CN102573613B - 用于增强肿瘤显像的paa纳米粒子 - Google Patents
用于增强肿瘤显像的paa纳米粒子 Download PDFInfo
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- CN102573613B CN102573613B CN201080042001.2A CN201080042001A CN102573613B CN 102573613 B CN102573613 B CN 102573613B CN 201080042001 A CN201080042001 A CN 201080042001A CN 102573613 B CN102573613 B CN 102573613B
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Abstract
本发明公开了含有PAA纳米粒子的组合物及其制备和使用方法,所述PAA纳米粒含有后负载的四吡咯光敏剂和显像剂。
Description
关于联邦资助的研究或开发的声明
本发明在国立卫生研究院(National Institute of Health)给予的资助号为CA19358和CA114053的美国政府支持下完成。美国政府在本发明中具有一定权利。
与相关申请的交叉参考
本申请根据美国法典第35篇第119条e款(35U.S.C.§119(e))要求2009年10月21日提交的美国临时专利申请No.61/279,522的利益,所述申请在此以引用的方式全文并入。
发明背景
纳米科学正结合高等医学发展以在诊断和治疗中更为精准。在生物医学应用中传送治疗剂和显像剂的纳米平台和纳米载体显示出癌症诊断和治疗的前景。治疗剂的例子包括含有PDT剂的纳米粒子、靶向受体的叶酸、用于捕获中子的含有硼的树枝状聚合物和纳米粒子导向的热疗。
当考虑用于光动力疗法(PDT)时,纳米粒子具有缺点。特别是,某些纳米粒子在癌症显像、PDT、化学传感、稳定性和生物降解方面没有较宽的知识基础;(2)具有体内毒性;(3)无表面修饰时血浆循环时间短且生物降解和生物清除速率不稳定或不可控;(4)具有与规模放大有关的问题且长期贮存不稳定;并且(5)有另外的局限性,包括相对难以掺入疏水化合物中、如果不“锚定”会渗漏出小亲水组分、和由于水凝胶溶胀导致在肿瘤块渗透性方面的未知限制。
癌症治疗的一个主要挑战是优先破坏恶性细胞并保留正常组织。成功根除恶性疾病的关键是早期检测和选择性消除恶性肿瘤。光动力疗法(PDT)在临床上有效并仍在逐渐发展癌症局部选择性疗法。PDT的效用已经被用于多类疾病的各种光敏剂所证实。它经FDA批准用于早期和晚期肺癌、梗阻性食道癌、巴瑞特氏(Barrett’s)食道症有关的高度发育不良、年龄相关性黄斑变性和光化性角化病。PDT采用吸收光时产生活性单线态氧的肿瘤定位光敏剂,其中活性单线态氧被认为造成肿瘤破坏。随后的氧化还原反应也可以产生有助于肿瘤消除的超氧阴离子、过氧化氢和羟自由基4。已经设计出相对特异地定位于某些亚细胞结构如线粒体的光敏剂,这些亚细胞结构是高度敏感的靶点。在肿瘤组织水平,直接光动力杀伤肿瘤细胞、破坏供养肿瘤的脉管系统及可能激活天然和获得性抗肿瘤免疫系统之间相互作用而摧毁恶性组织6。PDT的要点是优先杀伤靶细胞(如肿瘤)而非邻近的正常组织,且临床应用中实现优先靶点损伤是使用这种模式的主要推动力。PDT的成功有赖于优先滞留于恶性细胞而放过正常组织的亲肿瘤分子的发展。
