CN111184861A - 一种基于他莫昔芬的金属-纳米药物的制备方法及其产品与应用 - Google Patents
一种基于他莫昔芬的金属-纳米药物的制备方法及其产品与应用 Download PDFInfo
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Abstract
本发明公开一种基于他莫昔芬的金属‑纳米药物的制备方法及其产品与应用，本发明所述FePt@FeO@TAM@PSMA‑PEG纳米药物在肿瘤偏酸性的环境刺激下表现出很好的芬顿反应催化效果，利用肿瘤微环境内较低的pH来激活他莫昔芬和FePt@FeO释放，催化癌细胞内源性高表达的过氧化氢产生高毒性的羟基自由基，导致细胞内DNA的损伤，从而使癌细胞凋亡坏死，同时降低肿瘤细胞的耗氧量，抑制癌细胞的转移，实现了对肿瘤生长的高效抑制。这种双模协同治疗方式有效降低了抗癌药物他莫昔芬自身的机体毒性。
Description
技术领域
本发明属于纳米药物技术领域，具体涉及一种基于他莫昔芬的金属-纳米药物的制备方法及其产品与应用。
背景技术
癌症仍然是全球主要的公共卫生问题之一，也是世界上第二大死亡原因。目前，常用的化疗存在的问题主要有：1)本身递送至肿瘤部位的药物量有限；2)化疗药物他莫昔芬水溶性差，生物利用度低；3)具有很高的毒副作用等。另外，基于高毒性活性氧(ROS)的方法已广泛应用于癌症治疗。近年来，化学动力学治疗(CDT)由于其高效率和最小的副作用而备受关注。化学动力学治疗采用芬顿或类芬顿反应，可在酸性条件下将肿瘤内的过氧化氢转化为具有高氧化性的羟基自由基(·OH)，杀伤癌细胞，而无需外部刺激，从而避免了有限的穿透深度的问题和对健康组织的副作用。尽管纳米技术的进步为通过芬顿反应促进癌症治疗提供了一种有前景的方法，但仍有许多挑战尚待克服。例如：(1)化学动力学治疗效率低下；(2)对正常组织显著的副作用等，极大地阻碍了这一治疗方法向临床转化。基于此，很多课题组制备了在肿瘤原位生成过氧化氢以提高类芬顿反应效率的纳米材料，以实现更有效的化学动力学治疗。然而，这些策略不能很好地实现对肿瘤的选择性治疗。
为了解决这一难题，探索在肿瘤区域特异性激活后才能产生诊断和治疗效果的“turn-on”化学动力学治疗药物具有极大的意义。众所周知，肿瘤微环境具有自身的特性，例如偏酸性，高表达H2O2和GSH，缺氧和某些高表达酶等，因此，设计仅在肿瘤微环境下响应的药物可表现较低的正常组织毒性和较高的药物生物利用度，极大地减轻了治疗带来的副作用。
生物医学成像对于癌症的早期检测和诊断是必不可少的。科学家们已经探索了许多成像方式，例如磁共振成像和光声成像，但是每种方法都有其自身的缺点。磁共振成像虽然具有出色的组织穿透能力和空间分辨率，然而，T1造影剂在分子成像时灵敏度不高，T2造影剂成像时难以与本身磁共振信号的组织(例如骨骼，肺部)区分开。而光学成像会受到组织穿透深度的限制。因此，应设计一种多模式成像探针，以提供用于癌症诊断的补充成像信息。
发明内容
针对现有技术的缺陷，本发明的目的是提供一种药物利用度高、毒副作用小且可辅助医学成像的法基于他莫昔芬的金属-纳米药物的制备方及其产品与应用。
本发明这种基于他莫昔芬的金属-纳米药物的制备方法，包括以下步骤：
1)纳米酶FePt@FeO的合成：二乙酰丙酮铂(Pt(acac)2)、1,2-十六烷二醇和1-十八烯加入到三颈烧瓶中，抽真空后，在惰性气氛下，加入油酸，油胺和三乙酰丙酮铁(Fe(acac)3)，回流反应设定时间后，过滤洗涤，得到纳米酶FePt@FeO，将其分散在环己烷中保存；
