刺激响应性聚合物载药纳米胶束研究进展

刺激响应性聚合物纳米胶束是目前药物控制释放体系的研究热点之一,其原理是将疏水性药物以物理或化学方法包覆在具有核/壳结构的纳米微球中,通过环境刺激响应控制药物的包覆与释放,可增加疏水性药物溶解度、提高药物利用率、降低药物毒副作用,具有显著的研究价值和应用前景.本文中我们主要介绍了不同类型刺激响应性聚合物纳米胶束在药物控制释放体系的研究进展.     

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.     

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。     

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。     

智能纳米容器对缓蚀剂酸/碱双刺激的响应释放性能

以聚苯乙烯(PS)微球为硬模板,制备中空介孔二氧化硅纳米微球(HMSs),通过在其表面安装双稳态准轮烷分子作为超分子纳米阀门,实现对缓蚀剂分子苯骈三氮唑(BTA)的酸/碱双刺激的响应释放功效.采用透射电子显微镜(TEM)、X射线衍射(XRD)和比表面积分析等手段表征了HMSs的形貌和结构,使用傅里叶红外光谱(FTIR)和热重分析(TGA)验证了HMSs表面功能化过程,利用紫外-可见分光光度计(UV-Vis)实时监测缓蚀剂分子在不同pH值下的释放过程.实验结果表明,合成的HMSs呈单分散,比表面积为1141.16 m2/g.利用超分子自组装技术制得的智能纳米容器实现了在中性条件下"零释放",而在酸性或碱性条件下大量释放的效果.     

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。     

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。     

还原响应型羧甲基纤维素基纳米药物载体的构建及其性能研究

近年来,刺激响应型智能纳米药物载体以其可控的药物释放、毒副作用小等优点,在药物递送领域引起广泛关注。本研究以羧甲基纤维素(CMC)为骨架材料,通过还原性二硫代二丙酰肼(TPH)连接疏水小分子胆酸(CA),合成两亲性高分子聚合物CMC-TPH-CA (CTC)。然后以10-羟基喜树碱(HCPT)为抗肿瘤模型药物,在水溶液中自组装制备CTC/HCPT纳米粒子,并对其物化性质及体外抗肿瘤活性进行了评价。结果表明,CTC/HCPT纳米粒子具有较高的包封率(～87.6%)及载药量(～21.4wt%),适当的粒径大小(～140nm)及低的溶血性(5%)。体外释放结果表明,CTC/HCPT纳米粒子具有明显的还原敏感性。最后,以LLC肿瘤细胞为模型,考察CTC/HCPT纳米粒子的体外细胞毒性。结果表明,相较于纯HCPT,CTC/HCPT纳米粒子的细胞杀伤作用有了明显的提升。     

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。     

刺激响应聚合物微针在经皮给药中的应用

聚合物微针自身具有良好的机械性能和优异的生物相容性,能以微创的方式刺穿皮肤角质层,实现药物的高效经皮吸收,从而有效治疗各种疾病,如糖尿病、癌症、肥胖以及眼部疾病等.如何调控聚合物微针中负载药物的释放行为,是微针经皮给药需要关注的核心要素.刺激响应释放聚合物微针作为一种新兴的按需给药技术,能根据外界环境条件或自身生理环境...     

基于肿瘤微环境响应的DNA纳米结构递药系统

DNA分子由于其独特的生物相容性和可编程性,在增强药物靶向性和降低药物毒性方面展现了独特的优势和巨大的潜力。随着人们对肿瘤微环境研究的深入和环境响应性的DNA触发器的研制,近些年已报道了许多基于肿瘤微环境响应的DNA纳米结构递药系统,这些DNA纳米结构递药系统结合了纳米运载工具良好的生物分布和药代动力学特性,以及小型药物载体的快速扩散和渗透特性。通过靶向广泛的肿瘤栖息地而不是肿瘤特异性受体,该策略有可能克服肿瘤异质性问题,并可用于设计诊断和治疗多种实体肿瘤的纳米颗粒。在体内能够稳定地转运,在肿瘤组织独特的微环境刺激下释放药物,能有效地控制药物释放部位和释放速度,极大地降低了肿瘤治疗的毒副作用。本文主要从pH响应型、GSH响应型、ATP响应型、酶响应型、抗原响应型五个方面,综述了基于肿瘤微环境响应的DNA纳米结构递药系统的最新研究进展,分类介绍了这些DNA纳米载体的设计策略和响应释放机制,此外,还重点介绍了该领域面临的前景和挑战。     