在努力开发具有所需光物理特性的有效光敏剂中,具有四吡咯核心环的化合物得到利用。在合成中通常用叶绿素a和细菌叶绿素a作为中间体。对于焦脱镁叶绿酸a(660nm)的系列烷基醚衍生物的深入QSAR研究导致选择HPPH(己醚衍生物),HPPH目前处于有前景的二期临床试验中。光敏剂的发展现在已经延伸到单线态氧产能高的红紫素酰亚胺(700nm)和细菌红紫素酰亚胺(780-800nm)系列。长波长吸收对于治疗深部的大肿瘤是重要的,因为长波长光增加穿透并将肿瘤内光传输所需的光纤数量减到最少。
已对靶向肿瘤细胞作出多种努力,以使作用剂可以破坏肿瘤细胞而保留正常细胞。这样的系统依赖于特定受体并因此必须到达受体位置。这是其缺点,因为即使作用剂可以到达靶细胞也可能无效,除非其到达并结合特定受体。
用于肿瘤检测的多种补充技术,包括磁共振、闪烁显像和光学显像,正在积极开发中。各种方法都有具体的优缺点。光学显像包括测定内源分子(如血色素)或所施用染料的吸收、在临床前模型中检测生物发光、和检测内源性荧光团或外源靶分子发出的荧光。荧光,即吸收的光以更长的波长发射,其能够高度灵敏:具有0.6纳秒寿命的典型花青染料可以发出多达1032光子/秒/摩尔。灵敏的光检测器可以在<103光子/秒时显像。因而即使激发能量低,低水平的荧光分子信标也能够被检测到。选择性传递染料并具有足够高的浓度以检测小肿瘤是一个难题。仅利用ICG显像肿瘤周围的过多脉管或“渗漏的”血管生成性脉管因为其固有的肿瘤选择性有限而已经失败。已经采用多种方法改进光探针定位,包括以在肿瘤内活化的淬灭形式施用,或者将其与抗体或如受体配位体之类的小分子偶联。最近的研究集中于开发生物活性小分子的染料接合物,以促进向靶组织的快速扩散并利用组合和高通量策略来鉴别、优化和增强新探针在体内的稳定性。ICG衍生物的一些肽类似物具有中度肿瘤特异性并正进入临床前研究。然而,这些化合物均没有被设计为兼用于肿瘤检测和治疗。重要的是开发应对体内肿瘤异质性的靶向策略,在异质性的情况下可靶向位点的表达不一致且多变。
光敏剂通常产生荧光,它们在体内的荧光特性已经被利用于检测肺、膀胱和其它位置的早期癌症。对于早期疾病的治疗和深部肿瘤,可以用荧光引导活化光。但光敏剂不是用于肿瘤检测的最佳荧光团,其有若干原因:(i)它们的荧光量子产率低(特别是与菌绿素有关的长波长光敏剂)。有效的光敏剂往往荧光效率(量子产率)低于设计为荧光团的化合物,如花青染料,因为其作为荧光发出的激发的单线态能量被转移到三线态然后又转移到分子氧。(ii)它们的斯托克斯(Stokes)位移小,基于卟啉的光敏剂在长波长吸收带和荧光波长之间的差异(斯托克斯位移)相对较小,使得从技术上难以将其荧光与激发波长分开。(iii)大多数光敏剂荧光波长相对较短,<800nm,这对于探测深部组织不是最佳的。
已经尝试过开发双功能接合物,其利用亲肿瘤的光敏剂将NIR荧光团靶向至肿瘤。荧光团的功能是使肿瘤位置和治疗位点可见。光敏剂的存在允许后续的肿瘤消除。光显像允许临床医生进行PDT以持续地实时获取和显示患者数据。这种“即诊即治(see and treat)”的方法可以确定在哪里治疗浅表癌以及怎样用传输光活化光的光纤到达如乳腺、肺和大脑的位置的深部肿瘤。类似的方法也用于开发可能的PDT/MRI接合物,其中HPPH与Gd(III)DTPA接合。由于显像剂量和治疗剂量之间的显著差异,包括这两种模式形式的单一分子应用是有问题的。