2)FePt@FeO@TAM@PSMA纳米颗粒的合成：将步骤1)制备的纳米酶FePt@FeO、他莫昔芬(TAM)和苯乙烯-顺丁烯二酸酐(PSMA)置于THF中，超声后，快速注射到水中，进行第二次超声，然后向其中注射碳酸钠溶液，进行第三次超声，再将混合液进行旋蒸，除去四氢呋喃，得到含有FePt@FeO@TAM@PSMA纳米颗粒的溶液；
3)FePt@FeO@TAM@PSMA纳米颗粒的改性：向步骤2)中含有FePt@FeO@TAM@PSMA纳米颗粒溶液中加入氨基聚乙二醇(PEG-NH2)搅拌反应后，离心洗涤得到FePt@FeO@TAM@PSMA-PEG纳米颗粒，即为基于他莫昔芬的金属-纳米药物。
所述步骤1)中，Pt(acac)2、1,2-十六烷二醇、油酸，油胺和Fe(acac)3的摩尔比为1:(2～4):(1～3):(1～3):(20～30)，Pt(acac)2与1-十八烯的摩尔体积比为0.01～0.02mmol/mL；抽真空温度为70～90℃，抽真空时间为20～40min；回流反应温度为250～350℃，回流反应时间为0.5～2h；洗涤采用体积比为1:4的环己烷和乙醇混合溶液，洗涤次数为2～4次。
所述步骤2)中，纳米酶FePt@FeO、TAM和PSMA的质量比为1:(4～6):(20～30)，纳米酶FePt@FeO与THF的质量体积比为0.05～0.15mg/mL；THF与水的体积比为1:(8～10)；碳酸钠水溶液的浓度为9～11mg/mL，THF与碳酸钠水溶液的体积比为1:(0.3～0.7)；第一次超声时间为0.5～2min，第二次超声时间为0.5～2min，第三次超声时间为7～9min，旋蒸温度为40～50℃。
所述步骤3)中，PEG-NH2与步骤2)中TAM的质量比为(4～5):1，搅拌反应时间为5～7h，所得的FePt@FeO@TAM-PEG纳米颗粒在3～5℃温度下保存。根据所述的制备方法制备得到基于他莫昔芬的金属-纳米药物。
所述的基于他莫昔芬的金属-纳米药物的平均粒径在80～120nm。
所述的基于他莫昔芬的金属-纳米药物在作为诊断治疗癌症药物中的应用。
本发明的原理：本发明这种基于他莫昔芬的金属-纳米药物可以实现肿瘤特异性药物释放和ROS的生成，用于多模态成像指导的化疗/化学动力学治疗联合治疗。FePt@FeO@TAM@PSMA-PEG纳米颗粒由FePt@FeO和小分子化疗药物他莫昔芬制成，并用亲水性氨基聚乙二醇(PEG-NH2)修饰。在肿瘤微酸性环境中，由于他莫昔芬的结构在酸性条件下从疏水性变为亲水性(在酸性环境中TAM结合细胞内的H+质子化)，FePt@FeO@TAM-PEG纳米颗粒可以迅速分解为FePt@FeO复合物和他莫昔芬。更进一步而言，全身给药后，FePt@FeO@TAM@PSMA-PEG纳米粒子具有有效的肿瘤蓄积性，由于其pH响应解离行为，FePt@FeO和TAM的肿瘤内穿透性显着提高。同时，由于TAM能够通过抑制复合物I的线粒体电子传输链来减缓癌细胞的耗氧量，因此在静脉注射FePt@FeO@TAM@PSMA-PEG纳米颗粒可显著减轻肿瘤缺氧。因此，它减轻了由肿瘤缺氧引起的肿瘤增殖和转移，提高了治疗效果。此外，他莫昔芬可以增加细胞糖酵解过程，导致乳酸积累，增加的细胞内酸度反映了乳酸代谢的上调，从而促进了FePt@FeO@TAM@PSMA-PEG和FePt@FeO复合物的分解，释放的Fe2+可以与H2O2发生芬顿反应生成高毒性的ROS，从而导致氧化应激诱导的细胞凋亡，起到了“1+1>2”的效果。