肿瘤主动靶向磁性纳米粒子研究现状及其在肿瘤热疗中的应用

 磁性纳米粒子已广泛应用于肿瘤的成像和治疗,但限制其临床应用的重大障碍是纳米粒子在肿瘤部位不能达到足够的浓度。主动靶向磁性纳米粒子是磁性纳米粒子表面偶联特定的靶向配体,靶向性结合特定的肿瘤细胞。靶向配体的选择是提高主动靶向性的关键。主动靶向性提高了磁性纳米粒子在肿瘤组织内的浓度,减少对正常组织的毒性,从而使其在肿瘤成像与治疗成为可能。磁感应热疗利用磁介质在外加交变磁场的作用下感应发热,是一种新型的具有前景的肿瘤治疗手段。依靠磁性纳米粒子主动靶向性,磁感应热疗将更好地实现细胞内热疗,提高肿瘤治疗的疗效。     

用于高效磁转染的鱼精蛋白修饰的铁氧磁性纳米粒研究

 功能化铁氧磁性纳米粒在生物医学中应用广泛,可用于肿瘤磁感应热疗、磁共振成像（Magnetic Resonance Imaging,MRI）、药物输送及磁转染等方面。为了探讨鱼精蛋白功能化修饰的铁氧磁性纳米粒的制备及其作为基因载体在体外磁转染中的可行性,采用共沉淀法制备Fe3O4磁性纳米粒,经表面氨基化修饰后在其表面偶联鱼精蛋白。利用透射电镜、傅里叶红外光谱仪、zeta电位与粒度分析仪等,对磁性纳米粒进行形态、粒径及zeta电位分析等表征检测。共聚焦显微镜观察磁转染方法转染报告基因绿色荧光蛋白质粒pEGFP-N1进入HepG2细胞的表达,以真核转染试剂vigofect为对照。结果显示,实验中制备的磁性纳米粒粒径10nm左右,在交变磁场下具有良好的升温性能。鱼精蛋白功能化修饰磁性纳米粒后,其zeta电位进一步增大,更利于与DNA有效结合,在HepG2细胞系,其转染pEGFP-N1质粒的效率高于vigofect。研究表明,鱼精蛋白功能化修饰的铁氧磁性纳米粒可作为磁转染的有效载体,由于其同时具备在交变磁场下升温的性能,在基因治疗联合热疗的研究领域具有一定的应用价值。     

靶向振荡磁场发生器的研制

针对药物靶向治疗中难以产生足够磁场强度和梯度的交流脉冲磁场问题,提出了采用双极性脉冲电流产生靶向引导磁场的新思路,研制了一种适用于磁性药物聚焦和控制药物释放的靶向振荡磁场发生器,其主电路拓扑利用负载能量回馈,减少电路损耗,提高电流幅值和电流脉冲陡度,从而提高磁场强度和磁场强度变化率。该装置输出频率0.125~32 Hz,磁感应强度达1.3 T,正弦磁场、单极性和双极性脉冲磁场的磁性微粒聚焦效果和振荡效果的对比实验,证明双极性陡脉冲强磁场更适用于靶向治疗。双极性脉冲强磁场中磁性微粒聚集速度快,聚焦效果好,振荡现象明显。     

无机纳米载体在靶向药物输送中的应用研究进展

纳米材料在生物领域的渗透形成了纳米生物材料,而纳米药物载体的研究是纳米生物材料的前沿和热点之一.常见的无机纳米药物载体包括磁性纳米粒子、介孔二氧化硅、纳米碳材料、量子点等,这些无机纳米药物载体在实现靶向性给药、控释和缓释药物以及癌症靶向治疗等方面表现出良好的应用前景.而且,集成像、靶向给药和癌症治疗功能于一身的多功能纳米药物载体比常规化疗药物载体具有明显优势.文中综述了近年来上述无机纳米材料尤其是多功能无机纳米载体在靶向药物输送中的应用及其载药释药行为的研究进展.     