正电子发射断层扫描(PET)是允许非侵入性使用放射性同位素标记的分子显像探针在活体对象中显像和分析细胞功能水平的生物化学过程的技术20。PET已被主要用作代谢标记,而不是特异靶向到恶性肿瘤。最近,正在开展将放射性标记的肽配位体应用于靶向恶性肿瘤。目前,PET在临床治疗中很重要,并且是生物医学研究中的关键成分,支持着广泛的应用,包括肿瘤缺氧、凋亡和生长的研究21。长的循环时间对于靶向可能是适合的,因为能够增加作用剂传送到肿瘤中。HPPH和碘苄基脱镁叶绿酸a的血浆半衰期~25h。124I的长放射半衰期与脱镁叶绿酸良好匹配,允许随时间对从正常组织的清除连续显像。放射性碘标记技术明确具有良好产率和放射化学纯度22。尽管124I的复杂衰变纲图导致仅有25%的正电子丰度(与18F的100%正电子发射相比),但使用124I标记抗体的体内定量显像已经在现实条件下利用PET/CT扫描仪成功得以实现。各种各样的生物分子已经用124I标记。我们已经设计了快速并有效连接124I与亲肿瘤光敏剂的偶联反应23-25,并用接合物靶向和显像鼠乳腺肿瘤及其肺的转移肿瘤。可以缓慢获取临床PET图像,但PET-CT联合扫描仪允许实时指导干预治疗,同样地,示踪技术的新发展可以允许由PET数据集指导的实时干预。
发明简述
本发明涉及聚丙烯酸(PAA)纳米粒子,其含有光敏剂和显像增强剂。
根据本发明,评估了光敏剂囊化(encaphotosensitizerulated)、后负载并共价结合的光敏剂-纳米粒子的治疗和显像潜力。在PAA纳米粒子中,后负载功效显示出增强的体外/体内治疗和显像潜力。PAA纳米粒子具有可以容易并入分子或小纳米粒子有效载荷的核心基体,并可以制备为10-150nm粒度且粒度分布控制良好。纳米粒子的表面易于官能化,以允许附着靶向配体,且这二者都对光动力疗法(PDT)期间产生的单线态氧(1O2))稳定。PAA纳米粒子,即聚(丙烯酸)纳米粒子,具有以下优点:(1)在癌症显像、PDT、化学传感、稳定性和生物降解方面相对较宽的认识基础;(2)无已知的体内毒性;(3)血浆循环时间长,无需表面修饰,但通过(在反胶束内聚合期间引入的)选择性交联的类型和量可控制生物降解和生物清除速率;(4)规模放大到400g材料和长期贮存稳定性已经得到证实。其局限包括较难并入疏水化合物、如果不“锚定”会渗漏小亲水组分、和由于水凝胶溶胀导致的肿瘤块渗透性的未知限制。
根据本发明,作为可由PAA纳米粒子传送的治疗剂,光敏剂具有若干非常合适的性质。具体是,(1)施用的靶向非光动力药物只有很小一部分到达肿瘤位点,其余会导致全身毒性。然而PDT提供双重选择性,其中光敏剂在没有光时无活性,且不经光活化时无害。因此纳米粒子包含的光敏剂可以在疾病位点局部活化。(2)PDT的功效是由于单线态氧的产生,根据本发明的化合物和方法,单线态氧易于从纳米粒子的孔隙扩散。因此,与化疗剂相反,不需要从纳米粒子中释放光敏剂囊化(encaphotosensitizerulated)药物。相反地,可以使用血浆滞留时间长的稳定纳米粒子,其增加传送到肿瘤的药量。(3)无论光敏剂在细胞内的定位如何,PDT都是有效的。虽然线粒体是单线态氧的主要靶点,但进入溶酶体的光敏剂也是有活性的,光动力过程致使溶酶体破裂,释放蛋白酶,并导致细胞质中光敏剂的重新分配。纳米粒子平台也为PCT提供明显优势:(1)高水平显像剂可以在纳米粒子中与光敏剂结合,利用荧光显像引导的光纤摆放将光活化性光定向至大或浅表肿瘤、或早期无临床迹象的疾病,允许“即诊即治”方法。(2)有可能向纳米粒子加入靶向性部分,如cRGD和F3肽,以增加光敏剂的选择性传送。(3)纳米粒子可以携带大量光敏剂,并且可以修饰它们的表面以提供最佳血浆药动学所要求的亲水性。因此,它们可以传送高水平光敏剂至肿瘤,减少癌症治疗所需光量。
光敏剂优选为如下结构式所示的四吡咯光敏剂:
或其药学上可接受的衍生物,其中:
R1和R2各自独立地是取代的或未取代的烷基、取代的或未取代的烯基、-C(O)Ra或-COORa、或-CH(CH3)(ORa)或-CH(CH3)(O(CH2)nXRa),其中Ra是氢、或取代的或未取代的烷基、取代的或未取代的烯基、取代的或未取代的炔基、或取代的或未取代的环烷基;其中R2可以是-CH=CH2、-CH(OR20)CH3、-C(O)Me、-C(=NR21)CH3或-CH(NHR21)CH3
其中X是芳基或杂芳基基团;
n是0到6的整数;
其中R20是甲基、丁基、庚基、十二烷基或3,5-二(三氟甲基)苄基;且
R21是3,5-二(三氟甲基)苄基;
R1a和R2a各自独立地是氢、或取代的或未取代的烷基,或者一起形成共价键;
R3和R4各自独立地是氢、或取代的或未取代的烷基;
R3a和R4a各自独立地是氢、或取代的或未取代的烷基,或者一起形成共价键;
R5是氢、或取代的或未取代的烷基;
R6和R6a各自独立地是氢、或取代的或未取代的烷基,或者一起形成=O;
R7是共价键、亚烷基、氮杂烷基(azaalkyl)、或氮杂芳烷基(azaaraalkyl)或=NR20,其中R20是3,5-二(三-氟甲基)苄基或-CH2X-R1或-YR1,其中Y是芳基或杂芳基基团;
R8和R8a各自独立地是氢、或取代的或未取代的烷基,或一起形成=O;
R9和R10各自独立地是氢、或取代的或未取代的烷基,且R9可以是-CH2CH2COOR2,其中R2是可以任选被一个或多个氟原子取代的烷基基团;
当被取代时,各个R1-R10被一个或多个取代基取代,所述取代基各自独立地选自Q,其中Q是烷基,卤代烷基,卤基,photosensitizereudohalo,或其中Rb是氢、烷基、烯基、炔基、环烷基、芳基、杂芳基、芳烷基-COORb,或其中Rc是氢、烷基、烯基、炔基、环烷基或芳基的ORc,或其中Rd和Re各自独立地是氢、烷基、烯基、炔基、环烷基或芳基的CONRdRe,或其中Rf和Rg各自独立地是氢、烷基、烯基、炔基、环烷基或芳基的NRfRg,或其中Rh是氢、烷基、烯基、炔基、环烷基或芳基的=NRh,或氨基酸残基;
各个Q独立地未被取代或被一个或多个取代基取代,所述取代基各自独立地选自Q1,其中Q1是烷基,卤代烷基,卤基,photosensitizereudohalo,或其中Rb是氢、烷基、烯基、炔基、环烷基、芳基、杂芳基、芳烷基的-COORb,或其中Rc是氢、烷基、烯基、炔基、环烷基或芳基的ORc,或其中Rd和Re各自独立地是氢、烷基、烯基、炔基、环烷基或芳基的CONRdRe,或其中Rf和Rg各自独立地是氢、烷基、烯基、炔基、环烷基或芳基的NRfRg,或其中Rh是氢、烷基、烯基、炔基、环烷基或芳基的=NRh,或是氨基酸残基。
光敏剂可以在并入纳米粒子之前或并入纳米粒子之后与显像增强剂结合,或者光敏剂和/或显像增强剂可以与纳米粒子化学结合,和/或光敏剂和显像增强剂的一种或多种可以与纳米粒子物理结合。
显像增强剂可以用于基本上任何显像过程,例如,在之前论述的本发明背景中和本文作为背景技术参考并入的参考文献列举中论述了这类显像增强剂的例子。
应该理解,其它作用剂可以并入纳米粒子中,如肿瘤靶向部分和肿瘤抑制或肿瘤毒性部分。
附图说明
图1.(A):不同药物剂量下,带有RIF肿瘤的C3H小鼠中(10只小鼠/组)HPPH-CD接合物1的体内光敏功效。在注射后24h将肿瘤暴露于光(135J/cm2/75mW/cm2)。(B):注射(药物剂量0.3μmol/kg)后24h,接合物1在活鼠中的定位。光处理参数没有优化(进行中)[无PAA纳米粒子]
图2.施用PAA纳米粒子制剂(HPPH和花青染料(CD)以2比1的比率后负载),带有结肠26肿瘤的BALB/c小鼠的全身图像。在不同时间点获取的图像中,CD浓度保持不变(0.3μmol/kg)。A=注射后24h,B=注射后48h,C=注射后72h(λex:785nm;λEm:830nm)。L=低,H=高。
