基于碳点多功能纳米载药体系的制备及pH响应释药性能研究

采用一步微波法成功制备了表面带氨基的荧光纳米碳点CDots, 并通过酰胺化反应将靶向基团叶酸接枝到碳点表面, 成功获得中间产物CDots-FA. 在此基础上, 通过已合成四臂端酰肼基化合物2与抗肿瘤药物阿霉素(DOX)连接, 实现在碳点表面的阿霉素药物分子的化学键合, 最终获得多功能纳米载药体系DOX-CDots-FA. 利用原子力显微镜(AFM)、高分辨透射电镜(HR-TEM)和荧光光谱仪对荧光纳米碳点CDots的性能进行表征, 并通过核磁共振、紫外-可见吸收光谱对DOX-CDots-FA结构、接枝率进行了表征. 同时对纳米载药体系DOX-CDots-FA体外药物释放行为、细胞毒性及细胞摄取成像进行了系统的研究. 结果表明, DOX-CDots-FA具有良好的pH响应性. 叶酸靶向基团能加速DOX-CDots-FA被HeLa (FR+)细胞摄取, 并表现出更强的细胞毒性. 同时细胞摄入成像实验表明, 在叶酸靶向作用下, DOX-CDots-FA通过内吞作用进入HeLa细胞, 随后阿霉素被释放出来并进入细胞核区域, 抑制细胞的生长, 从而实现靶向治疗, 降低毒副作用.     

聚合物分子刷的合成与应用

本文综述了近年来在线形聚合物、树枝状大分子及树枝化聚合物等不同聚合物的每个重复单元上,高密度地、通过不同联接方式接枝上新的聚合物侧链而形成的刷形接枝共聚物,即聚合物分子刷的研究进展.主要介绍聚合物分子刷的三种合成途径,即“大单体聚合法“,“从主链接枝法“及“接枝到主链法“,并对不同路线的特点进行分析,同时对分子刷在制备纳米杂化材料、纳米导线及智能材料等方面的应用进行了综述.     

水溶性共轭聚合物分子刷的研究进展

水溶性共轭聚合物研究属于国际前沿研究领域,因其具有水溶性和超级信号放大作用,在生物传感领域展现出良好的应用前景.但由于传统水溶性线型共轭高分子两亲性结构特点,其含有的憎水性刚性共轭链在水溶液中易聚集,水分子对共轭链激发态的影响导致其发光效率低(一般小于30%),严重制约了其应用与拓展.如何方便有效构筑高分子的高支化是获得高荧光效率的关键.在本篇综述中,我们综述了水溶性共轭聚合物分子刷的合成技术,分析了其结构与光学性质的关系,为水溶性共轭聚合物分子刷的设计和制备提供指导.另外,总结了水溶性共轭聚合物分子刷在化学生物传感、生物成像、药物运输、癌症治疗等领域的应用,最后对水溶性共轭聚合物分子刷存在的主要问题以及未来的热点方向进行了分析和展望!     

基于枝化多肽的多功能药物递送系统用于肿瘤细胞核的精准靶向治疗

为了改善在肿瘤治疗过程中,药物载体靶向性差和药物靶点定位效率低等不足,设计了一种能精准靶向肿瘤细胞核,将药物高效递送至作用靶点的多功能纳米载药体系.利用具有细胞核定位能力的两亲性枝化多肽包载化疗药物阿霉素(DOX)形成载药纳米胶束DD,并通过静电作用将具有肿瘤靶向功能的透明质酸(HA)包覆在DD表面,得到具有靶向肿瘤细胞核能力的纳米药物HDD.HA的存在赋予了HDD对肿瘤的靶向功能和电荷屏蔽能力,可增加体系的稳定性,延长其血液循环时间,降低正常组织和细胞对HDD的非特异性摄取,实现其在肿瘤部位的特异性富集和肿瘤细胞的高效摄取.进入肿瘤细胞后,HA层的降解有利于纳米胶束DD在多肽的核定位作用下精准、快速地将DOX递送至细胞核,最终实现高效的肿瘤抑制效果.     