反相微乳液法制备5-Fu磁性靶向药物及其释药性能

以5-氟脲嘧啶（5-Fu）为模型药,壳聚糖（cs）为包覆材料,纳米四氧化三铁（Fe,O。）作为磁核,戊二醛为交联剂,通过反相微乳液制备5-Fu磁性靶向纳米微粒。最佳实验条件为：乳化剂用量为8％（v／v）,壳聚糖浓度为1．5％（w／w）,Fe3O4／CS为0．6（w／w）,复合乳化剂的HLB值为6,5-Fu／CS为0．4（w／w）,油水体积比为3：1,反应温度为55℃。磁性靶向药物的产率为83．06％、载药率为13．90％、包封率达到56．67％。通过模拟胃液（pH=1．8）和肠液（pH=7．6）做体外药物缓释实验。结果显示,在两种介质中,27小时内药物释放累积释药量分别为11．90％和10．23％,一定程度上达到了缓释、延长药效的目的。     

Glycyrrhetinic acid-modified nanoparticles for drug delivery: Preparation and characterization

In this work, glycyrrhetinic acid-modified chitosan （mGA-suc-CTS） used as liver targeted carrier for drug delivery, was prepared via hemisuccinate as a bridged group. The structure of the product was confirmed by IR and NMR methods and the degree of substitution （DS） of glycyrrhetinic acid groups was estimated via elemental analysis. Nanoparticles were formed by ionic gelation methold. The drug-loading and release behavior of the nanoparticles were investigated using BSA as the model drug. The results indicated that the carrier with a highest DS of 5.19% could be got and the DS was controlled by changing reaction temperature or feed ratio. BSA could be entrapped into the nanoparticles with the drug-loading ratio of 26.3% and the encapsulation efficiency of 81.5%. A sustained release over an 11-day period was observed in pH 7.4 in vitro.     

Heating effect and biocompati bility of bacteri al magnetoso mes as potential materials used in magnetic fluid hyperthermia

Magnetic fluid hyperthermia (MFH) promises to be a viable alternative in the treatment of localized cancerous tumors.The treatment consists of introducing nanoparticles as energy absorbent agents in tu...     

羧基磁流体制备和牛血清白蛋白表面修饰

 磁性纳米粒已被用作肿瘤磁感应热疗的介质，目前常用纳米Fe3O4，其经典制备方法是化学共沉淀法，得到具有超顺磁性的纳米Fe3O4粒径约为10～15nm。本文采用改进的化学共沉淀法制备聚丙烯酸（PAA）修饰的羧基纳米Fe3O4，通过EDC、NHS活化法偶联模型蛋白牛血清白蛋白（BSA），用BCA定量分析磁粒对BSA的偶联效率，并进一步偶联荧光标记的抗体，观察偶联效果。结果表明，改进的化学共沉淀法制备的羧基纳米粒粒径约10nm，水相分散性良好；定量分析和光学观察结果均显示，采用EDC、NHS活化法能使蛋白质与羧基化磁性颗粒稳定结合。本研究为靶向磁性纳米粒的制备提供一种新方法。     

ZnFe2O4@SiO2纳米核壳结构的合成及磁性随退火温度的演化

采用水热法合成了直径为10~15 nm的ZnFe2O4磁性纳米颗粒,将ZnFe2O4磁性纳米粒子添加到TEOS中,水解后得到ZnFe2O4@SiO2核壳结构的纳米复合材料,TEM图像证实了复合材料具有直径约为20 nm的核壳结构.制备出的ZnFe2O4磁性纳米粒子和ZnFe2O4@SiO2核壳结构纳米复合材料都表现出了顺磁性,温度低于800 ℃时ZnFe2O4磁性纳米粒子仍然具有顺磁性,温度高达580 ℃时ZnFe2O4@SiO2核壳结构纳米复合材料还是显示出了超顺磁性,这意味着ZnFe2O4和ZnFe2O4@SiO2磁性纳米粒子具有良好的磁稳定性.由于SiO2壳具有很好的亲水性和抗酸性,ZnFe2O4@SiO2核壳结构纳米复合材料未来可应用于磁疗法治疗癌症.     

纳米级Mn-Zn软磁铁氧体磁粉溶胶-凝胶法制备

目的提高超细粉合成反应活性,降低合成温度,改善超细粉烧结性能,从而提高锰锌铁氧体的性能。方法应用溶胶-凝胶法制备软磁Mn-Zn铁氧体磁粉。用X射线衍射(XRD)和透射电镜(TEM)对粉体材料进行分析表征,并用振动样品磁强计(VSM)测定样品的饱和磁化强度和矫顽力。结果所得样品为纳米级单相Mn-Zn铁氧体,其晶粒大小约为40 nm,M=0.14 552 EMU,HC=11 480 Oe,这表明该纳米级Mn-Zn铁氧体不具有超顺磁特性,而具有很好的活性。结论采用溶胶-凝胶法制备的纳米级Mn-Zn铁氧体磁粉,可以用来制备高性能的软磁Mn-Zn铁氧体材料。     