图3.以2∶1和4∶1的比率后负载到PAA和ORMOSIL纳米粒子中的HPPH和CD的体内PDT功效。注:HPPH剂量:在PAA纳米粒子中为0.47μmol/kg,在ORMOSIL纳米粒子中为0.78μmol/kg。
图4.用1%HSA洗若干次后,HPPH和CD从PAA纳米粒子的缓慢释放(以2∶1比率后负载)。
图5.用HPPH-CD接合物1和PAA纳米粒子接合的CD/与HPPH后负载,带有结肠26肿瘤的BALB/c小鼠在不同时间点的体内显像比较。纳米粒子对肿瘤更为特异。(小鼠1)
图6.图片1(4T1肿瘤):解剖的原发肿瘤(PT)和转移肿瘤(MT)。图片2(4T1肿瘤):解剖的原发肿瘤和转移肿瘤的PET显像。图片3(带有4T1肿瘤的BALB/C小鼠):全身PET显像。清楚观察到肿瘤的肺转移。图片4:用57Co源做穿透式扫描显示没有肺转移的小鼠中肺的位置。图片5:带有Colo-26(非转移肿瘤)的BALB/C小鼠:用PET全身显像。清楚观察到肿瘤中124I-光敏剂的高度累积,而在肺中没有任何明显累积(注射剂量:100μCi)。T=肿瘤,PT=原发肿瘤;MT=转移肿瘤。
图7.带有结肠26肿瘤的BALA/c小鼠中(3只小鼠/组),110min时18F-FDG(100μCi,2h半衰期)和48h时124I-光敏剂2(100μCi,4.2d半衰期)的体内生物分布。两种作用剂的肿瘤摄取类似。然而,很显然正常器官中FDG的摄取高于124I-光敏剂2。
图8.带有结肠26肿瘤的BALB/c小鼠中,有和无PAA纳米粒子的124I标记光敏剂2的体内PET显像比较(注射后72h)和生物分布比较(注射后24h、48h和72h)(见正文)。[PET显像剂2的生物分布:无PAA,有PAA]
图9.在富核仁素的MDA-MB-435细胞系中,由F3靶向纳米粒子(A系列)、F3-Cys靶向纳米粒子(B系列)和非靶向纳米粒子(F系列)靶向的细胞的荧光强度。
图10.接合HPPH、+或-F3-Cys肽的PAA纳米粒子与MDA-MB-435细胞温育15min的荧光(左)&活/死细胞测定(右)。
图11.显示9L神经胶质瘤细胞中F3-Cys肽靶特异性的共焦图像。左:F3-Cys PEG若丹明-PAA纳米粒子(9L细胞)。右:PEG若丹明-PAA纳米粒子(9L细胞)。
图12.带有结肠26肿瘤的BALB/c小鼠中,14C标记HPPH和后负载入PAA纳米粒子的14C标记HPPH的体内生物分布。给12只小鼠/组施用14C标记的光敏剂(3.8μCi/0.2ml)。注射后24、48、72h,处死三只小鼠/时间点。移除感兴趣的器官并测量其放射性。将原始数据转换为计数/克组织。
图13.注射后24、48和72h,使用不同粒度PAA纳米粒子的碘化光敏剂的体内生物分布。左:后负载入30nm PAA纳米粒子的531-ME。右:用150nm PAA纳米粒子预处理后的531-ME的生物分布。
图14显示HPPH的结构式。
图15是多功能PAA纳米粒子的图解。
图16显示本发明PAA纳米粒子制备方法的流程图。
发明详述
光敏剂通常产生荧光,它们在体内的荧光特性已经被利用于检测肺、膀胱和其它位置的早期癌症。对于早期疾病的治疗和深部肿瘤,可以用荧光引导活化光。但光敏剂不是用于肿瘤检测的最佳荧光团,其有若干原因:(i)它们的荧光量子产率低(特别是与菌绿素有关的长波长光敏剂)。有效的光敏剂往往荧光效率(量子产率)低于设计为荧光团的化合物,如花青染料,因为其作为荧光发出的激发单线态能量被转移到三线态然后又转移到分子氧。(ii)它们的斯托克斯位移小。基于卟啉的光敏剂在长波长吸收带和荧光波长之间的差异(斯托克斯位移)相对较小,使得从技术上难以将荧光与激发波长分开。(iii)大多数光敏剂荧光波长相对较短,<800nm,对于探测深部组织不是最佳的。
