一种阿霉素/NO供体光敏纳米复合物的合成与性质研究

以硫化铜纳米晶(CuS-NCs)为核心,聚N-异丙基丙烯酰胺接枝壳聚糖(PNIPAM-g-CS)微粒为壳合成一种新型光敏纳米复合材料.在温度的调节下,N-异丙基丙烯酰胺(NIPAM)包覆CuS纳米晶,并接枝壳聚糖(CS),合成CuS杂PNIPAM-g-CS纳米复合材料.CuS在近红外光(980 nm)照射下具有光热效应,导致纳米复合物中PNIPAM-g-CS微粒受热体积收缩.负载阿霉素,这种纳米复合物就可作为光热诱导释放阿霉素的多功能纳米载体.再负载NO光敏供体(RBS),就可制备出阿霉素/RBS双负载的CuS杂PNIPAM-g-CS纳米载体.在可见光(365 nm)照射下,RBS光解释放NO.近红外光和可见光分别触发纳米载体释放阿霉素和NO,加上CuS纳米晶的光热效应,这种纳米载体可实现光触发双药物释放协同光热化疗杀伤肿瘤细胞.     

水溶性IR-780聚合物用于线粒体靶向的光动力治疗※

11-氯-1,1'-二正丙基-3,3,3',3'-四甲基-10,12-三亚甲基吲哚三碳花青碘盐(IR-780)被具有较强组织穿透能力的近红外光照射后, 能快速高效地产生活性氧, 导致细胞死亡, 可用于光动力治疗. 但是IR-780的水溶性差, 这极大限制了其生物医学应用. 基于此我们设计合成了可高效靶向线粒体的水溶性IR-780聚合物Poly-IR, Poly-IR在水中自组装成为纳米粒子. Poly-IR纳米粒子受近红外光激活后, 在肿瘤细胞内外均能快速高效地产生活性氧, 并且该纳米粒子能够在线粒体中富集, 受近红外光的激发后产生的活性氧能够破坏线粒体, 导致线粒体膜电位降低. 细胞毒性、活死细胞染色及凋亡实验结果也进一步证明, 该纳米粒子在近红外光照下能够有效地抑制肿瘤细胞的增殖. 本体系为靶向线粒体的光动力治疗肿瘤领域拓展了思路.     

基于金属纳米材料的癌症光热切除疗法

在癌症治疗中,传统的手术疗法、放射疗法和化学疗法会伤害到体内正常的组织以及带来一些其他的副作用,因此新的治疗手段,如在近红外激光中利用感光增强布光热切除疗法（PTA）已经开始被研究应用于癌症治疗.在当前新兴的纳米科学领域中,有许多相关的研究成果被认为可以作为新的纳米技术手段直接应用于癌症的检测和治疗中.光热切除疗法（PTA）的基本原理是在激光照射条件下,利用光热转换产生的高热量来破坏消除癌细胞,其中,在癌细胞位点上强的光照吸收以及高的光热转换效率是光热切除疗法（PTA）能否成功实施的关键.在贵金属纳米材料中,如金纳米颗粒和银纳米颗粒,由于他们对光具有很强的表面等离子共振吸收效应,因而他们可以在光热切除疗法（PTA）应用中有效地增强光热转换效率,而且关于金属纳米材料的结构优化以及其相关的光热转换性质的研究目前也已经有了显著的成果.在光热切除疗法中,理想的纳米金属材料应该具有下列一些特征：具有强的以及可调的表面等离子共振吸收、容易传输、毒性低以及容易与目标癌细胞结合.在这篇综合评述文章中,我们将主要讲述包括金纳米颗粒、纳米棒、纳米壳结构、纳米笼状结构以及纳米空心球结构等不同结构的金纳米材料在光热切除疗法（PTA）应用中的研究.在这些不同结构的纳米材料中,金纳米空心球由于具有较小的尺寸（30～50nm）和球状结构,以及很强的、并且半峰宽较窄的可调节的表面等离子共振效应,因此在光热切除疗法（PTA）中表现出最佳的综合性质.     

