CN112472825A - 用于免疫细胞追踪的方法 - Google Patents
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Abstract
一种追踪免疫细胞以检测免疫反应的方法。该方法包括以下步骤:鉴别具有与器官相关的疾病的患者;施用生物相容性磁性纳米粒子至该患者的血流;以及获得该器官的磁共振图像。在该磁共振图像中高信号斑或低信号斑的存在表明在该患者中的免疫反应。
Description
背景
免疫细胞追踪,其涉及监测免疫细胞的移动和聚集,可以有效地检测诸如免疫排斥之类的免疫反应(immune response),其是在已接受器官移植的患者中的功能性衰竭的一种主要原因。
免疫反应通常是通过定期地分析活检样本(例如心肌内膜的活检样本)作监测,以检测在与疾病相关的器官中免疫细胞(例如T-细胞和巨噬细胞)的存在。
此监测程序具有多个缺点。首先,作为一种侵入性程序,其趋于造成不利的副作用。再者,其倾于可能产生假阴性结果的取样误差。此外,其经常无法检测早期急性排斥或者慢性排斥。最后,其是一种昂贵的程序。
免疫细胞追踪也可以通过对患者施用用磁性纳米粒子预先标记的免疫细胞而达成。此方法需要体表外预标记免疫细胞的冗长步骤。
需要研发一种简单且非侵入性方法,其对于追踪免疫细胞以检测疾病的早期病征是敏感的。
概述
本文公开一种使用磁共振成像(“MRI”)扫描,利用生物相容性磁性纳米粒子(biocompatible magnetic nanoparticle)的简单且非侵入性的用于追踪免疫细胞的方法。该方法提供出乎意料的高敏感度。
该方法包括以下步骤:(i)鉴别具有与器官(例如心脏、肾脏或淋巴结)相关的疾病的患者;(ii)提供水性悬浮液(aqueous suspension),其不含尺寸大于1000nm的粒子且含有生物相容性磁性纳米粒子;(iii)将该水性悬浮液施用到该患者的血流中;和(iv)随后获得该器官的磁共振图像。当该图像显示高信号斑或低信号斑的存在(例如T2、T2*或扩散加权的MRI显示低信号斑,或T1加权的MRI显示高信号斑)时,检测到免疫反应。例如,该疾病是癌症(例如淋巴瘤)或移植器官(例如心脏或肾脏)的排斥。
在一个实施方案中,该方法被用于检测免疫排斥,其中步骤(i)是鉴别具有移植器官的患者,并且步骤(iv)是获得该移植器官的T2-加权的磁共振图像。当该图像显示低信号斑的存在时,则检测到有免疫排斥。
本文描述的方法使用含有生物相容性磁性纳米粒子的造影剂从而利用MRI技术来检测免疫反应。
所述生物相容性磁性纳米粒子各自含有超顺磁性核心(superparamagneticcore),该超顺磁性核心被一种或多种生物相容性聚合物覆盖,所述生物相容性聚合物各自具有聚乙二醇基团、硅烷基团以及经由共价键连接该聚乙二醇基团和该硅烷基团的接头(连接基,linker)。典型地,这些生物相容性磁性纳米粒子各自具有10-1000nm的粒径(颗粒尺寸,particle size)和50-400的横向磁弛豫率(transverse magnetic relaxivityrate)。在一个实例中,它们各自具有15-200nm的粒径和120至400的横向磁弛豫率。
通常,该超顺磁性核心含有氧化铁、氧化钴、氧化镍或其组合。
在覆盖所述超顺磁性核心的所述生物相容性聚合物的每一个中,聚乙二醇基团通常具有5-1000个氧乙烯单元(oxyetheylene unit)(例如10-200个氧乙烯单元),且硅烷基团典型地具有C1-10亚烷基(例如C3-C10亚烷基)。