PtBA-g-PPEGMEMA接枝共聚物的合成及其包埋阿霉素的研究

通过可逆加成-裂解链转移聚合和原子转移自由基聚合,制备了以聚丙烯酸叔丁酯为主链、以聚(聚乙二醇单甲醚甲基丙烯酸酯)为侧链的两亲性接枝共聚物PtBA-g-PPEGMEMA,该方法克服了以往通过聚合物修饰来引入接枝点时所存在的接枝点密度不高和不可控的局限性.接着,以PtBA-g-PPEGMEMA为载体,对抗肿瘤药物阿霉素进行了负载,制备得到了尺寸为164.8nm的纳米载药胶束.其释放试验表明,该体系具有缓释特征.     

水溶性共轭聚合物在生物传感中的应用

水溶性共轭聚合物在化学、医学、生命科学以及材料科学等领域中备受研究者们的关注,利用其独特的光化学和光物理性质,研究者们开展了一系列创新性研究并取得了重大的研究进展,进而拓展了聚合物的应用范围.共轭聚合物是一种由多个重复发光单元通过彼此间共轭而形成的高分子化合物,通过对其结构的精准调控,可以获得具有不同性能的功能性分子.其中,通过改变其主链结构,可以获得具有不同吸收和发射波长的荧光探针;通过对侧链结构修饰以水溶性基团和/或选择性识别分子,可以实现与特定靶标间的静电作用或者特异性结合,进而实现选择性识别的目的.本文综述了近年来水溶性共轭聚合物在生物传感中的应用,主要介绍了水溶性共轭聚合物在DNA检测、蛋白质检测、细胞和细菌的检测与区分以及细胞成像等方面的研究进展.     

刺激响应共负载药物/基因微载体的制备

合成了聚乙烯亚胺接枝二茂铁(PEI-Fc)两亲聚合物, 采用水包油法制备包埋疏水性抗癌药阿霉素(DOX)的载药胶束, 并利用胶束表面正电荷的PEI链段有效缔合DNA, 获得尺寸合适、 表面带正电荷的阿霉素与基因共负载微载体. 在磷酸盐(PBS)缓冲溶液中, 共负载微载体能够缓慢释放出DOX. 在硝酸铈铵存在下, 二茂铁从疏水性转变为亲水性, 使载药胶束完全解离, 由于PEI-Fc与DNA之间的静电作用, 使基因超分子组装体稳定存在, 显示出很好的氧化响应特性. 细胞培养结果表明, 表面带正电荷的共负载微载体易被HepG2细胞内吞, 并可转染, 且随着DOX的释放逐渐杀死HepG2肝癌细胞, 为安全稳定、 具有刺激响应的药物与基因共负载微载体的制备提供了可行的途径.     

生物素功能化水溶性共轭聚合物的合成、表征及其生物分析应用

以四（三苯基膦）钯/碘化亚铜为催化剂,利用Sonogashira偶联反应,合成了一种主链含芴炔苯结构的侧链生物素（biotin）修饰的具有蓝光发射特性的水溶性共轭聚合物（PFPNBr-biotin）. 其结构通过核磁共振和红外光谱进行表征;分子量（分布）利用凝胶渗透色谱进行表征. 研究了该聚合物在不同溶剂、不同浓度及不同pH环境中的光物理性质变化. 与未功能化的共轭聚合物相比,这种生物素功能化的聚合物对亲和素蛋白显示出较高的选择性. 目前,生物素-亲和素系统已在生物分析领域广泛使用,因此,该聚合物在生物分子的特异性检测、荧光标记、细胞及分子成像等领域具有较好的应用前景.     