由于这些作用，FePt@FeO@TAM@PSMA-PEG纳米药物可以大大提高化学/化学动力学联合治疗的功效，以抑制肿瘤的生长。此外，FePt@FeO@TAM@PSMA-PEG纳米颗粒具有很好的磁性和光学性质，可用于磁共振(MR)和光声(PA)成像，以指导和跟踪癌症治疗。因此，本发明中的FePt@FeO@TAM@PSMA-PEG纳米药物可以显著提高癌症成像和治疗的准确性和特异性，具有很大的应用前景。
本发明的有益效果：
(1)本发明制备了一种用于高效的癌症联合治疗生物纳米药物：基于化疗药物他莫昔芬的金属-药物纳米材料及其制备方法和应用，该纳米药物以常用化疗药物他莫昔芬和纳米酶FePt@FeO通过疏水作用形成纳米颗粒，该药物仅在肿瘤处特异性激活，减轻对正常细胞的毒副作用，解决了小分子化疗药物本身存在的不足，极大改善了一般化疗药物存在的水溶性差、毒副作用高的问题，并结合肿瘤部位的特异性，激活纳米药物进行癌症高效治疗。
(2)本发明所述FePt@FeO@TAM@PSMA-PEG纳米药物在肿瘤偏酸性的环境刺激下表现出很好的芬顿反应催化效果，利用肿瘤微环境内较低的pH来激活他莫昔芬和FePt@FeO释放，催化癌细胞内源性高表达的过氧化氢产生高毒性的羟基自由基，导致细胞内DNA的损伤，从而使癌细胞凋亡坏死，同时降低肿瘤细胞的耗氧量，抑制癌细胞的转移，实现了对肿瘤生长的高效抑制。这种双模协同治疗方式有效降低了抗癌药物他莫昔芬自身的机体毒性(作用过程如图1所示)。
(3)本发明通过简单纳米共沉淀法制备纳米药物，制备流程短、操作简单、成本低。
(4)本发明还提供了所述FePt@FeO@TAM@PSMA-PEG纳米药物在肿瘤检测方面的应用。利用该纳米药物较好的磁性能和光学特性，通过磁共振成像和光声成像实现了该药物对肿瘤的成像及精准检测。因此，这一纳米药物对癌症的诊疗具有临床指导意义。
附图说明
图1本发明FePt@FeO@TAM@PSMA-PEG纳米药物的作用过程示意图；
图2本发明FePt@FeO@TAM@PSMA-PEG纳米药物制备过程图；
图3为实施例1制备的FePt@FeO@TAM@PSMA-PEG纳米药物的TEM图；
图4为实施例2中FePt@FeO@TAM@PSMA-PEG纳米药物磁性能的表征。
图5为实施例2中FePt@FeO@TAM@PSMA-PEG纳米药物光学特性的表征。
图6为实施例2中FePt@FeO@TAM@PSMA-PEG纳米药物的芬顿反应效果图。
图7为实施例2中FePt@FeO@TAM@PSMA-PEG纳米药物的荧光成像图；
图8为实施例2中FePt@FeO@TAM@PSMA-PEG纳米药物对癌细胞的细胞毒性分析图；
图9为实施例2中FePt@FeO@TAM@PSMA-PEG纳米药物癌毒性凋亡分析图；
图10为实施例2中FePt@FeO@TAM@PSMA-PEG纳米药物对小鼠肿瘤的光声成像图；
图11为实施例2中FePt@FeO@TAM@PSMA-PEG纳米药物对小鼠肿瘤的T2-MRI图像；
图12为实施例2中中FePt@FeO@TAM@PSMA-PEG纳米药物抑制肿瘤生长的数据分析图。
具体实施方式
本发明FePt@FeO@TAM@PSMA-PEG纳米药物的制备过程示意图如图2所示，具体制备过程如实施例中所述。
实施例1