下文将阐述一个或多个实施方案的细节。这些实施方案的其它特征、目的和优点将从说明书和权利要求书变得显而易见。
详述
在以下详细描述中,为了解释的目的,阐述大量具体的细节以提供对所公开实施方案的详尽了解。然而,显而易见的是,在没有这些具体细节的情况下,一个或多个实施方案可以被实施。
本发明的方法用于使用生物相容性磁性纳米粒子追踪免疫细胞,所述生物相容性磁性纳米粒子各自含有被一种或多种生物相容性聚合物覆盖的超顺磁性核心。
所述生物相容性聚合物是生物可降解的且对细胞是无毒的。含有硅烷的生物相容性聚合物,其可以如下所示被轻易地官能化,是适合用于制备本方法所需的生物相容性磁性纳米粒子。
一种示例性生物相容性聚合物具有以下式:
在式(I)中,R是H、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10环烷基、C1-C10杂环烷基、芳基(aryl)、杂芳基(heteroaryl)、C1-C10羰基或C1-C10胺基(amine group);L是接头;m是1至10;并且n是5至1000。
接头可以是O、S、Si、C1-C6亚烷基、含有两个羰基和2-20个碳原子的羰基部分(carbonyl moiety),或具有以下式中的一个的基团:
以及在这些式中,m、n、p、q和t各自独立地是1-6;W是O、S或NRb;L1、L3、L5、L7和L9各自独立地是键、O、S或NRc;L2、L4、L6、L8和L10各自独立地是键、O、S或NRd;并且V是ORe、SRf或NRgRh,其中Ra、Rb、Rc、Rd、Re、Rf、Rg和Rh各自独立地是H、OH、C1-C10氧脂族基(oxyaliphatic group)、C1-C10一价脂族基、C1-C10一价杂脂族基(monovalentheteroaliphatic radical)、一价芳基(一价芳香基,monovalent aryl radical)或一价杂芳基(一价杂芳香基,monovalent heteroaryl radical)。
另一种示例性生物相容性聚合物具有以下式:
在式(II)中,R1是H、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10环烷基、C1-C10杂环烷基、芳基、杂芳基、C1-C10羰基或C1-C10胺基;R2是H、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10环烷基、C1-C10杂环烷基、芳基或杂芳基;m是1至10(例如3-10);并且n是5至1000(10-200)。在一个优选的实施方案中,R2是H,并且式(II)中的接头是
术语“脂族(aliphatic)”在本文中指的是饱和或不饱和的、直链或支链的、无环的、环状的或多环的烃部分。实例包括但不限于烷基、亚烷基、烯基、亚烯基、炔基、亚炔基、环烷基、亚环烷基、环烯基、亚环烯基、环炔基和亚环炔基部分。术语“烷基”或“亚烷基”指的是饱和的、直链或支链的烃部分,例如甲基、亚甲基、乙基、亚乙基、丙基、亚丙基、丁基、亚丁基、戊基、亚戊基、己基、亚己基、庚基、亚庚基、辛基、亚辛基、壬基、亚壬基、癸基、亚癸基、十一烷基、亚十一烷基、十二烷基、亚十二烷基、十三烷基、亚十三烷基、十四烷基、亚十四烷基、十五烷基、亚十五烷基、十六烷基、亚十六烷基、十七烷基、亚十七烷基、十八烷基、亚十八烷基、十九烷基、亚十九烷基、二十烷基、亚二十烷基、三十烷基、亚三十烷基。术语“烯基”指的是含有至少一个双键的直链或支链的烃部分,如-CH=CH-CH3和-CH=CH-CH2-。术语“炔基”指的是含有至少一个三键的直链或支链的烃部分,如-C≡C-CH3和-C≡C-CH2-。术语“环烷基”指的是饱和的、环状烃部分,如环己基和亚环己基。