上转换光动力诊疗体系的构建及抗癌研究进展

具有创伤小、毒性低、选择性好、无耐药性等优点的光动力疗法已被广泛应用于癌症治疗研究。然而，多数光敏剂存在水溶性差易聚集、肿瘤组织选择性差的问题，且其激发光都在可见或紫外光范围内，组织穿透深度较浅导致治疗深度不够，限制了光动力疗效。稀土上转换纳米粒子具有低生物毒性、高化学稳定性、强组织穿透力等优点，可作为将近红外光转换成紫外/可见光的发光材料和光敏剂载体，因此，构建上转换光动力诊疗体系为增强光动力疗效提供新思路。本文介绍了上转换光动力诊疗体系的构建方法，包括物理吸附法、物理包封法、共价偶联法，并分析了其应用于光动力抗癌研究的优缺点，最后总结并展望了其存在的挑战及未来发展方向。     

基于共轭聚合物的纳米粒子用于肿瘤的近红外二区荧光成像及光热治疗

为提高生物组织荧光成像质量以及对肿瘤的高效光热治疗,设计合成了一种新型的窄带隙共轭聚合物(BDT-TTQ),并通过纳米沉积的方式将聚合物制备成水溶性纳米粒子(BDT-TTQ NPs).该共轭聚合物纳米粒子在1000~1200 nm近红外二区范围具有较好的吸收,在1064 nm的激发光下能实现1200~1400 nm的近红外二区荧光成像. BDT-TTQ NPs纳米粒子粒径分布较窄,形貌呈规则的球形且分散均匀,具有好的生物相容性.该纳米粒子既可以在体外实现较高的近红外二区荧光成像穿透深度,又可以实现对小鼠活体血管的高清晰度的近红外二区荧光成像.此外,BDT-TTQ NPs纳米粒子在1064 nm激光下展现出优异的光热转换效率,具有较高的光毒性,对体外的肿瘤细胞以及小鼠的异质瘤具有高的光热杀伤能力.     

具有近红外光热转换性能的双层氧化硅包覆金纳米花复合材料的制备及体内代谢研究

采用种子生长法和改良Stber法制备了双层氧化硅包覆的金纳米花复合材料,并测试了其近红外光热转换性能,研究了其在裸鼠体内的生物毒性,并以种植了人口腔鳞癌CAL27细胞的荷瘤裸鼠为体内模型,应用光声成像方法研究了其体内分布、代谢和在肿瘤组织的被动靶向富集行为.结果表明,所制备的金纳米花复合材料在近红外光区具有良好的光热转换性能,无明显体内生物毒性,是一种良好的光声成像剂,其在荷瘤裸鼠体内主要经肝脏代谢至肠道排出体外,可通过EPR效应实现在肿瘤组织的靶向富集.本研究证明所制备的双层氧化硅包覆金纳米花复合材料可用于生物体内治疗,可作为包括口腔癌在内的恶性肿瘤近红外光热诊疗的理想介导材料.     

适体功能化的金纳米棒用于癌症靶向治疗的研究进展

金纳米棒(gold nanorods,GNRs)具有特殊的光学性质、较大的比表面积、出色的光热转换性能、表面易修饰等特点,在药物递送、光疗、生物成像和化学传感等领域应用十分广泛。适体是短的单链DNA或RNA片段,可特异性识别癌细胞或其表面的膜蛋白。近年来,适体功能化的GNRs在癌症靶向治疗领域显示出良好的应用前景。根据GNRs对癌症作用机制的差异,本文从光热疗法、光动力疗法、化疗和联合疗法4个方面总结了适体功能化的GNRs在癌症靶向治疗中的最新进展,并对该领域面临的主要挑战和发展趋势进行了探讨与展望。     

基于介孔纳米碳球接枝聚胍类化合物协同光热抗菌策略的研究

细菌感染是严重威胁着人们生命健康的主要问题之一. 与传统抗生素疗法相比, 新型抗菌策略光热疗法(PTT)展现出可控、微创及不易使细菌产生耐药性的优良性能. 然而单模形式下PTT疗法并不理想, 且高温下通常伴随着炎性反应等副作用, 联合抗菌策略可有效解决这一问题. 本研究制备了富含羧基的氧化介孔纳米碳球(OMCN), 通过酰胺化反应, 共价接枝聚六亚甲基双胍(PHMB), 得到OMCN-PHMB纳米平台. 实验结果表明, OMCN的光热性能具有良好的浓度与近红外光照功率依赖性. 在808 nm激光照射下, OMCN-PHMB的体内外联合光热治疗效果显著优于单一模式下的其它治疗组, 且组织学分析结果表明, 该纳米平台对小鼠的主要器官没有产生明显的毒性, 具有较高的生物相容性.     