(1)FePt@FeO的合成，将Pt(acac)2(0.125mmol)，1,2-十六烷二醇(0.375mmol)和10mL 1-十八烯添加到装有搅拌磁子的三颈烧瓶中，并在80℃抽真空30分钟。在氮气流下加入油酸(0.25mmol)，油胺(0.25mmol)和Fe(acac)3(3mmol)。将混合物加热至300℃并回流1h，然后使其冷却至室温。用体积比为1:4的环己烷：乙醇溶液洗涤产物3次，并再分散在环己烷中保存。
(2)将合成的FePt@FeO配制成5mg/mL的四氢呋喃溶液，将他莫昔芬配制成3.2mg/mL的四氢呋喃溶液，将表面活性剂聚(苯乙烯-顺丁烯二酸酐)(PSMA)配制成20mg/mL的溶液，置于4℃冰箱保存。
(3)FePt@FeO@TAM纳米颗粒的合成：首先，取156μL TAM的四氢呋喃溶液，20μLFePt@FeO的四氢呋喃溶液和125μL PSMA的四氢呋喃溶液，再加入699μL四氢呋喃，将这1mL混合物超声1分钟，再将混合物快速注射到9mL水中，超声1分钟后快速注射500μL碳酸钠水溶液(10mg/mL)，超声处理8分钟后，将混合液在45℃下旋蒸除去四氢呋喃；然后将去除四氢呋喃的反应液用100K超滤管对进行水洗和离心3次，转速为4200r/min，每次离心时间为2min。
(4)取2.4mg PEG-NH2加入步骤(3)所得溶液，室温搅拌6小时，然后离心并用去离子水洗涤3次，转速为4200r/min，每次离心时间为6min；所得的FePt@FeO@TAM@PSMA-PEG纳米颗粒4℃保存。
对本实施例制备的FePt@FeO@TAM@PSMA-PEG纳米颗粒进行TEM测试，其结果如图3所示，从图3可以看出本实施例制备的FePt@FeO@TAM@PSMA-PEG的平均尺寸为100nm。
实施例2性能测试
1、基于他莫昔芬的金属-纳米药物的磁性能测试
将实施例1所得的FePt@FeO纳米粒子和FePt@FeO@TAM@PSMA-PEG水溶液分别配制不同的浓度梯度的水溶液，用Bruker Minispec分析仪(60MHz)测定T2加权的弛豫时间，其结果如图4所示，从图4可以看出FePt@FeO@TAM@PSMA-PEG纳米药物具有更好的T2成像效果，这是因为与FePt@FeO纳米粒子相比，FePt@FeO@TAM@PSMA-PEG中的Fe为聚集态，而聚类磁性纳米粒子与粒子之间的距离减小，可以显著增加横向弛豫，因此FePt@FeO@TAM@PSMA-PEG纳米粒子具有更好的T2成像效果。
2、基于他莫昔芬的金属-纳米药物光学性能的验证
将实施例1制备的FePt@FeO@TAM@PSMA-PEG溶液分别配制不同浓度(最终浓度：0、10、20、30、40和50μg/mL)，用光声成像仪器检测该药物在700nm处的光声信号。
图5为纳米药物光声特性的表征，从图5可以看出随着Fe浓度的增加，FePt@FeO@TAM@PSMA-PEG溶液的光声信号逐渐增强。
3、基于他莫昔芬的金属-纳米药物pH响应的芬顿反应效果测定
采用实施例1制备的FePt@FeO@TAM@PSMA-PEG纳米粒子(终浓度为60μg/mL)，与等量的不同pH(7.4，6.4，5.4，4.4，3.4)的磷酸缓冲液中反应6h，然后分别加入等量3,3,5,5-四甲基联苯胺(TMB)(终浓度为0.5mM)，H2O2(终浓度为0.3mM)，室温下孵育1h后测测紫外-可见吸收光谱(450～900nm)。