术语“杂脂族(基)(heteroaliphatic)”在本文中指的是含有至少一个杂原子(例如N、O、P、B、S、Si、Sb、Al、Sn、As、Se和Ge)的脂族(基)部分。术语“杂环烷基”指的是含有至少一个杂原子的环烷基部分。术语“氧脂族(基)”在本文中指的是-O-脂族(基)。氧脂族的实例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基以及叔丁氧基。
术语“芳基”在本文中指的是C6单环的、C10双环的、C14三环的、C20四环的或者C24五环的芳族环系统。芳基的实例包括但不限于苯基、亚苯基、萘基、亚萘基、蒽基、亚蒽基、芘基和亚芘基。术语“杂芳基”在本文中指的是具有一个或多个杂原子(如O、N、S或Se)的芳族5-8元单环、8-12元双环、11-14元三环以及15-20元四环的环体系。杂芳基的实例包括但不限于呋喃基、亚呋喃基、芴基、亚芴基、吡咯基、亚吡咯基、噻吩基、亚噻吩基、唑基、亚唑基、咪唑基、亚咪唑基、苯并咪唑基、亚苯并咪唑基、噻唑基、亚噻唑基、吡啶基、亚吡啶基、嘧啶基、亚嘧啶基、喹唑啉基、亚喹唑啉基、喹啉基、亚喹啉基、异喹啉基、亚异喹啉基、吲哚基和亚吲哚基。
除非另有规定,在本文中提及的脂族、杂脂族、氧脂族、烷基、亚烷基、烯基、炔基、环烷基、杂环烷基、芳基以及杂芳基包括取代和未取代部分二者。在环烷基、杂环烷基、芳基和杂芳基上的可能取代基包括但不限于C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C20环烷基、C3-C20环烯基、C3-C20杂环烷基、C3-C20杂环烯基、C1-C10烷氧基、芳基、芳氧基、杂芳基、杂芳氧基、氨基、C1-C10烷基氨基、C2-C20二烷基氨基、芳基氨基、二芳基氨基、C1-C10烷基磺氨基,芳基磺氨基、C1-C10烷基亚氨基、芳基亚氨基、C1-C10烷基磺亚氨基、芳基磺亚氨基、羟基、卤代、硫基(thio)、C1-C10烷硫基、芳硫基、C1-C10烷基磺酰基、芳基磺酰基、酰基氨基、氨基酰基、胺基硫酰基、酰胺基、甲脒基、胍、脲基、硫脲基、氰基、硝基、亚硝基、叠氮基、酰基、硫酰基、酰氧基、羧基和羧酸酯。另一方面,在脂族、杂脂族、氧脂族、烷基、亚烷基、烯基和炔基上的可能取代基包括所有上述除了C1-C10烷基的取代基。环烷基、杂环烷基、芳基和杂芳基也可以彼此稠合。
上述生物相容性聚合物包括聚合物本身、及其盐和溶剂化物(如果适用)。例如,盐可以在聚合物上的阴离子和带正电荷的基团(例如氨基)之间形成。合适的阴离子包括氯化物、溴化物、碘化物、硫酸盐、硝酸盐、磷酸盐、柠檬酸盐、甲磺酸盐、三氟乙酸盐、乙酸盐、苹果酸盐、甲苯磺酸盐、酒石酸盐、富马酸盐(fumurate)、谷氨酸盐、葡糖醛酸盐、乳酸盐、戊二酸盐和马来酸盐。同样地,盐也可以在聚合物上的阳离子和带负电荷基团(例如羧酸根)之间形成。合适的阳离子包括钠离子、钾离子、镁离子、钙离子和铵阳离子如四甲铵离子。所述聚合物也包括那些含有季氮原子的盐。溶剂化物指的是在聚合物和药学上可接受的溶剂之间形成的复合物。药学上可接受的溶剂的实例包括水、乙醇、异丙醇、乙酸乙酯、乙酸和乙醇胺。
以下方案(I)显示制备含有硅烷的一种示例性生物相容性聚合物的方法。
方案(I)
如方案(I)所示,在碱(例如二甲基氨基吡啶)的存在下,烷氧基-聚乙二醇(分子量2000)与琥珀酸酐反应以形成mPEG-COOH,接着使用亚硫酰氯将其转化为mPEG-COCl。混合mPEG-COCl与(3-氨基丙基)-三乙氧基硅烷,得到mPEG-硅烷。