之前我们已经说明,与NIR吸收性荧光团(非肿瘤特异的花青染料)接合的某些亲肿瘤光敏剂(如HPPH)可以作为双功能作用剂用于荧光肿瘤显像和光治疗(PDT)。在此,HPPH被用作向肿瘤传送显像剂的载体。这种方法的局限是所述接合物对于两种模式显示出显著不同的剂量要求。显像剂量比光治疗剂量低约10倍(图1),这可能由于激发光敏剂所产生的一部分单线态氧(造成肿瘤破坏的关键细胞毒性剂)被荧光团淬灭而导致其光破坏。肿瘤暴露于780nm(花青染料的激发波长)下在体内产生860nm发射,并且正如所预期的,没有观察到荧光团(CD)或光敏剂(HPPH)的明显光漂白。
为研究PAA纳米粒子的效用,运用了三种不同的方法。第一,HPPH和花青染料(荧光团)以不同比率(HPPG比CD:1∶1、2∶1、3∶1和4∶1摩尔浓度)后负载。简而言之,首先将HPPH后负载到PAA纳米粒子。旋转过滤除去游离HPPH,然后,后负载花青染料。再次旋转过滤,用1%小牛血清洗若干次,并测定浓度。在带有结肠26肿瘤的BALB/c小鼠中,2∶1制剂产生最好的肿瘤显像和长期肿瘤治愈。这种制剂含有单剂的HPPH治疗剂量(0.47μmol/kg)和花青染料显像剂量(0.27mol/kg),所述剂量与所述组分单独用于肿瘤显像和治疗相近,但具有好得多的肿瘤选择性(HPPH的皮肤与肿瘤比是4∶1,而没有纳米粒子时为2∶1)。在相近的治疗参数下,ORMOSIL纳米粒子显示出显著减弱的反应(显像和PDT,未显示)。通过具有100KDa或更大截留值膜的Amicon离心过滤装置用水性小牛血清反复洗,并用分光光度法测定滤液中的药物,确定了PAA纳米粒子中药物的稳定性。图2-4显示了ORMOSIL和PAA制剂的体内PDT功效比较、它们的肿瘤显像潜力和稳定性(体内释放动力学),其中清楚表明了PAA纳米粒子的优点,其使治疗剂量降低几乎8倍而不减弱肿瘤显像潜力,且也避免了HPPH-CD接合物1的吐温80制剂要求。在第二种方法中,HPPH CD接合物1后负载于PAA纳米粒子,其无疑增强了肿瘤显像,但治疗剂量仍高10倍(与HPPH CD接合物相近,图5)。在第三种方法中,花青染料首先从外围接合于PAA纳米粒子,然后后负载HPPH。与HPPH-CD接合物1相比,PAA制剂再次显示出增强的肿瘤特异性(显像)(图5)。
纳米粒子的肿瘤选择性作用
具有增加的选择性和更长波长的光敏剂可能是用于脑和深部肿瘤(特别是乳腺、脑和肺)的更合适候选物。对于医学领域光动力疗法(PDT)的进展而言,光源和传送系统的发展也是关键的。两种不同的技术:间质和腔内光传送已经被用于脑肿瘤的治疗。对具有复发性脑肿瘤的患者使用间质PDT的效力表明,多数患者在治疗两个月内肿瘤复发。然而,之后观察到治疗失败似乎发生在有效光治疗区域的外面。Chang等报道了22个神经胶质瘤患者中有效肿瘤细胞杀伤半径为8mm,与之相比,Pierria用腔内发光方法发现了1.5cm深度的坏死。应该相信肿瘤切除是重要的,以使剩余的要治疗的肿瘤细胞数量最小化。将立体定向植入的光纤用于间质PDT时,没有空腔来容纳肿胀和导致脑水肿的相当大体积的肿瘤坏死。然而,脑水肿容易用类固醇疗法控制。与化学疗法和放射疗法相比,用PDT治疗脑肿瘤患者无疑显示出长期存活,而用辅助化学疗法和放射疗法治疗的神经胶质瘤患者似乎没有显示出额外益处。正如基于我们的初步数据,αvβ3靶向纳米粒子可以改进肿瘤选择性和PDT结果。
PET显像和PDT:PAA纳米粒子降低124I光敏剂(PET显影剂)的肝摄取并增强肿瘤特异性
