靶向超声分子成像评价血管新生的研究进展

靶向超声分子成像技术是指将带有特定配体的靶向超声微泡经静脉注入体内,通过配体与受体结合的方式,使超声微泡选择性地聚集于靶组织或靶器官,并通过对比超声检查产生靶组织细胞水平、分子水平显影的一种新兴的成像技术。该技术标志着超声影像学从非特异性的物理成像向特异性的靶向分子成像的转变,是当今世界研究的热点之一,本文就应用靶向超声分子成像评价血管新生的相关进展作一简述和探讨。     

动态增强磁共振成像评价肿瘤血管新生

血管新生在肿瘤的生长及转移过程中起着重要的作用,抑制肿瘤血管生成已成为重要抗癌策略之一。为了正确评价肿瘤血管生成及抗血管生成治疗的疗效,需要一种敏感且特异的方式显示肿瘤血管的结构及功能变化。目前多种成像方法(CT、MRI、PET、超声以及光学成像)已用于监测肿瘤血管,但是由于核医学辐射性较大和分辨率较低,光学成像的低穿透性以及超声成像分辨率较低,其实际应用受到     

靶向超声微泡对结肠癌新生血管分子成像的实验研究

目的 探讨以VEGFR2 (kinase insert domain receptor,KDR)为靶点的靶向超声微泡对裸鼠结肠癌新生血管的成像效果.方法 以生物素-亲和素桥接法将特异性结合VEGF主要受体KDR的小肽K237与脂质微泡耦联构建靶向微泡,用同样方法将对照肽与脂质微泡耦联,构建对照微泡.以KDR阴性表达的人结肠癌LS174T细胞株建立人结肠癌裸鼠移植瘤模型.12只荷瘤鼠经尾静脉随机先后注射靶向微泡、对照微泡,2种微泡注射间隔30 min.注射靶向微泡后5 min和注射对照微泡后5 min荷瘤鼠均行超声造影检查,观察各组微泡在肿瘤组织造影增强情况,测量肿瘤组织的声强度(Ⅵ).另取6只荷瘤鼠预先注射K237肽后再注射靶向微泡,观察微泡的成像效果.靶向微泡组、对照微泡组、小肽预先封闭组肿瘤组织的Ⅵ值比较采用单因素方差分析,组间多重比较采用最小显著性差异t检验.用免疫组织化学技术检测KDR在肿瘤组织表达及分布规律.结果 成功制备了靶向微泡.注射超声微泡后5 min超声检查显示靶向微泡组肿瘤组织超声造影明显增强,对照微泡组及小肽预先封闭组仅见轻度的超声造影增强.3组Ⅵ值差异有统计学意义(F=39.130,P＜0.01).靶向微泡组与对照微泡组Ⅵ值差异有统计学意义(30.18±9.56与8.28±4.74,t=6.91,P＜0.01);小肽预先封闭组Ⅵ值与靶向微泡组差异有统计学意义(9.23±3.44与30.18±9.56,t =4.91,P＜0.01).免疫组织化学结果显示,荷瘤鼠结肠癌新生血管内皮细胞KDR表达较正常组织血管内皮细胞KDR表达显著增加.结论 以KDR为靶点的靶向超声微泡可以与荷瘤鼠肿瘤新生血管内皮特异性黏附并有效评价肿瘤新生血管形成.     