联合递送药物和基因的智能抗癌控释体系

癌症是严重威胁人类健康和生命的重大疾病之一,目前化疗是临床癌症治疗的主要手段。但是由于癌症发病机制的复杂性和异质性,单一疗法通常无法有效地抑制癌症的发展和转移。因此,包含多种抗癌机制的联合疗法成为越来越重要的治疗策略。凭借其增强抗癌疗效和降低毒副作用的能力,联合递送药物和基因的纳米载体已经成为生物医药领域的研究热点。本文综述了联合递送药物和基因的智能抗癌控释载体的最新研究进展,分类介绍了这些联合递送载体的制备方法和作用机制,它们可在肿瘤微环境的刺激因素(如p H、谷胱甘肽和酶等)或者外源性刺激(如温度、超声等)作用下发生结构或构象的变化,从而实现了药物和基因的可控释放,产生协同治疗作用。此外,本文还对联合递送载体的发展前景作了展望。     

还原氧化石墨烯-硫化铜纳米复合材料的制备及在癌症热疗中的应用

通过一步水热法制备了一种具有光热性能的纳米复合材料——还原氧化石墨烯-硫化铜(rGO-CuS),利用傅里叶变换红外光谱、拉曼光谱、紫外-可见光谱及高分辨透射电子显微镜对所合成纳米复合物的结构和形貌进行了表征,并通过细胞实验和动物实验考察其癌症热疗效果.结果表明,与未复合的氧化石墨烯(GO)和硫化铜相比,rGO-CuS在近红外光区域具有更高效的光热转换效率;rGO-CuS的光热治疗效果明显好于GO和CuS.     

Theranostic Gold Nanoclusters for NIR-II Imaging and Photodynamic Therapy

Fluorescence imaging in the second near-infrared window(NIR-II, 1000-1700 nm) has demonstrated tremendous promise for biomedical applications, with its extraordinarily high resolution and deep tissue penetration. Ultrasmall gold nanoclusters(AuNCs) have shown unique features for NIR-II imaging, such as photostability and biocompatibility, as compared to organic NIR-II molecules or other inorganic NIR-II nanoparticles. Here, we report the first-in-class protein-capped ultrasmall AuNCs(BSA-AuNCs, BSA=bovine serum albumin) for simultaneous NIR-II imaging and photodynamic therapy. The BSA-AuNCs show a uniform size, high quantum yield and excellent photostability, display a high accumulation and long retention in 4T1 tumor, and are used for clear imaging of blood vessels and lymph nodes. Moreover, laser irradiation of these AuNCs can rapidly trigger ROS generation, leading to effective inhibition of tumor cell growth in vitro and in vivo. This study demonstrates the feasibility of a protein-capped ultrasmall AuNCs platform for theranostic applications by combining NIR-II imaging and photodynamic cancer therapy.     

整合荧光成像和化疗的有机小分子诊疗探针的研究进展

将诊断与治疗功能结合为一体是当前应对癌症的一种新兴策略. 诊疗一体化作为一种潜在的新型医学诊治方式, 在快速获得体内信息、 改善生物分布、 减少剂量和降低毒副作用等方面具有潜在的应用前景. 荧光成像被广泛应用于医学诊断, 近年来近红外荧光成像技术得到飞速发展, 在活体成像方面具有较好的穿透深度和成像分辨率. 本文综合评述了部分整合荧光成像和化疗的有机单分子诊疗试剂的相关研究, 并对诊疗一体化探针的未来研究进行了展望.     

Bacteriochlorophyll-a as photosensitizer for photodynamic treatment of transplantable murine tumors.