聚合物分子刷的合成与应用

本文综述了近年来在线形聚合物、树枝状大分子及树枝化聚合物等不同聚合物的每个重复单元上,高密度地、通过不同联接方式接枝上新的聚合物侧链而形成的刷形接枝共聚物,即聚合物分子刷的研究进展。主要介绍聚合物分子刷的三种合成途径,即“大单体聚合法”,“从主链接枝法”及“接枝到主链法”,并对不同路线的特点进行分析,同时对分子刷在制备纳米杂化材料、纳米导线及智能材料等方面的应用进行了综述。     

基于主客体模块组装的多功能药物载体的研究

基于β-环糊精和胆固醇之间的主客体识别作用,通过对主客体分子的设计,构筑模块化的组装基元;通过主客体分子组装,将具有靶向功能的乳糖酸、成像功能的异硫氰酸荧光素和治疗作用的阿霉素引入同一超分子聚合物前药胶束中,制备得到多功能的纳米药物传递系统.研究结果表明,具有不同功能的模块基元可通过超分子主客体组装在水中自组装成一定尺寸的前药胶束,并通过二维1H NOESY谱证明了主客体作用的发生.该前药胶束具有p H值响应的药物释放行为,在细胞内涵体/溶酶体酸性环境下药物释放速率显著加快.用荧光显微镜和流式细胞仪对此聚合物前药胶束的细胞内吞行为进行了研究.在乳糖酸受体介导作用下,聚合物前药胶束能在肿瘤细胞内有效富集,并同时观察到阿霉素和异硫氰酸荧光素的荧光,用以跟踪载体在细胞内的位置.MTT的结果进一步表明,该前药胶束能有效地抑制癌细胞的增殖.     

PEGylated anti-MUC1 aptamer-doxorubicin complex for targeted drug delivery to MCF7 breast cancer cells

Targeted drug delivery is especially important in cancer treatment as many anti-cancer drugs are non-specific and highly toxic to both cancer and normal cells. The targeted drug delivery of DOX to the MUC1-expressing breast cancer cell line (MCF7) was obtained using APT as a carrier. Modification of the APT-DOX complex by PEG increases the survivability of the macrophage control (RAW 264.7) by about six-fold as compared to free DOX treatment without significantly affecting the cytotoxicity toward the target cell line. Thus, PEG-APT-DOX is potentially a new therapeutic agent for targeted drug delivery to MUC1-expressing cell lines.     

具有pH-响应性的聚天冬氨酸类载药胶束的制备和释放能力研究

通过大分子引发剂ω-氨基-α-甲氧基聚乙二醇引发N-羧基-α-氨基环内酸酐开环聚合和水合肼侧基改性,制备了一系列聚乙二醇-聚氨基酸类三嵌段共聚物.其中聚氨基酸链段包括具有酰肼基的聚天冬氨酸衍生物(PAHy),以及疏水性的聚丙氨酸链段.引入具有pH响应性的腙键键合阿霉素,利用键合阿霉素与游离阿霉素之间的π-π叠合作用,在聚合物自组装形成胶束过程中通过化学键合+物理包埋的方式充分负载药物.该胶束以聚丙氨酸链段为核心,以PEG链段为冠层,以PAHy链段为包裹药物的壳层.载药胶束的粒径在170 nm左右.研究不同pH值条件下载药胶束的药物释放能力,随环境pH值的降低药物的释放速率显著增加.     

Control of surface properties using fluorinated polymer brushes produced by surface-initiated controlled radical polymerization

Surface-grafted styrene-based homopolymer and diblock copolymer brushes bearing semifluorinated alkyl side groups were synthesized by nitroxide-mediated controlled radical polymerization on planar silicon oxide surfaces. The polymer brushes were characterized by X-ray photoelectron spectroscopy (XPS), near-edge X-ray absorption fine structure (NEXAFS), and time-dependent water contact angle measurements. Angle-resolved XPS studies and water contact angle measurements showed that, in the case of the diblock copolymer brushes, the second block to be added was always exposed at the polymer-air interface regardless of its surface energy. Values of z*/Rg were estimated based on the radius of gyration, Rg, of the grafted homopolymer or block copolymer chains for the grafted brushes and thickness of the brush, z*. The fact that z*/Rg > 1 suggests that all these brushes are stretched. These results support the idea that after grafting the first block onto the surface the nitroxide-end capped polymer chains were able to polymerize the second block in a "living" fashion and the stretched brush so formed was dense enough that the outermost block in all cases completely covers the surface. NEXAFS analysis showed a relationship between the surface orientation of the fluorinated side chains and brush thickness with thicker brushes having more oriented side chains. Time-dependent water contact angle measurements revealed that the orientation of the side chains of the brush improved the surface stability toward reconstruction upon prolonged exposure to water.     