本领域技术人员可以使用已知方法更改在用来制备生物相容性聚合物的上述方案(I)中所示的方法。参见R.Larock,Comprehensive Organic Transformations(综合有机转化)(VCH出版社1989);T.W.Greene和P.G.M.Wuts,Protective Groups in OrganicSynthesis(有机合成中的保护基)(第三版,John Wiley和Sons 1999);L.Fieser和M.Fieser,Fieser,Fieser and Fieser’s Reagents for Organic Synthesis(费瑟和费瑟试剂用于有机合成)(John Wiley和Sons 1994);以及L.Paquette编辑,Encyclopedia ofReagents for Organic Synthesis(用于有机合成的试剂的百科全书)(John Wiley和Sons1995)及其后续版本。可用于合成所述生物相容性聚合物的具体路线也可在以下文献中找到:(a)Rist等人,Molecules,2005,10,1169-1178,(b)Koheler等人,JACS,2004,126,7206-7211;以及(c)Zhang等人,Biom.Mircod.,2004,6:1 33-40。
上述的生物相容性聚合物各自可以经由共价键结合被涂覆在超顺磁性核心(例如氧化铁纳米粒子)上以形成用于造影剂中的生物相容性磁性纳米粒子。该超顺磁性核心具有8至25nm(例如12至25nm和15至20nm)的粒径以及120至250(mM·S)-1(例如150至230(mM·S)-1和170至210(mM·S)-1)的r2弛豫(率)。超顺磁性核心的制备在本领域是已知的。参见Laurent等人,Chem.Rev.,2008,108,2064-2110。
以下描述的是一种用以制备超顺磁性纳米粒子的典型方法。首先,将氧化铁纳米粒子悬浮于甲苯中,接着在室温下将其与mPEG-硅烷搅拌24小时。所得的生物相容性磁性纳米粒子是亲水性的且可以被萃取至水相,随后通过超滤进行纯化。如此制备的生物相容性磁性纳米粒子各自具有120至250(mM·S)-1(例如150至230(mM·S)-1和170至210(mM·S)-1)的r2弛豫(率)。
上述生物相容性磁性纳米粒子可以配制到造影剂中,其可以口服施用。造影剂的实例包括乳剂、水性悬浮液、分散液和溶液。如需要,可添加某些甜味剂、调味剂或着色剂。
生物相容性磁性纳米粒子可以施用到患者中以标记免疫细胞(体内),如以下实施例中所述。不同于施用利用纳米粒子预先标记的免疫细胞(体内),在没有免疫细胞下施用生物相容性磁性纳米粒子明显地具有较少操作步骤以及较少监管障碍的优点。
不受任何理论拘束,所述生物相容性磁性纳米粒子在施用至移植患者后,会被免疫细胞(例如巨噬细胞)摄入,其在免疫反应发生时会在器官处聚集。换言之,如此标记的免疫细胞可轻易地通过T1、T2、T2*或扩散加权的MRI来监测,其如T1加权的MRI图像中的高信号斑(hyperintense spot)所示,或者如T2、T2*或扩散加权的MRI图像中的低信号斑(hypointense spot)所示。进行T1、T2*或扩散加权的MRI的程序与在Mol.Imaging Biol.,2011,13(5),825-839中报道的进行T2加权的MRI的程序相似
上述的生物相容性磁性纳米粒子,当施用至患者时,对于用于追踪免疫细胞以监测免疫反应的MRI展现出出乎意料的高敏感度。