铁炭复合磁性载体的制备及性能测定

采用中和沉淀法对球磨法制备的Fe3O4/C初级复合磁性载体进行了表面改性,并经过固相高温还原得到了铁炭复合磁性载体。制备的载体分别用TEM、XRD、TG及TPM-7 BH仪进行了表征。考察了磁靶向药物载体的热稳定性,并对其在空气中磁性能的变化规律及其在类似人体的环境中磁性能的变化趋势进行了考察。结果表明:所制备的复合磁性载体能满足实际应用的要求。     

反相乳液聚合制备阿霉素磁性抗癌毫微粒

以阿霉素为模型药物,Fe3O4为磁核,乙烯吡咯烷酮(NVP)为载体,通过反相乳液聚合法制备了阿霉素磁性抗癌毫微粒,并对影响阿霉素磁性毫微粒大小及粒径分布的因素进行了考察.环境扫描电镜表明,最佳制备条件下制得的毫微粒外观光滑,大小均匀;激光光散射测定表明该产物平均粒径为500 nm,粒径分布系数0.23,呈单分散分布;红外光谱测试证明本实验所制备的毫微粒是由阿霉素、Fe3O4和聚乙烯吡咯烷酮共同组成.     

PEI修饰磁性Fe3O4纳米粒的制备和表征

 为了制备性能良好的聚乙烯亚胺（PEI）修饰的磁性Fe3O4纳米粒,以及为进一步开展体内外生物学效应分析奠定基础,采用化学共沉淀法制备PEI修饰的磁性Fe3O4纳米粒。PEI-Fe3O4纳米粒的制备包括磁性Fe3O4纳米粒的制备和PEI修饰磁性Fe3O4纳米粒两部分,采用4因素2水平的正交实验对各因素进行优化,得到较佳的制备工艺。反应过程中用过量氨水保持pH值为9.3~9.7,Fe2+与Fe3+的物质的量比为1:1.75,PEI水溶液的质量百分数为20%,反应温度始终保持为85℃,机械搅拌速率为1400r/min。采用傅里叶变换红外光谱仪（FTIR）、透射电子显微镜（TEM）、X射线衍射分析仪（XRD）、振动样品磁强计（VSM）、热重分析仪（TGA）对磁性纳米粒的物化特征进行表征。结果表明,制得的磁性PEI-Fe3O4纳米粒为接近圆形或椭圆形粒子,具尖晶石结构,粒径约9.4nm,磁含量为82.3%,饱和磁化强度为61.962emu/g,矫顽力几乎为0,具超顺磁性,稳定性和分散性良好。     

一种具有磁光性能的潜在药物载体的研制

磁小体是磁靶向给药领域的研究热点,为了精准示踪生物体内的磁小体来指导靶向,基于磁小体和量子点构建一种新型磁光载体.利用静置培养和磁吸附的方法收集富含磁小体的趋磁细菌AMB-1,并通过超声破碎及磁吸附方法提取长度为5~10个的磁小体链,运用点击化学反应将含有羧基的CdTe/CdS量子点修饰到磁小体膜上,并利用人肝癌细胞HepG2初步开展光示踪有效性的验证.结果发现该载体可以成功地被细胞摄取,并在细胞内观测到磁小体的分布.笔者成功地研制出磁光载体,为后续的磁靶向给药、磁靶向热疗及荧光一体化的研究及应用提供了坚实的基础.     

Preparation of folateconjugated starch nanoparticles and its application to tumor-targeted drug delivery vector

The lower toxicity and high effect of drug are very important for clinic therapy. So more and more atten-tion has been paid to the targeted drug delivery system. Folate receptor (FR) has been reported to be vastly overexpressed in most human tumors but se…     

磁热响应复合载药胶束的热化疗协同效应

以N-异丙基丙烯酰胺(NIPAM)、N,N-二甲基丙烯酰胺(DMAM)为单体,通过可逆加成-断裂链转移聚合(RAFT),制备了一种临界相转变温度(LCST)为42.5℃的温敏性两亲性嵌段共聚物PLA29-b-P(NIPAM29-co-DMAM13)。通过高温前驱体分解法制备了单分散超顺磁性纳米粒子Mn_(0.6)Zn_(0.4)Fe_2O_4;并采用自组装得到了载有药物(喜树碱,CPT)和磁性纳米粒子的磁热温敏复合载药胶束。通过透射电子显微镜、紫外光分光光度计以及MTT等对该胶束的形态、药物控释能力和细胞毒性进行了研究。结果表明,该胶束具有良好的生物学和药物控释性能。同时,通过激光共聚焦显微镜与流式细胞仪研究了磁热温敏复合载药胶束在不同条件下对特定肿瘤细胞的生长抑制作用。结果表明,磁热疗和化疗的高效协同效应可促进肿瘤细胞对药物的吞噬,增强药物对肿瘤细胞的毒性。对该载药胶束的磁热化疗协同增效机制也进行了初步探究。     

