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.     

聚多巴胺修饰金纳米花的可控制备及在光热治疗中的应用

采用无模板法制备了金纳米花, 其形状与粒径大小可以通过改变反应温度和还原剂抗坏血酸的用量来调控; 然后, 通过多巴胺的表面原位聚合反应制备了聚多巴胺修饰的金纳米花, 以提高其在近红外区的吸收能力及生物相容性. 采用透射电子显微镜(TEM)、 紫外-可见吸收光谱(UV-Vis)和纳米粒度/Zeta电位仪等对金纳米花和聚多巴胺修饰金纳米花的形态、 粒径和光学特性进行了表征; 通过傅里叶变换红外吸收光谱(FTIR)分析证明聚多巴胺修饰成功; X射线衍射(XRD)分析结果表明, 聚多巴胺修饰前后金纳米花的晶体结构未变; 最后, 采用噻唑蓝(MTT)法体外评价了聚多巴胺修饰金纳米花的细胞毒性. 研究结果表明, 反应温度越低, 金纳米花表面分支结构越丰富, 以0 ℃为最佳反应温度; 还原剂抗血酸的用量越高, 金纳米花粒径越小; 金纳米花粒径在60~100 nm范围内可调, 最大吸收波长为575~650 nm. 经聚多巴胺修饰后, 金纳米花的最大吸收波长发生了显著红移(>80 nm), 近红外区的吸收范围显著扩大. 通过调控多巴胺溶液浓度, 可将金纳米花表面聚多巴胺层的厚度控制在8~14 nm. 在808 nm激光辐照下, 聚多巴胺修饰金纳米花溶液可迅速升温至57 ℃. 此外, 细胞实验结果表明, 聚多巴胺修饰后金纳米花的细胞毒性更低. 用其对HeLa肿瘤细胞进行光热治疗后, 细胞存活率仅为10%. 因此, 聚多巴胺修饰金纳米花作为光热试剂在肿瘤治疗领域具有潜在的应用前景.     

沉淀法高效制备聚多巴胺纳米粒子

为得到分散性和稳定性较好的聚多巴胺纳米粒子,利用“沉淀-再分散法”高效制备了聚多巴胺纳米粒子水分散液。 首先利用溶液氧化法制备了分散在水/乙醇中的聚多巴胺纳米粒子,然后向分散液中加入丙酮使聚多巴胺纳米粒子絮凝。 收集沉降物,用丙酮冲洗并干燥后,加水重新分散得到纯化的聚多巴胺纳米粒子水分散液。 丙酮沉淀法得到的聚多巴胺纳米粒子形貌规整,分散性好,粒径分布在250 nm左右,在水中具有良好的储存稳定性和光热性能,与传统的超速离心提纯法相比,产率可提高57.4%。 此方法为其之后在药物载体及光热治疗等方面的应用研究提供了便利。     

聚乳酸-乙醇酸/纳米氧化锌复合电纺纤维装载亲疏水药物的控释及体外细胞毒性

利用静电纺丝技术制备了负载亲水性药物阿霉素(DOX)以及疏水性药物喜树碱(CPT)的复合纳米纤维. 先用巯基封端的普朗尼克(F127)修饰纳米氧化锌(FZnO), 再将FZnO负载盐酸阿霉素(DOX@FZnO), 最后将DOX@FZnO与CPT一起纺入聚乳酸-乙醇酸(PLGA)纤维中. 体外药物释放结果表明, 复合纳米纤维能够减小亲水性药物的突释, 减缓药物释放速率, 延长药物释放时间. 体外细胞活性结果表明, 双载药复合纤维比单载药复合纤维具有更强的细胞毒性, 能够有效抑制癌细胞生长.     