图6为纳米药物的芬顿反应效果图，证明在H2O2存在的条件下，FePt@FeO@TAM@PSMA-PEG能够催化过氧化氢产生足够的羟基自由基，氧化TMB。这是因为在肿瘤微酸性条件下，FePt@FeO@TAM@PSMA-PEG发生分解，释放出铁离子，其能与癌细胞内源性H2O2反应，产生高毒性ROS—羟基自由基(羟基自由基能够氧化TMB)，造成癌细胞DNA损伤，高效杀伤癌细胞。
4、基于他莫昔芬的金属-纳米药物对细胞pH的影响及细胞毒性和凋亡坏死分析(药物实验)
a)对细胞pH的影响：我们使用了可以穿透细胞膜荧光探针2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein,acetoxymethyl este(BCECF-AM)，以检测细胞内的pH。将4T1细胞与TAM(10μg/mL)孵育3小时，然后将这些细胞在37℃下，用BCECF-AM(2.5μM)避光染色30分钟，最后，使用荧光成像共聚焦显微镜测定，相对荧光强度通过Image J软件分析；其结果如图7所示，可以得知：用BCECF-AM荧光探针测量TAM处理3h的4T1细胞的细胞内pH，可以看到TAM处理过的细胞荧光强度更高，说明了TAM使细胞内pH降低了。
b)毒性分析：将癌细胞(4T1)培养于96孔板，细胞贴壁后，加入不同浓度的材料(FePt@FeO、TAM、FePt@FeO@TAM@PSMA-PEG三组)孵育24h，然后用标准的MTT方法进行毒性测试。图8为不同浓度纳米药物对癌细胞的毒性分析结果，从图8可以看出FePt@FeO@TAM@PSMA-PEG纳米药物对癌细胞4T1有很好的杀伤作用。
c)凋亡坏死检测：将4T1细胞培养在6孔板中，细胞贴壁后，分别加入不同浓度材料(空白组和FePt@FeO@TAM@PSMA-PEG组，其中含药物TAM浓度为200μg/mL)，孵育24h后，按照凋亡坏死染色步骤进行操作，染色后用流式细胞仪进行测试。其结果如图9所示，从图9可以看出FePt@FeO@TAM@PSMA-PEG纳米药物能够造成癌细胞凋亡。
从以上分析可知，该实施例1制备的纳米药物能够被癌细胞摄取，导致癌细胞内乳酸堆积，细胞内pH下降，促进药物对肿瘤的杀伤作用，实现肿瘤微环境响应的化疗-化学动力学治疗；同时，该纳米药物对癌细胞(4T1)具有很好的抑制效果，并能有效降低小分子化疗药物他莫昔芬的机体毒性。
5、基于他莫昔芬的金属-纳米药物多模态成像
对于体内光声成像，将带有4T1肿瘤的小鼠尾静脉注射FePt@FeO@TAM@PSMA-PEG(200μL；2mg/mL ofFePt)，然后用异氟烷在氧气中麻醉进行光声成像。在不同时间点(0小时，0.5小时，1小时，1.5小时和2小时)在700nm波长处记录光声图像。
对于体内磁共振成像，将带有4T1肿瘤的小鼠尾静脉注射FePt@FeO@TAM@PSMA-PEG(140μL；2mg/mL of FePt)，然后在磁共振成像过程中小鼠用异氟烷麻醉。注射FePt@FeO@TAM@PSMA-PEG后，在不同时间点(35分钟，45分钟，55分钟，65分钟和80分钟)记录T2加权磁共振图像。
图10为不同时间点在700nm波长处记录的光声图像，可以看出在700nm波长的光激发下，随着时间的推移，肿瘤区域的光声信号逐渐增强。
图11为不同时间点的T2-MRI图像，随着注射时间的延长，肿瘤逐渐变暗，肿瘤区域的信号对比度增强。
因此，实施例1制备的纳米药物能够通过EPR效应在肿瘤富集，而且可以用于肿瘤的成像，实现了对肿瘤的精准检测。
6、基于他莫昔芬的金属-纳米药物对肿瘤细胞的生长抑制作用