以下的具体实施例应解释为仅为举例说明性的,而不以任何方式显示本公开内容的其余部分。在没有进一步的阐述下,相信本领域技术人员可基于在本文中的描述而将本发明的实施例利用至充分程度。本文中引述的所有出版物以其整体并入本文。
生物相容性氧化铁纳米粒子的制备
这些实施方案的两种生物相容性氧化铁纳米粒子依据以下所描述的程序制备。
氧化铁核心的制备
在25℃下在三颈烧瓶中以300rpm搅拌FeCl2·4H2O(11.6g;0.058摩尔)、FeCl3·6H2O(11.6g;0.096摩尔)和水(400mL)的混合物。以47μl/sec的速率将氢氧化钠溶液(2.5N;170mL)加入至该烧瓶,获得11-12的pH值。在25℃下在三颈烧瓶中以300rpm搅拌FeCl2·4H2O(11.6g;0.058摩尔)、FeCl3·6H2O(11.6g;0.096摩尔)和水(400mL)的混合物。以47μl/sec的速率将氢氧化钠溶液(2.5N;170mL)添加至该烧瓶,获得11-12的pH值。随后,加入油酸(20mL)并搅拌30分钟,接着加入6N HCl溶液以调整pH值至1。通过过滤,收集从混合物沉淀出的氧化铁核心,且用水清洗4-5次以除去过量的油酸。然后将其在真空下干燥以用于如下所述的与生物相容性聚合物偶联。
生物相容性聚合物mPEG-硅烷-750和mPEG-硅烷-2000的制备
生物相容性聚合物mPEG-硅烷-750依据以下所描述的程序制备。
允许300g(0.4摩尔)的甲氧基-PEG(mPEG,分子量750)、琥珀酸酐(48g;0.48摩尔)和4-二甲基氨基-吡啶(DMAP;19.5g;0.159摩尔)的混合物在1000-mL圆底烧瓶中在真空下(20托)静置2小时。将600mL的甲苯加入至该混合物,然后将其在30℃搅拌一天以形成mPEG-COOH。
随后,以1mL/min的速率加入36mL(0.48摩尔)的亚硫酰氯并将混合物搅拌2至3个小时。之后,以1mL/min的速率加入333.8mL(2.4摩尔)的三乙胺以获得大约6~7的pH。在冷却至室温后,将含有mPEG-COCl的混合物与94.5mL(0.4摩尔)的3-氨基丙基三乙氧基硅烷在室温下反应至少8小时以得到mPEG-硅烷-750。
在将9L的异丙基乙醚加入至该反应混合物之后,mPEG-硅烷-750沉淀。通过过滤收集固体产物,再溶解于500mL的甲苯中,并以5000rpm离心5分钟以收集上清液,向其中加入9L的异丙基乙醚。将褐色油状液体与异丙基乙醚分离,且在真空下干燥以获得生物相容性聚合物mPEG-硅烷-750。
生物相容性聚合物mPEG-硅烷-2000依据上述相同的程序制备,其中使用800g(0.4摩尔)的甲氧基-PEG(mPEG,分子量2000)、琥珀酸酐(48g;0.48摩尔)和4-二甲基氨基-吡啶(DMAP;19.5g;0.159摩尔)的混合物。
将mPEG-硅烷-750和mPEG-硅烷-2000各自与氧化铁核心偶联
将如此获得的生物相容性聚合物mPEG-硅烷-750和mPEG-硅烷-2000(250g)各自悬浮于1-1.2L的含有如上述制备的10g氧化铁核心的甲苯溶液中。将该悬浮液搅拌24小时,接着加入水(1.5L)以萃取。萃取的水性溶液用超滤装置过滤,用水清洗,然后浓缩至100mL,以获得生物相容性氧化铁纳米粒子悬浮液。不管是否从mPEG-硅烷-750或mPEG-硅烷-2000制备,将氧化铁纳米粒子指定为iTrast。
生物相容性氧化铁纳米粒子(iTrast)的表征
如此获得的生物相容性磁性纳米粒子iTrast的透射电子显微镜(TEM)图像使用JEOL JEM-2100F场发射透射电子显微镜获取。这些图像显示iTrast具有尺寸为10-12nm的氧化铁核心。