新型聚多巴胺/聚丙烯酸-氢氧化铜双面神纳米粒子的制备及在体外光声影像和化疗-热疗协同癌症治疗中的应用

制备了双面神(Janus)结构的聚多巴胺/聚丙烯酸-氢氧化铜纳米粒子(PDA/PAA-Cu(OH)₂ JNPs)。PDA在近红外(NIR)区有较强的吸收,并且具有优异的生物相容性和可降解性;PAA纳米球与铜离子(Cu²⁺)配位后形成的PAA-Cu(OH)₂纳米粒子具有介孔结构,可用于装载抗癌药物;Cu(OH)₂在NIR区有较强的吸收,可用于光热治疗,实现不同功能有机融合,展现协同增效。选用亲水的阿霉素(DOX)作为药物模型,研究了此药物递送系统对肿瘤细胞(HepG-2)的抑制效果。合成的双面神纳米粒子具有高的药物(阿霉素)装载能力(药物负载容量=0.87 mg/mg)、良好的光热转换效率(45.9%)、 pH/近红外(NIR)双重响应药物释放性质和光声(PA)成像能力,可用于体外PA影像和化疗-热疗协同癌症治疗。体外毒性实验结果表明,DOX负载的PDA/PAA-Cu(OH)₂ JNPs加激光组呈现明显的癌细胞死亡,细胞存活率极低(7.9%)。     

用于卵巢癌化疗-光热联合治疗的吉西他滨/聚吡咯复合纳米粒子

利用铁离子诱发吡咯氧化聚合反应制备了尺寸均一的聚吡咯纳米粒子, 并进一步负载化疗药物吉西他滨, 得到了吉西他滨/聚吡咯复合纳米粒子. 该复合纳米粒子对吉西他滨的负载能力强, 在水溶液中的稳定性好, 有助于降低吉西他滨对正常组织的毒副作用. 此外, 该复合纳米粒子在近红外光区有较强的吸收, 能够将吸收的光能转化为热, 是一种良好的光热试剂, 具有光热治疗功能. 同时, 该复合纳米粒子能够在热刺激下释放吉西他滨, 具有光热介导的化疗功能. 因此, 吉西他滨/聚吡咯复合纳米粒子是一种兼具化疗和光热治疗功能的联合治疗试剂. 复合纳米粒子在808 nm近红外激光照射下能够快速提升系统温度, 实现光热治疗与化疗联合杀伤卵巢癌细胞, 具有良好的生物医学应用潜力.     

高分散共轭聚合物-金属有机框架纳米立方体的制备及抗肿瘤应用

纳米尺寸的金属有机框架材料兼具传统框架材料的规整孔隙、高比表面积,和纳米材料在活体中的高渗透和长滞留效应,被广泛应用于药物递送领域.然而,单纯递送化疗药物对肿瘤的治疗效果有限,通常需要联合其他治疗方式以提高治疗效果.本工作开发了一种普适的合成方案,用于共轭聚合物-沸石咪唑酯骨架-8(ZIF-8)复合纳米立方体的制备.借助表面活性剂十六烷基三甲基溴化铵,将疏水共轭聚合物聚[2,6-(4,4-双-(2-乙基己基)-4H-环戊二烯并[2,1-b;3,4-b’]二噻吩)-alt-4,7(2,1,3-苯并噻二唑)](PCPDTBT)包裹在ZIF-8中,得到大小约60 nm的纳米立方体.接着,通过两亲性嵌段共聚物F127的修饰实现其在水溶液中的高分散性和胶体稳定性.该复合材料能够高效负载抗肿瘤药物阿霉素并实现酸响应的药物释放,有助于肿瘤的化疗.同时,ZIF-8的包裹也将PCPDTBT的光热转换效率大幅提升至42.5%,可用于高效的光热治疗.动物实验表明,通过化疗和光热治疗的联合,载药后的复合纳米立方体能够在激光照射下显著抑制肿瘤的生长且不会对正常组织造成明显损伤,是一种高效的抗肿瘤试剂.     

α-环糊精/聚乙二醇自组装超分子纳米药物载体

研究了一种新型超分子纳米药物载体的制备方法及其药物释放性能. 将α-环糊精(α-CD)穿入肉桂酸改性的PEG分子链形成包含复合物(inclusion complex, IC), 通过超分子自组装成为纳米粒子. 将抗肿瘤药物阿霉素负载到纳米粒子中, 研究药物释放行为及其对肿瘤细胞的抑制效果. 以核磁共振(1H NMR)、X射线衍射(XRD)、紫外吸收光谱(UV)、动态光散射(DLS)、扫描电镜(SEM)、透射电镜(TEM)和原子力显微镜(AFM)表征了纳米粒子的结构和形貌, 用激光共聚焦显微镜(Confocal)研究了载药纳米粒子在细胞内的分布及其对肿瘤细胞的抑制效果. 结果显示超分子纳米粒子具有很好的生物相容性和药物缓释作用, 载药纳米粒子对肿瘤细胞具有很好的杀伤效果.     