Effect of local hyperthermia induced by nanometer magnetic fluid on the rabbit VX2 liver tumor model

Hyperthermia induced by magnetic nanoparticles is a recent therapeutic approach for local targeting of hyperthermia and thermoablation and is a promising treatment of malignant tumors.The purpose of this study is to evaluate the potential and therapeutic effect of magnetic fluid hyperthermia on the rabbit VX2 liver tumor model.Rabbits bearing liver tumors 14 days after tumor implantation were randomly divided into five groups of 10 cases each,including three control groups and two hyperthermia groups.Hyperthermia was carried out immediately after a single intratumoral injection of uncoated water-based Fe3O4 magnetic fluid under an alternating magnetic field only once as one hyperthermia group and repeated hyperthermia after 5 days as the other treated group.The distribution of magnetic fluid was evaluated by CT scanning.All animals were sacrificed 4 weeks after tumor implantation.The therapeutic effect was determined by tumor size and macroscopic and pathological examination of the liver tumor.The local higher density imaging of intratumoral magnetic fluid deposits compared to the surrounding tissue was clearly observed by CT scanning.Twenty-eight days after tumor implantation,the tumor maximal diameter and tumor volume of two hyperthermia were both significantly less than those of control groups (P＜0.05).Tumor volume inhibition by single or repeated hyperthermia compared to the three control groups was 71.93-79.91% and 92.34-94.46% (P＜0.05),respectively.Under a microscope,coagulation necrosis was observed in the heated area,which had a clear boundary line with the surrounding tissue.The intratumoral distribution of magnetic nanoparticles,especially in the area of necrosis,appeared much more homogenous than in the untreated ones.This study demonstrates that hyperthermia induced by direct intratumoral injection of magnetic fluid can be used safely,and a well-homogenized distribution of high intratumoral temperature without heating adjacent to normal tissue can be achieved.     

磁性纳米颗粒的二维光操纵及团聚效应

我们利用暗场显微镜系统地研究了水剂磁性液体中Fe3O4磁性纳米颗粒在高度聚焦激光作用下的动力学过程.实验研究表明:当激光聚焦在样品池中间时,由于受到沿激光入射方向强散射力和吸收力的作用,磁性纳米颗粒会被排开至光斑的外围;当激光聚焦在样品池上表面时,在光力和样品池上玻片的共同作用下,磁性纳米颗粒会被捕获在样品池的上玻片的下表面并发生团聚效应;此外,我们还研究了不同激光功率作用下形成的磁性纳米团簇对入射白光的透过谱的影响,随着入射激光功率的增加,透过磁性液体的白光的透过率会急剧下降,而且透射谱的中心波长会随着入射激光功率的增加往长波方向移动.     

Effect of EGF1 peptides in directing nanoparticles to thrombi

In order to examine the effect of EGF1 peptides in directing nanoparticles to thrombi, the synthesized EGF1 peptide was conjugated to poly (ethyleneglycol)-poly (lactide) (PEG-PLA) nanoparticles (NP) to form EGF1-NP. A lipophilic fluorescent dye, coumarin-6, was incorporated into EGF1-NP so as to detect its loading and release capacity. The binding ability of EGF1-NP with TF-expressing cells was shown to be significantly higher than that of the non-conjugated NP. Following an intravenous administration, fluorescence was distributed along the vessel wall of the thrombosis regions in the model rats injected with coumarin-6-loaded EGF1-NP. The in vitro and in vivo results suggest that EGF1-NP is a promising drug delivery system for targeting cerebral thrombi.     

Solid lipid nanoparticles loading adefovir dipivoxil for antiviral therapy

Herein, solid lipid nanoparticles （SLN） were proposed as a new drug delivery system for adefovir dipivoxil （ADV）. The octadecylamine-fluorescein isothiocynate （ODA-FITC） was synthesized and used as a fluorescence maker to be incorporated into SLN to investigate the time-dependent cellular uptake of SLN by HepG2.2.15. The SLN of monostearin with ODA-FITC or ADV were prepared by solvent diffusion method in an aqueous system. About 15 wt% drug entrapment efficiency （EE） and 3 wt% drug loading （DL） could be reached in SLN loading ADV. Comparing with free ADV, the inhibitory effects of ADV loaded in SLN on hepatitis B surface antigen （HBsAg）, hepatitis B e antigen （HBeAg） and hepatitis B virus （HBV） DNA levels in vitro were significantly enhanced.