Stimuli-Responsive Polypeptide Nanoparticles for Enhanced DNA Delivery

The development of non-viral delivery systems for effective gene therapy is one of the current challenges in modern biomedicinal chemistry. In this paper, the synthesis of pH- and redox-responsive amphiphilic polypeptides for intracellular DNA delivery is reported and discussed. Two series of polypeptides consisting of L-lysine, L-phenylalanine, L-histidine, and L-cysteine as well as the same amino acids with L-glutamic acid were synthesized by a combination of copolymerization of N-carboxyanhydrides of α-amino acids and post-polymerization modification of the resulting copolymers. The presence of histidine provided pH-sensitive properties under weakly acidic conditions specific to endosomal pH. In turn, the presence of cysteine allowed for the formation of redox-responsive disulfide bonds, which stabilized the self-assembled nanoparticles in the extracellular environment but could degrade inside the cell. The formation of intraparticle disulfide bonds resulted in their compactization from 200–250 to 55–100 nm. Empty and pDNA-loaded cross-linked nanoparticles showed enhanced stability in various media compared to non-crosslinked nanoparticles. At the same time, the addition of glutathione promoted particle degradation and nucleic acid release. The delivery systems were able to retain their size and surface charge at polypeptide/pDNA ratios of 10 or higher. GFP expression in HEK 293 was induced by the delivery of pEGFP-N3 with the developed polypeptide nanoparticles. The maximal transfection efficacy (70%) was observed when the polypeptide/pDNA ratio was 100.     

Dual Stimuli-Responsive Self-Assembly Behavior of a Tailor-Made ABC-Type Amphiphilic Tri-Block Copolymer

This investigation describes the synthesis of a dual stimuli-responsive, amphiphilic ABC tri-block copolymer (BCP) based on the functional monomers via RAFT polymerization. In this case, ABC-type BCP was prepared based on N-isopropylacrylamide, n-butyl acrylate, and 4-vinylpyridine in DMF solvent using cyanomethyl dodecyl trithiocarbonate as the RAFT agent and azobisisobutyronitrile as a thermal initiator in a subsequent macro-RAFT approach, respectively. The BCPs were characterized by SEC, ¹H-NMR, FTIR spectroscopy, and DSC analyses. Temperature and pH-dependent properties of the smart BCP micelles in aqueous medium were investigated using dynamic light scattering. Transmission electron microscopic images were taken at cryogenic and dry conditions to study the morphology of molecular assemblies of block copolymers in an aqueous medium. The phase and topographical images were captured by atomic force microscopy to understand the assembly of block copolymers in solvents of different polarities. The morphology of BCP micelles was transformed from flower-like to spherical in the presence of solvents with different polarities (H₂O or CHCl₃).     

Dual Stimuli-Responsive Controlled Release Nanocarrier for Multidrug Resistance Cancer Therapy

Multidrug resistance of cancer cells is a major obstacle for cancer chemotherapy. Herein, we present a nanocarrier that can release chemotherapeutic agents to induce tumor cell death and generate NO under NIR to overcome multidrug resistance in cancer chemotherapy. Owing to the unique structure of the water channel in this controlled release system for chemotherapeutic agents, the nanocarrier surface is equipped with more active sites to graft NO donor molecules. The released NO performs very well in reversing multidrug resistance by inhibiting P-gp expression. Our findings provide new insight into multidrug resistance cancer therapy and controlled release nanocarriers for multiple drugs.     