骨髓基质抗原蛋白2靶向微泡的制备及小鼠肿瘤新生血管超声分子成像研究

目的 研究制备针对骨髓基质抗原蛋白2(BST2)的TMBs造影剂(BST2-TMBs),通过超声分子成像技术对小鼠肿瘤血管内皮细胞进行检测,为肿瘤的发生、发展及早期诊断提供实验依据.方法 将抗BST2的抗体通过生物素-亲和素桥接的方式连接于微泡(MBs)表面,获得BST2-TMBs,在光学显微镜下观察TMBs的形态,用粒径分析仪测定其粒径及其分布;通过体外细胞黏附实验研究TMBs与血管内皮细胞的结合性能,并对小鼠前列腺癌肿瘤血管内皮细胞行超声分子成像,用免疫组织化学染色分析BST2在肿瘤血管内皮细胞的表达.采用SPSS 19.0软件行统计学分析,对独立样本行t检验.结果 制备的BST2-TMBs的平均粒径为1.61μm,其中95％的微泡在1～5 μm之间.BST2 -TMBs能够与血管内皮细胞结合,平均每个视野有(165±25)个TMBs结合在内皮细胞表面,远高于非靶向微泡(IgG-MBs)对照组的(10±3)个微泡(t=10.662,P＜0.01).黏附的TMBs能够明显增强内皮细胞的超声信号强度,TMBs为27.93±5.14(灰度值),非靶向微泡为3.61±1.67(灰度值)(t=7.239,P＜0.01).小鼠在体肿瘤超声分子成像表明:BST2-TMBs处理组在微泡注射7min时信号强度(扣除微泡击碎后的信号强度)为38.79±0.29(灰度值),能保持47.65％的微泡注射30 s时的信号强度(灰度值81.40±0.37),而IgG-MBs处理组在微泡注射7 min时的信号强度(扣除微泡击碎后的信号强度)是9.46 ±0.17(灰度值),仅能保持11.39％的微泡注射30 s时的信号强度(灰度值83.01±0.60).相比之下,TMBs在肿瘤部位的超声信号强度较非靶向微泡提高4.27倍(t=65.587,P＜0.01).免疫组织化学证实BST2蛋白在小鼠前列腺癌肿瘤血管内皮细胞上有表达.结论BST2 -TMBs可以用于小鼠前列腺癌血管内皮细胞的超声分子成像,这为肿瘤的发生发展以及早期诊断提供了实验依据.     

在肿瘤生长中肿瘤血管源性标记物的表达水平:运用分子靶向微泡和超声成像进行纵向评估

目的针对肿瘤生长中活体的肿瘤血管内皮细胞,评价分子靶向微泡(MB)和超声的应用在无创性评估3种血管源性标记物αvβ3整合蛋白、endoglin和血管内皮生长因子     

实时微泡增强超声评估肾细胞癌病人抗血管生成靶向治疗效果的临床研究

目的应用实时微泡对比增强超声(DCEUS)技术设计并实施一项评价行靶向治疗的肾细胞癌血管反应特征的循证标准。材料与方法本研究获伦理委员会批准,病人签     

肝脏快速容积采集动态增强扫描对前列腺癌的诊断价值及与血管生成对照分析

目的:探讨肝脏快速容积采集技术(LAVA)动态增强扫描对前列腺癌的诊断价值,并结合病理初步分析前列腺病变与血管生成的相关关系。方法:回顾性分析经穿刺活检及手术病理证实的前列腺癌和前列腺增生各40例的MRI表现,术前均行MRI常规平扫和LAVA动态增强扫描,观察病灶LAVA动态强化特征并获得TIC,分析其参数变化,同时对证实的病理标本行血管内皮生长因子(VEGF)和微血管密度(MVD)测定。结果:病变TIC分为3型:Ⅰ型为缓慢强化型,Ⅱ型为平台型,Ⅲ型为速升下降型;Ⅰ型多见于前列腺增生,Ⅱ型既可见于前列腺癌,又可见于前列腺增生,Ⅲ型以前列腺癌为主。前列腺癌组病灶强化峰值时间早于前列腺增生组,强化程度和强化率均高于前列腺增生组(均P0.05)。前列腺癌组MVD值及VEGF表达明显高于前列腺增生组(均P0.05)。结论:LAVA动态增强扫描强化特征有助于前列腺增生与前列腺癌的诊断与鉴别诊断,且能反映前列腺癌及前列腺增生血管生成的不同状况。     

动脉粥样硬化的分子成像:血管细胞黏附分子-1为靶向的磁性微泡和对比增强超声诊断效能

目的评价经血管细胞黏附分子-1(VCAM-1)(CD106)靶向的微泡,在磁性导引系统帮助下,能否提高对比增强分子超声(US)对主动脉粥样硬化的检出效能。材料与方     

血管生成抑制剂对肝脏肿瘤灌注以及细胞毒性治疗的影响

摘要目的评价CT动态增强扫描(dynamic contrast material-enhanced,DCE)肝脏肿瘤灌注是否可以在兔模型中反映抗血管生成药物诱导的血管重建情况。材料与方法本研究经过大学动物保护委员会动物使用小组委员会(Animal Use Subcommittee of the University Councilon AnimalCare)     

MR弹性成像和扩散加权成像联合评价小鼠结肠肿瘤的生长和抗血管治疗后改变

摘要目的研究MR弹性图及扩散加权成像检测小鼠结肠肿瘤在生长及抗血管治疗期间微结构变化的潜在价值。材料与方法本研究通过地方动物保护伦理委员会批准。将60只Balb-C小鼠接种原位和异位结肠肿瘤,并利用7TMR高分辨T2WI,3D稳态MR弹性图及扩散加权成像监测3周,同时对12只小鼠注射CA4P12h后进行成像。测量小鼠肿瘤活性区域的合成剪切模量绝对值(|G*|)和扩散系数(ADC),与微血管密度(MVD)、细胞构成和纤维坏死情况进行比较,数据间的相关性用Pearson相关分析。     