以磁纳米粒为核的pH敏感型聚谷氨酸树状分子药物载体

报道了一种新的肽类树枝状分子改性磁性纳米药物载体.以天然氨基酸L-谷氨酸为原料,通过收敛法合成了聚(L-谷氨酸)树状分子,将多巴胺配体键合到聚(L-谷氨酸)树状分子上,用核磁(1H-NMR)、质谱(MS)对合成出的树状分子配体进行了表征,然后通过配体交换对四氧化三铁磁纳米粒表面进行多功能化.以阿霉素为模型药物通过pH敏...     

pH‐sensitive carbon quantum dots−doxorubicin nanoparticles for tumor cellular targeted drug delivery

A kind of pH‐responsive carbon quantum dots?doxorubicin nanoparticles drug delivery platform (D‐Biotin/DOX‐loaded mPEG‐OAL/N‐CQDs) was designed and synthesized. The system consists of fluorescent carbon dots as cross‐linkers, and D‐Biotin worked as targeting groups, which made the system have a pH correspondence, doxorubicin hydrochloride (DOX) as the target drug, oxidized sodium alginate (OAL) as carrier materials. Ultraviolet (UV)‐Vis spectrum showed that the drug‐loading rate of DOX is 10.5%, and the drug release in vitro suggested that the system had a pH response and tumor cellular targeted, the drug release rate is 65.6% at the value of pH is 5.0, which is much higher than that at the value of pH is 7.4. The cytotoxicity test and laser confocal fluorescence imaging showed that the synthesized drug delivery system has high cytotoxicity to cancer cells, and the drug‐loaded nanoparticles could enter the cells through endocytosis.     

Mesoporous silica nanoparticles for 19F magnetic resonance imaging,fluorescence imaging,and drug delivery

Multifunctional mesoporous silica nanoparticles (MSNs) are good candidates for multimodal applications in drug delivery, bioimaging, and cell targeting. In particular, controlled release of drugs from MSN pores constitutes one of the superior features of MSNs. In this study, a novel drug delivery carrier based on MSNs, which encapsulated highly sensitive ¹⁹F magnetic resonance imaging (MRI) contrast agents inside MSNs, was developed. The nanoparticles were labeled with fluorescent dyes and functionalized with small molecule-based ligands for active targeting. This drug delivery system facilitated the monitoring of the biodistribution of the drug carrier by dual modal imaging (NIR/¹⁹F MRI). Furthermore, we demonstrated targeted drug delivery and cellular imaging by the conjugation of nanoparticles with folic acid. An anticancer drug (doxorubicin, DOX) was loaded in the pores of folate-functionalized MSNs for intracellular drug delivery. The release rates of DOX from the nanoparticles increased under acidic conditions, and were favorable for controlled drug release to cancer cells. Our results suggested that MSNs may serve as promising ¹⁹F MRI-traceable drug carriers for application in cancer therapy and bio-imaging.     

Radio-immunoconjugated,Dox-loaded,surface-modified superparamagnetic iron oxide nanoparticles (SPIONs) as a bioprobe for breast cancer tumor theranostics