横向弛豫(率)(r2)以及纵向(r1)弛豫(率)依据在美国申请公开2012/0329129以及Mol Imaging Biol,Chen等人,2011,13,825-839中所描述的程序确定。iTrast被确定具有205.3±2.3(mM·s)-1的r2以及18.6±0.5(mM·s)-1的r1。
检测移植中巨噬细胞的移动和聚集
用于追踪移植器官中的巨噬细胞的研究是依据下述程序进行。
大鼠中的心脏移植
使用异位工作心脏模型(heterotopic working-heart model)的操作程序描述于PNAS,2006,103(6):1852-1857。近交系Brown Norway(BN;RT1n)大鼠和Dark Agouti(DA;RT1a)大鼠从Harlan Laboratories Inc.获得(Indianapolis,IN)。在不同品系的大鼠之间(DA→BN)的同种异体移植导致排斥,而在相同品系的大鼠之间(DA→DA或BN→BN)的同系移植不引起排斥。根据在J.Heart Lung Transplant.,1998,17,754–760以及J.HeartTransplant.,1990,9,587–593中描述的指南,组织病理学地确定心脏移植物的排斥等级。
在心脏移植后1天,将每只大鼠静脉注射3mg/kg的iTrast纳米粒子。观察到巨噬细胞不均匀地分布在急性排斥的大鼠心脏中。出乎意料地,在手术后第6天进行的体内MRI表明用iTrast纳米粒子标记的巨噬细胞在该同种异体移植心脏处聚集。
组织病理学确认心外膜至心内膜发展模式。更具体地,随着排斥随时间发展,巨噬细胞浸润朝向心肌膜的内部扩展。
在来自在体内MRI之后所收获的心脏移植物的组织上进行H&E和Perl的铁染色。这些移植物的组织学和免疫组织化学分析显示由Perl的铁染色所描绘的含有铁的细胞与巨噬细胞谱系ED1+细胞相关联。如通过H&E染色所揭示的,这些含有铁的细胞在具有更大侵入性免疫细胞浸润和中断的心肌膜完整性的区域中与ED1+巨噬细胞相关联。
在猪中的肾脏移植
将主要组织相容性复合体(MHC)-错配的猪用高剂量的他克莫司(tacrolimus)处理12天。然后将肾脏同种异体移植物(n=5)移植到这些猪中。如预期的,在第14天,所有经分离的肾脏同种异体移植物被排斥,如相比于第0天,血清肌酸酐浓度加倍。
在肾脏移植后1天,将每只猪静脉注射3mg/kg或6mg/kg的iTrast粒子。在第3、6、9、12和16天,通过体内MRI出乎意料地检测到在被排斥的肾脏中聚集的由纳米尺寸的iTrast标记的巨噬细胞。
事实上,还发现相比于血清肌酸酐,在3mg/kg和6mg/kg的iTrast分别在第9天和第6天增强在皮质附近的低信号斑,表明所有分离的肾脏的免疫排斥。
追踪在淋巴结上的巨噬细胞
根据以下所显示的程序研究iTrast以检测淋巴结的形态变化。
在前爪诱发使用B16-F10细胞的小鼠黑素瘤转移模型。在肿瘤发展期间施用iTrast(2、4和6mg Fe/kg)至这些小鼠,且在该iTrast施用之后,通过MRI T2、T2*和扩散加权成像(即T2WI、T2*WI、DWI)重复地评价这些动物。
发现肿瘤阶段显著地影响标记结果。当静脉给予剂量为4mg Fe/kg的iTrast时,在具有早期肿瘤的动物的前哨淋巴结和随后淋巴结中出乎意料地观察到短暂标记。当肿瘤达到晚期时,在这些淋巴结中的短暂信号的程度减弱。组织学确认早期肿瘤为非转移性的,而晚期肿瘤为转移性的。
其它实施方案