Vessel imaging with viable tumor analysis for quantification of tumor angiogenesis

An “uncorrected” version of the following article was published in the June 2010 issue of MRM. The corrected version of the article is provided here. The publisher regrets the error. Imaging of tumor microvasculature has become an important tool for studying angiogenesis and monitoring antiangiogenic therapies. Ultrasmall paramagnetic iron oxide contrast agents for indirect imaging of vasculature offer a method for quantitative measurements of vascular biomarkers such as vessel size index, blood volume, and vessel density (Q). Here, this technique is validated with direct comparisons to ex vivo micro‐computed tomography angiography and histologic vessel measurements, showing significant correlations between in vivo vascular MRI measurements and ex vivo structural vessel measurements. The sensitivity of the MRI vascular parameters is also demonstrated, in combination with a multispectral analysis technique for segmenting tumor tissue to restrict the analysis to viable tumor tissue and exclude regions of necrosis. It is shown that this viable tumor segmentation increases sensitivity for detection of significant effects on blood volume and Q by two antiangiogenic therapeutics [anti‐vascular endothelial growth factor (anti‐VEGF) and anti‐neuropilin‐1] on an HM7 colorectal tumor model. Anti‐vascular endothelial growth factor reduced blood volume by 36 ± 3% (p < 0.0001) and Q by 52 ± 3% (p < 0.0001) at 48 h post‐treatment; the effects of anti‐neuropilin‐1 were roughly half as strong with a reduction in blood volume of 18 ± 6% (p < 0.05) and a reduction in Q of 33± 5% (p < 0.05) at 48 h post‐treatment. Magn Reson Med 63:1637–1647, 2010. © 2010 Wiley‐Liss, Inc.     

Vessel imaging with viable tumor analysis for quantification of tumor angiogenesis

Imaging of tumor microvasculature has become an important tool for studying angiogenesis and monitoring antiangiogenic therapies. Ultrasmall paramagnetic iron oxide contrast agents for indirect imaging of vasculature offer a method for quantitative measurements of vascular biomarkers such as vessel size index, blood volume, and vessel density. Here, this technique is validated with direct comparisons to ex vivo micro‐CT angiography and histologic vessel measurements, showing significant correlations between in vivo vascular MRI measurements and ex vivo structural vessel measurements. The sensitivity of the MRI vascular parameters is also demonstrated, in combination with a multispectral analysis technique for segmenting tumor tissue to restrict the analysis to viable tumor tissue and exclude regions of necrosis. It is shown that this viable tumor segmentation increases sensitivity for detection of significant effects on blood volume and vessel density by two antiangiogenic therapeutics (anti‐VEGF and anti‐neuropilin‐1) on an HM7 colorectal tumor model. Anti‐VEGF reduced blood volume by 36 ± 3% (P < 0.0001) and vessel density by 52 ± 3% (P < 0.0001) at 48 h posttreatment; the effects of anti‐neuropilin‐1 were roughly half as strong with a reduction in blood volume of 18 ± 6% (P < 0.05) and a reduction in vessel density of 33 ± 5% (P < 0.05) at 48 h posttreatment. Magn Reson Med 63:1637–1647, 2010. © 2010 Wiley‐Liss, Inc.     

肿瘤血管生成的PET检测

肿瘤血管生成作为肿瘤的主要特征,在肿瘤生长和转移中起着重要作用,为肿瘤治疗提供了新策略.通过标记血管生成相关的受体、多肽、激酶或细胞外基质蛋白,形成高亲和力的分子探针,与肿瘤血管生成过程中产生的特异性靶分子结合,从而显示包括整合素、VEGF/VEGFR、基质金属蛋白酶(MMPs)等与血管生成关系密切的特征性血管生成因子,可从分子水平对肿瘤新生血管及血管靶向治疗疗效进行无创性检测.笔者就肿瘤血管生成PET影像学检测研究进展及未来发展作一综述.     