肿瘤靶向pH响应药物递送-成像体系的合成与控制释放研究

对聚烯丙基胺修饰合成了一种苯硼酸靶向的聚合物配体:聚烯丙基胺/马来酸酐-聚乙二醇-硫辛酸-苯硼酸(PAH/SA-PEG-LA-PBA),共轭作用在ZnO、CdTe/CdS量子点表面,连接抗癌药物阿霉素后形成苯硼酸靶向-示踪诊疗一体体系:ZnO、CdTe/CdS@(PAH/SA-PEG-LA-PBA)-DOX(量子点的荧光可示踪/显像药物递送过程),核磁共振(~1H-NMR)测试表明成功合成了(PAH/SA-PEG-LA-PBA)聚合物,透射电镜(TEM)测得该体系呈规整球形且分布均匀,平均粒径约30 nm;紫外-可见光谱(UV-Vis)和荧光谱图显示该体系具有ZnO、CdTe/CdS量子点的吸收峰,还出现了较强的荧光发射峰,由此说明了苯硼酸靶向的诊疗示踪一体体系的成功制得,负载阿霉素的纳米粒子的载药量为80%.体外释放研究表明,pH 5.0时药物释放速度比pH 7.4时快,48 h后累计释放率达87.1%.因此,该pH响应性纳米颗粒作为抗癌药物载体具有潜在的应用价值.     

氟尿嘧啶-壳寡糖/硒纳米微球的制备及抑制肿瘤细胞生长活性

为研究抗肿瘤药物与辅药负载于同一药物载体的作用效果, 首先以壳寡糖和广谱抗肿瘤药物5-氟尿嘧啶(5-Fu)为原料通过化学键合合成氟尿嘧啶-壳寡糖前体, 然后以其为模板通过溶胶-凝胶法制备了同时负载氟尿嘧啶和硒纳米颗粒的壳寡糖微球. 采用透射电子显微镜(TEM)、 Zeta电位仪和红外光谱(IR)对制备的微球进行了表征, 结果表明, 微球粒径为433 nm, 硒纳米颗粒包裹在微球内; 对微球包裹药物进行检测发现, 5-Fu装载率为(8.2±0.3)%, 硒装载率为(7.96±0.34)%; 体外缓释检测和细胞实验结果证实, 微球能够缓慢释放2种药物, 其缓释作用能很好地抑制肝癌细胞SMMC-7721的生长.     

A Sweet Polydopamine Nanoplatform for Synergistic Combination of Targeted Chemo‐Photothermal Therapy

Inspired by sweet or sugar‐coated bullets that are used for medications in clinics and the structure and function of biological melanin, a novel kind of sweet polydopamine nanoparticles and their anticancer drug doxorubicin loaded counterparts are prepared, which integrate an active targeting function, photothermal therapy, and chemotherapy into one polymeric nanocarrier. The oxidative polymerization of lactosylated dopamine and/or with dopamine are performed under mild conditions and the resulting sweet nanoparticles are thoroughly characterized. When exposed to an 808 nm continuous‐wave diode laser, the magnitude of temperature elevation not only increases with the concentration of nanoparticles, but can also be tuned by the laser power density. The nanoparticles possess strong near infrared light absorption, high photothermal conversion efficiency, and good photostability. The nanoparticles present tunable binding with RCA₁₂₀ lectin and a targeting effect to HepG2 cells, confirmed by dynamic light scattering, turbidity analysis, MTT assay, and flow cytometry. Importantly, the sweet nanoparticles give the lowest IC₅₀ value of 11.67 μg mL⁻¹ for chemo‐photothermal therapy compared with 43.19 μg mL⁻¹ for single chemotherapy and 67.38 μg mL⁻¹ for photothermal therapy alone, demonstrating a good synergistic effect for the combination therapy.     