我们利用124I标记光敏剂2的初步研究表明了其体内PDT功效和检测肿瘤104-106(RIF、结肠26、U87、GL261、胰腺肿瘤异种移植物)与肿瘤转移(带有同位4T1(乳腺)肿瘤的BALB/c小鼠)的能力(图6)。有趣的是,与18F FDG相比,光敏剂2在多数肿瘤中显示出增强的对比,包括那些18F FDG-PET提供有限显像潜力的地方(如脑、肺和胰腺肿瘤)。生物分布比较见图7。这是显示基于卟啉的化合物作为用于乳腺肿瘤和肿瘤转移显像的“双功能剂”用途的初次报道。与多数纳米粒子类似,PAA纳米粒子在肝脏和脾中累积。它们从多数器官的清除速率显著快于ORMOSIL纳米粒子并且它们没有显示出长期器官毒性。即使亲肿瘤的基于卟啉的光敏剂在肝脏和脾中显示出高摄取,但在暴露于光之前无毒。所述光敏剂从全身快速清除(天)而没有器官毒性。然而,T1/2为4.2天的放射性光敏剂如124I标记类似物2(在肺、脑、乳腺和胰腺肿瘤的PET显像中优于18F-FDG)可以导致正常器官的放射损伤。基于对PAA纳米粒子在肝和脾中高摄取的观察(下文),我们推测在注射PET剂前用无毒的PAA纳米粒子使器官饱和可以减少124I显像剂的摄取和放射损伤。为了原理证明,首先向带有结肠26肿瘤的小鼠注射(i.v.)空白PAA纳米粒子,24h后i.v.124I类似物(100-50μCi)。小鼠在注射后24、48和72h时显像,并在每一时间点进行生物分布研究,概括于图8(只显示72h显像)。
PAA纳米粒子在肿瘤中的存在显著不同(对比脑、肺和胰腺肿瘤)。生物分布比较见图7。
PAA纳米粒子可以用F3-Cys靶向核仁素:
用两种F3肽制备F3-靶向纳米粒子:F3肽通过其序列中现有的8个赖氨酸之一与纳米粒子接合,F3-Cys肽通过半胱氨酸与纳米粒子接合。半胱氨酸加帽的纳米粒子充当非靶向对照。各类纳米粒子的三个25mg批次含有:分别2.6、5.1和7.7mg F3(A3-A5);分别2.7、5.3和8mg F3-Cys(B3-B5);分别0.29、0.58和0.87mg Cys(C3-C5)。图9显示了与核仁素阳性的MDA-MB-435细胞一起体外温育的PAA纳米粒子发出的荧光强度。F3-Cys接合的纳米粒子显示出远高于非靶向纳米粒子的结合效率,而F3接合的纳米粒子则不是。通过半胱氨酸连接进行接合保持了F3肽对核仁素的特异性。此外,纳米粒子上多余的半胱氨酸帮助光敏剂最小化非特异结合。另外的试验(未显示)表明B4纳米粒子采用的F3-Cys肽的量(5.3mg/25mg纳米粒子)是最优的。
后负载PAA纳米粒子的光特性。后负载HPPH和花青染料(平均为0.5mg/ml)的PAA纳米粒子的吸收光谱清楚显示了光敏剂和染料的特征标记,没有聚集引发的增宽,而荧光光谱显示了来自两种成分的强信号。
外表面具有F3-Cys的HPPH接合PAA纳米粒子显示靶向特异性:
存在接合的HPPH时,F3介导的特异性保留。F3靶向纳米粒子有靶向特异性,靶向纳米粒子无靶向特异性,表明F3介导的特异性在存在接合的HPPH时被保留。F3靶向纳米粒子不在细胞核中累积。用660nm的光活化细胞时,只有F3靶向纳米粒子导致细胞杀伤(图11)。荧光共焦显微镜证实了F3靶向纳米粒子的细胞内化。
外表面具有F3-Cys的HPPH接合PAA纳米粒子显示靶向特异性:
用荧光显像检验了靶向纳米粒子的特异性(图10)。F3靶向的HPPH接合PAA纳米粒子特异性结合于MDA-MB-435细胞(表达核仁素)而非靶向纳米粒子则没有,表明F3介导的特异性在存在接合的HPPH时被保留。F3靶向纳米粒子不在细胞核中累积。用660nm光活化细胞时,只有F3靶向纳米粒子导致细胞杀伤(图11)。荧光共焦显微镜证实了F3靶向纳米粒子的细胞内化。