动物实验分为四组(空白、FePt@FeO、TAM和FePt@FeO@TAM@PSMA-PEG)，采用瘤内注射(含TAM 10mg/mL)，并从第1天开始每隔1天记录肿瘤尺寸。
图12为肿瘤生长曲线，从图12可以看出FePt@FeO@TAM@PSMA-PEG纳米药物能够显著抑制肿瘤的生长。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。
实施例3
(1)FePt@FeO的合成：将Pt(acac)2(0.125mmol)，1,2-十六烷二醇(0.250mmol)和12.5mL 1-十八烯添加到装有搅拌磁子的三颈烧瓶中，并在70℃抽真空40分钟。在氮气流下加入油酸(0.375mmol)，油胺(0.125mmol)和Fe(acac)3(3.75mmol)。将混合物加热至350℃并回流0.5h，然后使其冷却至室温。用体积比为1:4的环己烷：乙醇溶液洗涤产物4次，并再分散在环己烷中保存。
(2)将合成的FePt@FeO配制成5mg/mL的四氢呋喃溶液，将他莫昔芬配制成3.2mg/mL的四氢呋喃溶液，将表面活性剂聚(苯乙烯-顺丁烯二酸酐)(PSMA)配制成20mg/mL的溶液，置于4℃冰箱保存。
(3)FePt@FeO@TAM纳米颗粒的合成：首先，取125μL TAM的四氢呋喃溶液，20μLFePt@FeO的四氢呋喃溶液和150μL PSMA的四氢呋喃溶液，再加入705μL四氢呋喃，将这1mL混合物超声0.5分钟，再将混合物快速注射到8mL水中，超声2分钟后快速注射300μL碳酸钠水溶液(11mg/mL)，超声处理7分钟后，将混合液在50℃下旋蒸除去四氢呋喃；然后将去除四氢呋喃的反应液用100K超滤管对进行水洗和离心3次，转速为4200r/min，每次离心时间为2min。
(4)取1.6mg PEG-NH2加入步骤(3)所得溶液，室温搅拌5小时，然后离心并用去离子水洗涤3次，转速为4200r/min，每次离心时间为6min；所得的FePt@FeO@TAM@PSMA-PEG纳米颗粒4℃保存。
实施例4
(1)FePt@FeO的合成：将Pt(acac)2(0.125mmol)，1,2-十六烷二醇(0.50mmol)和6.25mL 1-十八烯添加到装有搅拌磁子的三颈烧瓶中，并在90℃抽真空20分钟。在氮气流下加入油酸(0.125mmol)，油胺(0.375mmol)和Fe(acac)3(2.5mmol)。将混合物加热至250℃并回流2h，然后使其冷却至室温。用体积比为1:4的环己烷：乙醇溶液洗涤产物2次，并再分散在环己烷中保存。
(2)将合成的FePt@FeO配制成5mg/mL的四氢呋喃溶液，将他莫昔芬配制成3.2mg/mL的四氢呋喃溶液，将表面活性剂聚(苯乙烯-顺丁烯二酸酐)(PSMA)配制成20mg/mL的溶液，置于4℃冰箱保存。
(3)FePt@FeO@TAM纳米颗粒的合成：首先，取187μL TAM的四氢呋喃溶液，20μLFePt@FeO的四氢呋喃溶液和100μL PSMA的四氢呋喃溶液，再加入693μL四氢呋喃，将这1mL混合物超声2分钟，再将混合物快速注射到10mL水中，超声0.5分钟后快速注射500μL碳酸钠水溶液(8mg/mL)，超声处理9分钟后，将混合液在40℃下旋蒸除去四氢呋喃；然后将去除四氢呋喃的反应液用100K超滤管对进行水洗和离心3次，转速为4200r/min，每次离心时间为2min。