Dual‐Targeted Selenium Nanoparticles for Synergistic Photothermal Therapy and Chemotherapy of Tumors

A combination of chemo‐ and photothermal therapy has emerged as a promising tactic for cancer therapy. However, the intricacy of accurate delivery and the ability to initiate drug release in specific tumor sites remains a challenging puzzle. Hence, to assure that the chemotherapeutic drug and photothermal agent are synchronously delivered to a tumor area for their synergistic effect, dual‐target (RC‐12 and PG‐6 peptides) functionalized selenium nanoparticles loaded with both doxorubicin (DOX) and indocyanine green (ICG) were designed and successfully synthesized. The as‐synthesized nanoparticles exhibited good monodispersity, size stability, and consistent spectral characteristics compared with those of ICG or DOX alone. The nanoparticles underwent self‐immolated cleavage under irradiation from a near‐IR laser and released the loaded drug owing to sufficient hyperthermia. Moreover, the internalized nanoparticles triggered the overproduction of intracellular reactive oxygen species to induce cell apoptosis. Taken together, this study provides a sequentially triggered nanosystem to achieve precise drug delivery by chemo‐photothermal combination.     

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.     

Multiplex fluorescence imaging-guided programmed delivery of doxorubicin and curcumin from a nanoparticles/hydrogel system for synergistic chemotherapy

Synergistic chemotherapy of doxorubicin and curcumin (CUR) is an important strategy for cancer therapy to compensate for the single drug chemotherapy. Programmed and precise delivery of drugs plays a crucial role for optimizing the mode of administration and revealing the mechanism of synergistic chemotherapy. Herein, multiplex fluorescence imaging-guided programmed delivery of doxorubicin and CUR was achieved by a nanoparticles/hydrogel system for synergistic chemotherapy. CUR-loaded nanoparticles and doxorubicin were co-loaded into hydrogel to construct a synergistic chemotherapy drug delivery system. The hydrogel-nanoparticles combined system can effectively achieve the programmed delivery of hydrophilic drug and hydrophobic drug for the synergistic chemotherapy. They exerted the on-demand spatiotemporal delivery of doxorubicin and CUR. The combined chemotherapy system significantly inhibited the tumor growth compared to single therapy. Moreover, the programmed delivery of doxorubicin and CUR was visualized precisely based on their self-fluorescence instead of extra fluorescent tags at the cellular level and in vivo lever using multiplex fluorescence imaging technology. It afforded an imaging guidance for the controllable synergistic chemotherapy based on programmed delivery.     

葡聚糖分子量和接枝度对阿霉素/白蛋白-葡聚糖纳米粒子体外抗肿瘤效果的影响

以Maillard反应制备的牛血清白蛋白-葡聚糖共价接枝物作为载体, 通过调节混合溶液的pH值和温度制备负载阿霉素的白蛋白-葡聚糖纳米粒子. 利用分子量为5×10³, 10×10³和62×10³的葡聚糖制备了多种共价接枝物, 研究了共价接枝物分子量对载药纳米粒子的粒径和稳定性及载药量的影响. 用短链葡聚糖(分子量5×10³和10×10³)制备的纳米粒子粒径为60 nm左右, 用长链葡聚糖(分子量62×10³)制备的纳米粒子粒径约为200 nm; 阿霉素的包埋效率为81%~98%, 包埋量为7.4%~16.9%. 细胞实验结果表明, 共价接枝物具有很好的生物相容性; 与自由阿霉素相比, 纳米粒子可以促进阿霉素进入人口腔上皮癌细胞; 受缓释性质的影响, 纳米粒子在低浓度时的细胞毒性要小于自由阿霉素. 与长链葡聚糖纳米粒子相比, 接枝度高的短链葡聚糖纳米粒子由于具有较小的粒径、 密集的葡聚糖分子刷表面、 一定的自由阿霉素浓度和较快的阿霉素释放速率, 因而更容易进入细胞并具有更好的体外抗肿瘤活性.     