F3-Cys在9L神经胶质瘤细胞中显示靶点特异性:
与F3-Cys相似,PAA纳米粒子上的PEG化形式F3-Cys PEG在也表达核仁素的9L大鼠神经胶质瘤细胞中也显示出明显的靶点特异性,图11(注:用若丹明部分代替HPPH)。
生物分布研究:PAA纳米粒子增强HPPH的肿瘤摄取
带有结肠26肿瘤的BALB/c小鼠在注射后24、48和72h执行14C-HPPH和14C-HPPH后负载的PAA纳米粒子的生物分布(3只小鼠/时间点),结果概括于图12中。正如可以看到的,PAA纳米粒子的存在导致肿瘤摄取的显著增加和其它器官摄取的减少。
PAA纳米粒子的粒度导致肿瘤增强方面的显著差异
用各种粒度的纳米粒子研究124I-光敏剂的生物分布,先注射纳米粒子并随后施用标记的光敏剂或者将标记的光敏剂后负载于PAA纳米粒子,然后于24、48和72h执行小鼠的体内生物分布。图13中概括的结果清楚表明PAA纳米粒子的粒度在肿瘤增强方面构成显著影响。与这些制剂的体内PDT功效有关的试验目前正在进行。
本发明显示了基于卟啉的化合物在用于乳腺肿瘤和肿瘤转移显像的“双功能作用剂”方面的用途。与多数纳米粒子相似,PAA纳米粒子在肝和脾中累积。它们从多数器官的清除速率明显快于ORMOSIL纳米粒子,且它们没有显示长期器官毒性。即使亲肿瘤的基于卟啉的光敏剂在肝和脾中显示高摄取,但在暴露于光之前无毒。所述光敏剂从全身快速清除(天)而没有器官毒性。然而,T1/2为4.2天的放射性光敏剂如124I标记类似物2(在肺、脑、乳腺和胰腺肿瘤的PET显像中优于18F-FDG)可以导致正常器官的放射损伤。基于对PAA纳米粒子在肝和脾中高摄取的观察(下文),我们推测在注射PET剂前用无毒的PAA纳米粒子使器官饱和可以减少124I显像剂的摄取和放射损伤。为了原理证明,首先向带有结肠26肿瘤的小鼠注射(i.v.)空白PAA纳米粒子,24h后i.v.124I类似物(100-150μCi)。小鼠在注射后24、48和72h时显像并在每一时间点进行生物分布研究,概括于图8(只显示72h显像)。
对比脾和肝中显著降低的摄取和增加的肿瘤摄取,PAA纳米粒子的存在在肿瘤中造成显著差异,/注射后24、48和72小时对比(3只小鼠/组)。类似的研究(肿瘤显像和PDT功效)中标记的光敏剂后负载到各种粒度。标记的光敏剂后负载到各种粒度的PAA纳米粒子中的类似研究(肿瘤显像和PDT功效)目前正在进行。
Claims (9)
1.含有PAA纳米粒子的组合物,所述PAA纳米粒子含有在所述PAA纳米粒子形成后被后负载到所述纳米粒子上的四吡咯光敏剂和显像剂,其中所述光敏剂是HPPH。
2.权利要求1的组合物,其中显像剂是花青染料。
3.权利要求1的组合物,其中所述PAA纳米粒子含有在所述PAA纳米粒子形成后被后负载到所述纳米粒子上的如下图所示的HPPH-花青染料接合物,
4.权利要求1的组合物,其中显像剂是124I标记的化合物。
5.权利要求1的组合物,其中显像剂是PET显像剂、荧光显像剂或MR显像剂。
6.权利要求5的组合物,其中纳米粒子含有靶向部分。
7.权利要求6的组合物,其中靶向部分是肽、叶酸或碳水化合物。
8.制备含有HPPH光敏剂和显像剂的PAA纳米粒子的方法,所述方法通过在预制的PAA纳米粒子上后负载HPPH光敏剂和荧光团进行。
9.制备PAA纳米粒子的方法,所述方法通过将荧光团接合于PAA纳米粒子、然后向PAA纳米粒子后负载HPPH光敏剂进行。
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