Gadopentetate dimeglumine versus ultrasmall superparamagnetic iron oxide for dynamic contrast-enhanced MR imaging of tumor angiogenesis in human colon carcinoma in mice

PURPOSE: To compare the kinetic physiologic properties of a clinical contrast agent, gadopentetate dimeglumine, with those of ultrasmall superparamagnetic iron oxide (USPIO) particles for dynamic contrast material-enhanced magnetic resonance (MR) imaging of tumor angiogenesis in human colon carcinoma in mice with a clinical MR imaging unit. MATERIALS AND METHODS: Thirty-two mice with human colon carcinoma were injected with either gadopentetate dimeglumine (n = 16) or USPIO (n = 16) for dynamic contrast-enhanced MR imaging and pre- and postcontrast T2 and T2* measurements. Dynamic contrast-enhanced MR imaging measurements were analyzed by using a two-compartment model to calculate the endothelial transfer coefficient surface area product (KPS) for the tumor microvasculature, the reflux coefficient (k), and the fractional plasma volume (fPV). KPS, k, and fPV maps were compared with histologic microvessel density (MVD) and used to observe differences between core and rim regions of tumor. RESULTS: Results in 30 mice (15 in the gadopentetate dimeglumine group and 15 in the USPIO group) could be used. KPS values measured with both agents correlated well with MVD in hot spots (gadopentetate dimeglumine: r = 0.6, P =.02; USPIO: r = 0.6, P =.01). No significant difference (P =.4) in correlation was found between the two agents. Both USPIO and gadopentetate dimeglumine demonstrated higher MVD and KPS values in tumor rim than in tumor core (P <.01). Tumor k values correlated poorly with whole-tumor MVD for both gadopentetate dimeglumine (r = 0.3, P =.4) and USPIO (r = 0.2, P =.6), while fPV values correlated well with whole-tumor MVD for USPIO (r = 0.6, P =.02) but not gadopentetate dimeglumine (r = -0.01, P =.98). T2 and T2* measurements showed small differences between areas of high and low angiogenic activity with both agents. CONCLUSION: The kinetic physiologic properties of gadopentetate dimeglumine are as good as those of USPIO for dynamic contrast-enhanced MR imaging for calculating KPS as a measurement of angiogenesis in human colon carcinoma. Further studies with patients may reveal whether gadopentetate dimeglumine might be used for this purpose in clinical practice.     

肝细胞癌螺旋CT同层动态扫描表现与肿瘤血管生成的相关性

目的 探讨肝细胞癌螺旋CT同层动态扫描所获部分参数和形态学表现特征与肿瘤血管生成的相关性。方法 经病理证实的肝细胞癌26例、全肝平扫后选择靶平面行同层动态扫描和门脉期全肝扫描,评价癌灶形态表现特征、时间－密度曲线（T－DC）走势,并计算癌灶强化峰值（PV）和强化比值（CER）。组织切片经Ⅷ因子相关抗原（F8RA）和血管内皮生长因子（VEGF）免疫组化染色,分析癌组织微血管数（MVC）和癌细胞VEGF表达阳性率。将CT形态表现和所获部分参数与组织病理学改变进行比较研究。结果 癌灶PV7．9－75．2HU,CER3．8％－36．0％;MVC6－91,VEGF阳性率32％－78％。癌灶PV、CER与MVC呈显著正相关（r分别为0．508、0．423,P值分别＜0．01、0．05）,癌灶PV、CER与VEGF阳性率无显著相关性（r分别炎0．256、0．347,P值均＞0．05）;肿瘤新生血管分布影响TDC走势,肿瘤血管是否丰富及其组织结构特点影响肿瘤强化特征。结论 根据肝细胞癌螺旋CT同层动态扫描部分参数及T－DC走势和增强大体形态表现,可推测癌组织MVC和肿瘤新生血管分布特征,并可反映肿瘤血管是否丰富及肿瘤组织结构特点。     

肿瘤血管新生分子影像的研究进展

血管新生在肿瘤生长、转移中起到重要的作用.分子影像的出现为及早定量评价肿瘤血管新生提供了新方法.本文介绍了分子影像在肿瘤血管新生中应用进展.     

肿瘤血管生成的分子影像学研究进展

肿瘤血管生成与肿瘤的生长、恶变、转移以及患者的预后有着密切的关系,因此,肿瘤的抗血管生成治疗引起了人们的极大兴趣.分子影像学应用高亲和力的分子探针与靶分子特异性结合的原理,可在活体细胞和分子水平上特征性地显示及测量生物机体的生化过程.近年来,分子影像学技术在肿瘤血管生成的可视化及定量研究中取得了一定的进展,有望成为肿瘤早期诊断与靶向治疗评价的重要手段.该文综述了肿瘤血管生成的分子影像学技术的最新进展.