Bacteriochlorophyll-a (bChla), which absorbs light of 780 nm wavelength, was tested for in vivo photodynamic activity in the SMT-F and RIF transplantable mouse tumor systems. High performance liquid chromatography (HPLC) analysis of tissue extracts showed that bChla was rapidly degraded in vivo to bacteriopheophytin-a (bPheoa) and other breakdown products. These were also photodynamically active, and tumor response could be achieved over a wavelength range of 660 to 780 nm, while tumor cure was restricted to wavelengths of 755 (bPheoa) to 780 nm. A photosensitizing product absorbing at 660 nm was also present in isolated tumor cells. Photodynamic cell kill of tumor cells isolated from tumors after bChla accumulation in vivo, using 755 or 780 nm light _vitro, was exponential up to 20–40 J cm⁻². Above this light dose little or no further damage could be achieved, which is an indication of the rapid photobleaching of these sensitizers. In vivo, vascular occlusion occurred readily if light treatment was delivered shortly after sensitizer administration, but was delayed if light treatment was carried out 24 h after injection. Although up to 70% of tumor cells were lethally damaged after completion of in vivo light treatment, concurrent severe vascular destruction seemed necessary for tumor cure. Normal tissue photosensitivity totally subsided within 5 days after sensitizer administration.     

L-Arginine/nanofish bone nanocomplex enhances bone regeneration via antioxidant activities and osteoimmunomodulatory properties

In this study,a promising strategy has been developed to promote bone regeneration by combining antioxidant activities and osteoimmunomodulatory properties.Herein,an L-arginine/nanofish bone(Arg/NFB) nanocomplex has been prepared and evaluated in vitro and in vivo.The Arg/NFB nanocomplex possesses good antioxidant activities and could modulate the polarization of non-activated macrophage into different types and induce the secretion of pre-inflammato ry,anti-inflammatory,osteogenic as well as angiogenic cytokines.Additionally,the regulated immune microenvironment can enhance the osteogenic differentiation of mouse embryo osteoblast precursor cells(MC3 T3-E1) and angiogenic capacity of human umbilical vein endothelial cells(HUVECs),leading to the improved formation of mineralized nodules,alkaline phosphatase activity and angiogenic effects.In vivo results with cranial defect models reveal that the treatment of Arg/NFB nanocomplex exhibited significant improvement of new bone formation and angiogenesis.All the results demonstrate Arg/NFB nanocomplex with antioxidant activities and osteoimmunomodulatory properties could be a new idea for developing the next generation of bone regeneration biomaterials.     

基于Cy7类菁染料分子探针的设计策略

菁染料是一类经典的荧光染料母核, 具有摩尔消光系数大、 吸收波长可调、 溶解性良好及生物兼容性好等优点, 被广泛用于蛋白标记、 痕量金属离子检测、 生物活性物质检测、 细胞和活体成像及肿瘤靶向治疗等领域. 近年来, 生物医学领域对活体结构及功能成像深度提出更高的需求, 基于优异的长波长染料母核开发近红外荧光分子探针逐渐成为领域的研究重点. 吲哚七甲川菁染料(Cy7)是一类最具代表性的菁染料, 本文重点综合评述了自1992年以来基于Cy7结构开发的分子探针, 并介绍了该类荧光探针的设计策略. 最后, 讨论了该领域研究面临的挑战, 并对未来的发展方向进行了总结和展望.     

In vivo Self-assembled Peptide Nanoprobes for Disease Diagnosis

In vivo imaging is creating great opportunities for disease diagnosis as a research tool. Probes are usually used to observe physiological structures in vivo clearly. Recent progresses of nanoprobes are important for the generation of high resolution and high contrast images required by accurate and precision disease diagnosis. In vivo self-assembled peptide(SAP) nanoprobes are playing major roles in in vivo imaging by modularity of design, high imaging contrast, response to the location of the lesion, and long-time retention in the lesion. And the response to lesion and long-term retention in there can enhance imaging sensitivity and specificity of in vivo SAP nanoprobes. Therefore, in vivo SAP nanoprobes are simple ancillary contrast entities to optimize the imaging effect. In this review, the recent progress of in vivo SAP nanoprobes for in vivo imaging, from molecular design of peptides to biomedical and clinical applications including disease diagnosis and disease-related molecular imaging is systematically summarized. We evaluate their ability, including sensitivity and specificity to provide relevant information under preoperative and during surgery circumstances and critically their likelihood to be clinically translated. Finally, a brief outlook on remaining challenges and potential directions for future research in this area is presented.     

