body. This review summarizes recent development of various strategies to the design and synthesis of self-assembled micellar aggregates based on novel amphiphilic block copolymers having different numbers of stimuli-responsive cleavable elements at various locations. These cleavable linkages including disulfide, acid-labile, and photo-cleavable linkages are incorporated into micelles, and then are cleaved in response to cellular triggers such as reductive reaction, light, and low acid. The well-designed SRD micelles have been explored as controlled/enhanced delivery vehicles of drugs and genes. For future design and development of effective stimuli-responsive degradable micelles toward tumor-targeting delivery applications in vivo, a high degree of control over degradation for tunable release of encapsulated anticancer drugs as well as bioconjugation for active tumor-targeting is required.     

Rapidly disassembling nanomicelles with disulfide-linked PEG shells for glutathione-mediated intracellular drug delivery

The synthesis and biological efficacy of novel nanomicelles that rapidly disassemble and release their encapsulated payload intracellularly under tumor-relevant glutathione (GSH) levels are reported. The unique design includes a PEG-sheddable shell and poly(ε-benzyloxycarbonyl-l-lysine) core with a redox-sensitive disulfide linkage.     

Recent advances in targeted stimuli-responsive nano-based drug delivery systems combating atherosclerosis

Atherosclerosis(AS), mainly caused by the changed immune system functions and inflammation, is the central pathogenesis of cardiovascular disease, which is a leading cause of death in the world. In modern medicine, the development of carriers precisely delivering the therapeutic agents to the target sites is the primary goal, which could minimize the potential adverse effects and be more effective in treating lesions. Due to the precise location, real-time monitoring, AS microenvironment respons...     

Ultrasonically controlled polymeric drug delivery

The area of polymeric controlled drug delivery systems has been a field of increasing interest. However, relatively little attention has been given to developing systems in which the rate of delivery can be manipulated externally. We now report that release rates of biologically active substances from a polymeric matrix can be repeatedly modulated from a position external to the environment of use by ultrasonic energy. The ultrasound affects the degradation rate of bioerodible polymers as well as permeation through non-erodible polymers. The system has been shown to be responsive in vivo. Skin histopathology of the ultrasound treated area didn't reveal any differences between the treated skin and the untreated controls.     

pH-responsive lyotropic liquid crystals for controlled drug delivery

We present a food-grade lyotropic liquid crystal system, capable of responding to pH variations with a reversible switch in both the structure and physical properties. The system, which is composed by monolinolein and linoleic acid (97:3 wt % ratio) in the presence of excess water at 37 °C and 150 mM ionic strength, is specifically designed to reversibly change from a Im3m reverse bicontinuous cubic phase to a H(II) reverse columnar hexagonal phase, when changing the pH from neutral (pH 7) to acidic (pH 2) conditions, to simulate intestine and stomach conditions, respectively. The pH responsiveness is provided by the linoleic acid, which, being a weak acid (pK(a) ≈ 5), is essentially in the deprotonated charged state at pH 7 and mainly protonated and neutral at pH 2, imposing changes in the critical packing parameter (CPP) of the lyotropic liquid crystal. The use of this system as an efficient controlled-release delivery vehicle is demonstrated on the model hydrophilic drug phloroglucinol, by both release and diffusion studies at different pH, as followed by ultraviolet-visible (UV-vis) spectroscopy. The Im3m cubic phase at pH 7 is shown to release 4 times faster than the H(II) phase at pH 2, making this system an ideal candidate for oral administration of drugs for targeted delivery in intestine or colon tracts.     

DNA origami nanostructures for controlled therapeutic drug delivery

DNA nanostructures are emerging as a versatile platform for controlled drug delivery as a result of recent progress in production yield and strategies to obtain prolonged stability in biological environments. The construction of nanostructures from this unique biomaterial provides unparalleled control over structural and functional parameters. Recent applications of DNA origami-based nanocarriers for therapeutic drug delivery in preclinical phases highlight them as promising alternatives to conventional nanomaterials, as they benefit from the inherent favorable properties of DNA including biocompatibility and precise spatial addressability. By incorporating targeting aptamers and responsive properties into the nanocarrier design, more selective DNA origami-based nanocarriers are successfully prepared. On the other hand, current systems remain poorly understood in terms of biodistribution, final fate, and controlled drug release. As such, advances are needed to translate this material platform in its full potential for therapeutic applications.     

Functionalized mesoporous silica materials for controlled drug delivery

In the past decade, non-invasive and biocompatible mesoporous silica materials as efficient drug delivery systems have attracted special attention. Great progress in structure control and functionalization (magnetism and luminescence) design has been achieved for biotechnological and biomedical applications. This review highlights the most recent research progress on silica-based controlled drug delivery systems, including: (i) pure mesoporous silica sustained-release systems, (ii) magnetism and/or luminescence functionalized mesoporous silica systems which integrate targeting and tracking abilities of drug molecules, and (iii) stimuli-responsive controlled release systems which are able to respond to environmental changes, such as pH, redox potential, temperature, photoirradiation, and biomolecules. Although encouraging and potential developments have been achieved, design and mass production of novel multifunctional carriers, some practical biological application, such as biodistribution, the acute and chronic toxicities, long-term stability, circulation properties and targeting efficacy in vivo are still challenging.     

Subcutaneous hydrogel reservoir system for controlled drug delivery

Hydro Med Sciences has developed a subcutaneous reservoir hydrogel implant capable of long term delivery of predetermined doses of various active compounds. The implant is a small-diameter, thin-walled cylindrical capsule containing a therapeutic agent. The hydrogels used for this application were Hydron* type copolymers of 2-hydroxyethyl methacrylate (HEMA). These non-erodible hydrogels are known to be biocompatible, swell reversibly in an aqueous environment, resist biodegradation and do not support microbial growth.