(4)取3.0mg PEG-NH2加入步骤(3)所得溶液，室温搅拌7小时，然后离心并用去离子水洗涤3次，转速为4200r/min，每次离心时间为6min；所得的FePt@FeO@TAM@PSMA-PEG纳米颗粒4℃保存。
Claims (9)
1.一种基于他莫昔芬的金属-纳米药物的制备方法，包括以下步骤：
1)纳米酶FePt@FeO的合成：二乙酰丙酮铂Pt(acac)2、1,2-十六烷二醇和1-十八烯加入到三颈烧瓶中，抽真空后，在惰性气氛下，加入油酸，油胺和三乙酰丙酮铁Fe(acac)3，回流反应设定时间后，过滤洗涤，得到纳米酶FePt@FeO，将其分散在环己烷中保存；
2)FePt@FeO@TAM@PSMA纳米颗粒的合成：将步骤1)制备的纳米酶FePt@FeO、他莫昔芬TAM和苯乙烯-顺丁烯二酸酐PSMA置于THF中，超声后，注射到水中，进行第二次超声，然后向其中注射碳酸钠溶液，进行第三次超声，再然后将混合液进行旋蒸，去除THF，得到含有FePt@FeO@TAM@PSMA纳米颗粒溶液；
3)FePt@FeO@TAM@PSMA纳米颗粒的改性：向步骤2)中含有FePt@FeO@TAM@PSMA纳米颗粒溶液中加入PEG-NH2搅拌反应后，离心洗涤得到FePt@FeO@TAM@PSMA-PEG纳米颗粒，即为基于他莫昔芬的金属-纳米药物。
2.根据权利要求1所述的基于他莫昔芬的金属-纳米药物的制备方法，其特征在于，所述步骤1)中，Pt(acac)2、1,2-十六烷二醇、油酸，油胺和Fe(acac)3的摩尔比为1:(2～4):(1～3):(1～3):(20～30)，Pt(acac)2与1-十八烯的摩尔体积比为0.01～0.02mmol/mL。
3.根据权利要求1所述的基于他莫昔芬的金属-纳米药物的制备方法，其特征在于，所述步骤1)中，抽真空温度为70～90℃，抽真空时间为20～40min；回流反应温度为250～350℃，回流反应时间为0.5～2h；洗涤采用体积比为1:4的环己烷和乙醇混合溶液，洗涤次数为2～4次。
4.根据权利要求1所述的基于他莫昔芬的金属-纳米药物的制备方法，其特征在于，所述步骤2)中，纳米酶FePt@FeO、TAM和苯乙烯-顺丁烯二酸酐的质量比为1:(4～6):(20～30)，纳米酶FePt@FeO与THF的质量体积比为0.05～0.15mg/mL；THF与水的体积比为1:(8～10)；碳酸钠水溶液的浓度为9～11mg/mL，THF与碳酸钠水溶液的体积比为1:(0.3～0.7)。
5.根据权利要求1所述的基于他莫昔芬的金属-纳米药物的制备方法，其特征在于，所述步骤2)中，第一次超声时间为0.5～2min，第二次超声时间为0.5～2min，第三次超声时间为7～9min，旋蒸温度为40～50℃。
6.根据权利要求1所述的基于他莫昔芬的金属-纳米药物的制备方法，其特征在于，所述步骤3)中，PEG-NH2与步骤2)中TAM的质量比为(4～5):1，搅拌反应时间为5～7h，所得的FePt@FeO@TAM-PEG纳米颗粒在3～5℃温度下保存。
7.根据权利要求1～6任意一项所述的基于他莫昔芬的金属-纳米药物的制备方法制备得到基于他莫昔芬的金属-纳米药物。
8.根据权利要求7所述的基于他莫昔芬的金属-纳米药物，其特征在于，所述的基于他莫昔芬的金属-纳米药物的平均粒径在80～120nm。
9.根据权利要求7所述的基于他莫昔芬的金属-纳米药物在做为诊断治疗癌症药物中的应用。
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