在本说明书中公开的所有特征可以任意组合予以结合。在本说明书中公开的各个特征可被用于相同、等同或相似目的的备选特征所替代。因此,除非另有明确说明,公开的各个特征仅为宽泛系列的等同或相似特征的实例。
根据以上描述,本领域技术人员可以容易地确定所描述的实施方案的必要特性,且在不背离其精神和范围的情况下,可以作出多种改变和修改以使其适合于多种用途和情形。因此,其它实施方案也在权利要求书的范围内。对本领域技术人员来说明显的是,可以对所公开的实施方案做出多种修改和变化。意图的是,本说明书和实施例仅被认为是例示性的,其中公开内容的真实范围由所附权利要求及其等同替换所指定。
Claims (23)
1.一种追踪免疫细胞的方法,所述方法包括:
鉴别具有与器官相关的疾病的患者;
提供含有生物相容性磁性纳米粒子的水性悬浮液,所述水性悬浮液不具有尺寸大于1000nm的粒子,所述生物相容性磁性纳米粒子各自含有被一种或多种生物相容性聚合物覆盖的超顺磁性核心,所述生物相容性聚合物各自具有聚乙二醇基团、硅烷基团以及经由共价键连接所述聚乙二醇基团和所述硅烷基团的接头;
将所述水性悬浮液施用到所述患者的血流中;和
在所述施用步骤后,获得所述器官的磁共振图像,
其中在所述磁共振图像中高信号斑或低信号斑的存在表明在所述患者中的免疫反应。
2.权利要求1所述的方法,其中所述磁共振图像是T2或T2*加权的磁共振图像。
3.权利要求1所述的方法,其中所述疾病是癌症或者移植器官的排斥。
4.权利要求3所述的方法,其中所述移植器官是心脏或肾脏。
5.权利要求3所述的方法,其中所述癌症是淋巴瘤。
6.权利要求1所述的方法,其中所述器官是心脏、肾脏或淋巴结。
7.权利要求1所述的方法,其中所述超顺磁性核心含有氧化铁、氧化钴、氧化镍或其组合;所述聚乙二醇基团具有5-1000个氧乙烯单元;所述硅烷基团含有C1-10亚烷基;并且所述接头是O、S、Si、C1-C6亚烷基、含有两个羰基和2-20个碳原子的羰基部分,或具有以下式中的一个的基团:
8.权利要求7所述的方法,其中所述生物相容性磁性纳米粒子各自具有10-1000nm的粒径和50至400的横向磁弛豫率。
9.权利要求8所述的方法,其中所述生物相容性磁性纳米粒子各自具有15-200nm的粒径和120至400的横向磁弛豫率。
11.权利要求10所述的方法,其中所述生物相容性磁性纳米粒子各自具有1-1000nm的粒径和50至400的横向磁弛豫率。
12.权利要求11所述的方法,其中所述生物相容性磁性纳米粒子各自具有15-200nm的粒径和120至400的横向磁弛豫率。
13.权利要求1所述的方法,其中所述生物相容性磁性纳米粒子各自具有1-1000nm的粒径和50至400的横向磁弛豫率。
14.权利要求13所述的方法,其中所述生物相容性磁性纳米粒子各自具有15-200nm的粒径和120至400的横向磁弛豫率。
18.权利要求17所述的方法,其中所述生物相容性磁性纳米粒子各自具有10-1000nm的粒径和50至400的横向磁弛豫率。
19.权利要求18所述的方法,其中所述生物相容性磁性纳米粒子各自具有15-200nm的粒径和120至400的横向磁弛豫率。
21.权利要求17所述的方法,其中R1是H;R2是H、C1-C6烷基、C1-C10羰基或C1-C10胺基;m是3至10;并且n是10至200。
22.权利要求21所述的方法,其中所述生物相容性磁性纳米粒子各自具有10-1000nm的粒径和50至400的横向磁弛豫率。
23.权利要求22所述的方法,其中所述生物相容性磁性纳米粒子各自具有15-200nm的粒径和120至400的横向磁弛豫率。
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