白山毛桃根抗脑胶质瘤活性成分及其纳米胶束的制备

采用溶剂提取和萃取方法得到白山毛桃根乙酸乙酯、 正丁醇和水层萃取物. 通过噻唑蓝(MTT)比色法考察了各萃取物对脑胶质瘤细胞U87MG活性的抑制作用. 采用高效液相色谱(HPLC)指纹图谱法比对确认活性部位的主要化学成分为2α,3α,24-三羟基-12-烯-28-乌苏酸. 采用溶剂挥发法制备了2α,3α,24-三羟基-12-烯-28-乌苏酸纳米胶束, 对其包封率、 粒径及ζ电位等进行了表征, 并考察了其抗肿瘤活性. 体外细胞实验结果表明, 白山毛桃根乙酸乙酯萃取物对脑胶质瘤细胞U87MG具有抑制作用, 通过与标准品比对确认2α,3α,24-三羟基-12-烯-28-乌苏酸为乙酸乙酯部位的主要成分, 且该成分对脑胶质瘤细胞活性具有较强抑制作用. 通过溶剂挥发法制备的2α,3α,4-三羟基-12-烯-28-乌苏酸纳米胶束包封率为64.7%, 粒径为20 nm, 粒径分布宽度(PDI)为0.246, ζ电位为-5.7 mV. 细胞实验结果进一步证明, 与单体化合物相比, 2α,3α,24-三羟基-12-烯-28-乌苏酸纳米胶束对脑胶质瘤细胞活性具有更强的抑制作用, 为白山毛桃根在脑胶质瘤治疗中的应用提供了实验依据.     

A facile preparation method for nanosized MOFs as a multifunctional material for cellular imaging and drug delivery

Tb-based metal-organic framework nanoparticles (Tb-MOF NPs) with good colloidal stability and stable fluorescence properties in an aqueous solution were prepared by a simple mechanical grinding of Tb-MOF with a biocompatible polymer surfactant (F127). The characteristic fluorescence property of Tb-MOF NPs allowed us to use this nanomaterial as a cell imaging probe. Efficient cellular uptake of Tb-MOF NPs apparently via an energy-dependent endocytosis was observed by confocal laser scanning microscopy. By taking advantage of the porous nature of the Tb-MOF NPs an anticancer drug (doxorubicin) was successfully loaded and delivered to kill cancer cells to demonstrate their usage as a drug delivery vehicle. This simple grinding method afforded a nanosized, multifunctional biomaterial that was used for cell imaging and drug delivery, and it can be extended to other MOFs to widen their applications.     

Mild hyperthermia-enhanced chemo-photothermal synergistic therapy using doxorubicin-loaded gold nanovesicles

Gold nanovesicles(GVs) with unique plasmonic property and large cavity hold great potential as a stimuli-responsive nanocarrier to deliver drugs for efficient tumor chemotherapy and other therapies synergistically.Herein,we developed doxorubicin-loaded gold nanovesicles(DGVs),offering infrared thermal(IRT) and photoacoustic(PA) dual-modal imaging guided mild hype rthermia-enhanced chemophotothermal cancer synergistic therapy.The DGVs are self-assembled by gold nanoparticles modified with amphiphilic copolymer in a predetermined concentration of doxorubicin through film rehydration method.Under the influence of laser excitation,the as-prepared DGVs exhibited good photothermal effect,which triggered the structural disruption of GVs and thus,allowed the efficient release of encapsulated DOX to enhance cell uptake for fluorescence imaging and tumor chemotherapy,respectively.In addition,DGVs also showed a strong PA and IRT signals in vivo.Our study demonstrated the potential of DGVs as stimuli-responsive drug delivery systems and cancer theranostics.     

pH/酶/光热多重响应的金纳米笼/透明质酸核壳结构纳米载体的制备与性能

以金纳米笼(AuNC)为核, 巯基化改性的透明质酸(LC-HA)为壳, 盐酸阿霉素(DOX)为药物模型, 通过简单的一锅法制备了核壳结构载药纳米粒子DOX@AuNC@HA(DAH). 金纳米笼为药物装载提供容器且赋予载体光热性能, 改性的透明质酸对金纳米笼进行包封并提供pH/酶响应及靶向介导功能. 对DAH的结构进行了表征, 并进行了载药、 控释性能以及细胞摄取和细胞毒性的研究. 结果表明, 核壳结构纳米微粒DAH具有较高的载药能力, 在激光源的照射下具有较好的循环稳定性和较高的光热转换率. 在pH=7.4的磷酸盐缓冲液中, DAH具有较高的稳定性, 20 h的药物泄露率低于20%; 而在酸性环境、 透明质酸酶(HAase)及光热作用下, DAH均能较快地释放出装载的药物, 展现出较好的刺激响应性. 此外, DAH能够更多地被肿瘤细胞摄取, 表现出一定的靶向性; 当化疗与光热疗法共同作用时, 肿瘤细胞的活性大大减弱, 展现出了联合疗法的优势及潜力.