In this research, we develop dual modality molecular imaging and also radio-immunotherapy (RIT) bioprobes, in the form of modified superparamagnetic iron oxide nanoparticles (SPIONs) conjugated to radiolabeled antibodies, for PET and MRI of HER2 expressing cancers as well as a PH sensitive drug carrier by embedded an anticancer agent for cancer therapeutic applications. The bioprobes were developed by conjugating ⁶⁴Cu labeled trastuzumab (herceptin) and rituximab (Anti CD-20) antibodies to modified SPIONs. The SPIONs were modified with carboxymethyl chitosan and functionalized with acrylic acid (AA). Also, with the purpose of identifying more effective bifunctional chelator (BFC), we compared the properties of novel BFC, p-NO₂-Bn-PCTA with the commonly used DOTA-NHS for radio-immunoconjugate preparations. Moreover, a chemotherapy drug, doxorubicin, was then loaded onto engineered nanoparticles for targeted intracellular drug delivery and selective cancer cell killing. Resulting radio-immunoconjugated-SPIONs were evaluated for molecular imaging and effective targeting of the HER2+ receptors in SKBR3 cell lines and breast tumor bearing Balb/C mice. Therefore, our biocompatible SPIONs could serve as a promising multifunctional theranostics nanoplatform in dual modality imaging guided RIT of HER2 overexpressing cancer applicable to drug delivery and controlled drug release for trigger both intrinsic and extrinsic pathways of apoptosis.     

Grafted semiconducting polymer amphiphiles for multimodal optical imaging and combination phototherapy

Semiconducting polymer nanoparticles (SPNs) have gained growing attention in biomedical applications. However, the preparation of SPNs is usually limited to nanoprecipitation in the presence of amphiphilic copolymers, which encounters the issue of dissociation. As an alternative to SPNs, grafted semiconducting polymer amphiphiles (SPAs) composed of a semiconducting polymer (SP) backbone and hydrophilic side chains show increased physiological stability and improved optical properties. This review summarizes recent advances in SPAs for cancer imaging and combination phototherapy. The applications of SPAs in optical imaging including fluorescence, photoacoustic, multimodal and activatable imaging are first described, followed by the discussion of applications in imaging-guided phototherapy and combination therapy, light-triggered drug delivery and gene regulation. At last, the conclusion and future prospects in this field are discussed.

This review summarizes the applications of grafted semiconducting polymer amphiphiles (SPAs) as multimodal optical nanoagents for cancer imaging and combination phototherapy.     

甲基丙烯酸甲酯/苯乙烯在硅片表面的RAFT接枝聚合

将3-(2-二硫代苯甲酸基丙酰氧基)丙基二甲基甲氧基硅烷化学键合于硅片表面.以甲基丙烯酸甲酯和苯乙烯为单体,在硅片表面进行可逆加成-断裂链转移(RAFT)接枝聚合.X-射线光电子能谱仪证实聚甲基丙烯酸甲酯(PMMA)、聚苯乙烯(PS)、苯乙烯/甲基丙烯酸甲酯的共聚物(poly(MMA-co-St))都接枝到硅片表面.但3个体系表现出不同的性质,甲基丙烯酸甲酯的RAFT聚合可控性差,分子量比设计分子量大得多,分子量分布指数宽,接枝密度仅为0·03chains/nm2;苯乙烯均聚合的活性/可控性好、分子量分布窄,接枝密度提高到0·21chains/nm2;共聚合体系综合了两个均聚体系的优点,分子量分布较窄,接枝密度最高为0·31chains/nm2,聚合物膜厚随转化率、数均分子量基本呈线性增长.     

The Role of Hydrophobicity in the Cellular Uptake of Negatively Charged Macromolecules

It is generally accepted that positively charged molecules are the gold standard to by‐pass the negatively charged cell membrane. Here, it is shown that cellular uptake is also possible for polymers with negatively charged side chains and hydrophobic backbones. Specifically, poly[5‐methoxy‐2‐(3‐sulfopropoxy)‐1,4‐phenylenevinylene], a conjugated polyelectrolyte with sulfonate, as water‐soluble functional groups, is shown to accumulate in the intracellular region. When the polymer hydrophobic backbone is dissolved using polyvinylpyrrolidone, an amphiphilic macromolecule, the cellular uptake is dramatically reduced. The report sheds light on the fine balance between negatively charged side groups and the hydrophobicity of polymers to either enhance or reduce cellular uptake. As a result, these findings will have important ramifications on the future design of targeted cellular delivery nanocarriers for imaging and therapeutic applications.