Stimuli-Responsive Delivery of Antimicrobial Peptides Using Polyelectrolyte Complexes

Antimicrobial peptides (AMPs) are antibiotics with the potential to address antimicrobial resistance. However, their translation to the clinic is hampered by issues such as off-target toxicity and low stability in biological media. Stimuli-responsive delivery from polyelectrolyte complexes offers a simple avenue to address these limitations, wherein delivery is triggered by changes occurring during microbial infection. The review first provides an overview of pH-responsive delivery, which exploits the intrinsic pH-responsive nature of polyelectrolytes as a mechanism to deliver these antimicrobials. The examples included illustrate the challenges faced when developing these systems, in particular balancing antimicrobial efficacy and stability, and the potential of this approach to prepare switchable surfaces or nanoparticles for intracellular delivery. The review subsequently highlights the use of other stimuli associated with microbial infection, such as the expression of degrading enzymes or changes in temperature. Polyelectrolyte complexes with dual stimuli-response based on pH and temperature are also discussed. Finally, the review presents a summary and an outlook of the challenges and opportunities faced by this field. This review is expected to encourage researchers to develop stimuli-responsive polyelectrolyte complexes that increase the stability of AMPs while providing targeted delivery, and thereby facilitate the translation of these antimicrobials.     

Polysaccharide Nanoparticles Bearing HDAC Inhibitor as Nontoxic Nanocarrier for Drug Delivery

The histone deacetylase inhibitors (HDACi) are potent drugs in the treatment of inflammatory diseases and defined cancer types. However, major drawbacks of HDACi, such as valproic acid (VPA), are limited serum half‐life, side effects and the short circulation time. Thus, the immobilization of VPA in a polysaccharide matrix is used to circumvent these problems and to design a suitable nanocarrier system. Therefore, VPA is covalently attached to cellulose and dextran via esterification with degree of substitution (DS) values of up to 2.20. The resulting hydrophobic polymers are shaped to spherical nanoparticles (NPs) with hydrodynamic diameter between 138 to 221 nm and polydispersity indices from 0.064 to 0.094 by nanoprecipitation and emulsification technique. Lipase treatment of the NPs leads to in vitro release of VPA and hence to an inhibition of HDAC2 activity in a HDAC2 assay. NPs are rapidly taken up by HeLa cells and mainly localize in the cytoplasm. The NPs are hemocompatible and nontoxic as revealed by the shell‐less hen’s egg model.     

刺激响应星形聚合物的合成及其药物可控释放研究

星形聚合物是从一个枝化点呈放射形连接出三条及三条以上线形链的一类具有特殊拓扑结构的聚合物.与组成和分子量相同的线形聚合物相比,星形聚合物具有明确的结构、较窄的分子量分布、较低的黏度和多功能性,已成为高分子领域的研究热点之一.引入刺激响应基团的刺激响应星形聚合物具有随外界环境变化而发生敏感调整的结构特征,并在药物可控释放方面具有重要的应用价值,受到广泛关注.本文总结现阶段刺激响应星形聚合物应用于药物可控释放方面的最新研究成果,主要根据不同的环境刺激信号进行分类,分别介绍了pH、温度、双重或多重刺激响应星形聚合物的合成方法,分析其在溶液中的自组装行为、刺激响应情况和药物可控释放功能,并对相关聚合物体系的改进和发展进行展望.     

Pillararene-Based Supramolecular Vesicles for Stimuli-Responsive Drug Delivery

Supramolecular vesicles (SMVs) self-assembled from the supra-amphiphiles, consisting of two scaffolds linked together through noncovalent interactions, can realize stimuli-responsive controlled release of encapsulated drugs for enhanced therapeutic efficacy and minimized side effect of drugs. Pillararenes (PAs), an emerging kind of macrocyclic hosts in 2008, are easy to modify with a variety of functionalities. SMVs from PAs and specific guests mainly based on the host–guest interactions have attracted increasing attention because of their drug delivery and controlled drug release. A great progress in the construction and stimuli-responsive drug delivery of the PA-based SMVs has been made since the first work was reported in 2012. This review summarizes the major achievements of the PA-based SMVs for stimuli-responsive drug delivery over the past 5 years, including the microstructures of SMVs, multiple stimuli-responsive SMVs, prodrug SMVs from prodrug PAs and guests, bola-type SMVs, multifunctional SMVs, glucose-responsive SMVs for insulin delivery, novel SMVs from responsive PAs, thermo-responsive SMVs, and ternary SMVs, for chemotherapy, photothermal therapy, photodynamic therapy, and other biological applications. The future challenges and research directions of PA-based SMVs are also outlined from the points of views of the fundamental research, biological applications, and clinical applications of PA-based SMVs.