Target delivery of photo-triggered nanocarrier for externally activated chemo-photodynamic therapy of prostate cancer

Objective therapeutics such as photodynamic therapy (PDT) play an imperative role where targeted delivery of nanotherapeutics could achieve the highest level of therapeutic efficiency for the treatment of cancer. For an effective combination of chemotherapy and PDT, a multimodal-targeted system is vital to achieving effective therapeutic efficacy to counter cancer. In this study, an upconversion nanoparticle-based dual-mode nanocarrier was established where doxorubicin, a chemotherapeutic drug, and tetra carboxy zinc phthalocyanine, a reactive oxygen species (ROS) generator, were successfully embedded onto metal-organic framework (ZIF-8) for synergistic photodynamic therapy. For controlled drug release, amine-PEG was wrapped around UCNPs@MOF. In addition, targeting efficiency was enhanced by employing a prostate cancer-specific ligand (folic acid, FA), which is recognized by prostate-specific membrane antigen (PSMA). Indeed, the nanocomposite-coupled FA was uptaken more in LNCaP (PSMA positive) cells compared to DU145 (PSMA negative) cells. Interestingly, coating the nanocomposite with biocompatible polyethylene glycol significantly inhibited doxorubicin (DOX) release even under a lower pH condition. This effect is abrogated by near-infrared irradiation, whereupon NIR irradiation, the nanocomposite accelerates the production of ROS, as well as chemotherapeutic drug release. These results suggest that the release of DOX was more tightly controlled by a polymer coating. As observed by in vitro cytotoxicity experiment, LNCaP cells showed descending pattern in the cell viability than DU145 cells under the NIR irradiation condition. All these results, taken together, show a promising system for NIR-based targeted PDT where burst release of drug and ROS is achieved to improve the synergistic therapeutics.     

线粒体靶向的近红外HClO/ClO-荧光探针的研究进展

HClO/ClO-作为细胞质中一种重要的活性氧(ROS),源自线粒体,参与各种生理和病理过程,因此快速有效检测HClO/ClO-具有重要的生物学及生理学意义.荧光分析法因其灵敏度高、响应时间快、选择性高、成本低和操作简便等优点而备受关注.更重要的是,使用荧光探针可以在体外和体内可视化检测.近年来,为了研究HClO/Cl...     

Initiator-Loaded Gold Nanocages as a Light-Induced Free-Radical Generator for Cancer Therapy

Tumor hypoxia greatly suppresses the therapeutic efficacy of photodynamic therapy (PDT), mainly because the generation of toxic reactive oxygen species (ROS) in PDT is highly oxygen-dependent. In contrast to ROS, the generation of oxygen-irrelevant free radicals is oxygen-independent. A new therapeutic strategy based on the light-induced generation of free radicals for cancer therapy is reported. Initiator-loaded gold nanocages (AuNCs) as the free-radical generator were synthesized. Under near-infrared light (NIR) irradiation, the plasmonic heating effect of AuNCs can induce the decomposition of the initiator to generate alkyl radicals (R^.), which can elevate oxidative-stress (OS) and cause DNA damages in cancer cells, and finally lead to apoptotic cell death under different oxygen tensions. As a proof of concept, this research opens up a new field to use various free radicals for cancer therapy.     

胺解改性聚L-谷氨酸苄酯引导骨再生膜的制备

以聚L-谷氨酸苄酯(PBLG)为原料, 通过溶剂浇铸与粒子沥滤法分别构建PBLG单层致密和PBLG单层多孔膜, 利用乙醇胺对薄膜表面改性, 构筑双层引导骨再生膜. 研究了不同胺解改性时间对PBLG-s-PHEG双层膜亲水性和力学性能的影响, 结果表明, 随着PBLG分子量的增大, 薄膜的力学性能增强而降解速率减缓. 延长胺解改性时间可提高薄膜亲水性和体内外降解速率. 细胞实验结果表明, 双层薄膜的致密结构能够有效阻隔成纤维细胞的侵入, 多孔结构能够支持细胞贴壁黏附和铺展. 体外生物活性评价结果表明, 表面改性的PBLG基材料可用于体内骨缺损修复. 本文所构建的双层引导骨再生膜在体外具有良好的力学性能和降解性能, 与组织具有一定的贴合性, 同时可有效阻碍成纤维细胞侵入, 具有潜在应用价值.