肿瘤血管生成的MR分子成像与纳米氧化铁的生物学效应研究
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摘要
在肿瘤血管生成过程中,活化血管内皮细胞整合素表达明显上调。精氨酸-甘氨酸-天冬氨酸(RGD)三肽序列能够特异性识别整合素α_vβ_3,构建含RGD肽的高特异性MR探针对肿瘤血管生成进行分子成像,可以达到早期诊断,评估治疗效果及预测预后的目的。本项研究制备了RGD肽标记的以聚乳酸(PLA)为包被材料的超小超顺磁性氧化铁(USPIO)(以RGD-PLA-USPIO指代),并在体外和体内实验中考察了其检测肿瘤血管生成的能力。此外,本研究探讨了柠檬酸和右旋糖酐包被的磁性纳米粒子标记脐静脉血管内皮细胞(HUVECs)后,对其增殖、迁移、侵袭、分化等生物学行为的影响。具体研究内容主要包括以下四个部分：
第一部分采用改良共沉淀法(乙醇水溶液为溶剂的超声共沉淀法)制备PLA-USPIO,以透射电镜(TEM)和傅里叶变换红外光谱(FTIR)表征,显示经PLA包覆的USPIO呈球形结构,且表面富有羧基,为进一步偶联配体或其他靶分子提供了条件。PLA-USPIO具有较好的弛豫效能,在T_2和T_2*图像可以呈现明显的信号改变。将PLA-USPIO静脉注射后,可以有效的减少网状巨噬细胞系统(RES)对USPIO的摄取,延长在血液循环中停留的时间。通过计算USPIO注射前后T_2*和T_2弛豫时间改变,发现T_2*WI和T_2*值的测量对USPIO引起的磁场不均一更为敏感。
第二部分将RGD与PLA-USPIO经crosslink反应偶联制备RGD-PLA-USPIO探针。RGD-PLA-USPIO与B16F10、SPC-Al和HUVECs的结合实验证明,探针与整合素特异性结合的能力,并且其结合的多少与细胞表达整合素水平高低相关。透射电镜结果进一步证实了细胞内纳米氧化铁颗粒的存在。RGD-PLA-USPIO与HUVECs孵育后行MR扫描显示浓度相关性T2WI信号降低,提示RGD-PLA-USPIO作为对比剂所构建的MR探针具有应用于MR成像的可能性。
第三部分Vx-2肿瘤恶性度高,病理组织学证实肿瘤内小血管α_vβ_3整合素表达强阳性,是研究肿瘤血管生成的理想模型。将体外实验验证后的RGD-PLA-USPIO探针在VX-2肿瘤进行活体成像,以PLA-USPIO作为对照,结果表明RGD-PLA-USPIO可特异性降低VX-2肿瘤组织T_2*WI和T_2WI信号强度,在肿瘤周边富血管区域呈点片状信号降低。注射RGD-PLA-USPIO前后的T_2和T_2*弛豫时间变化量与PLA-USPIO相比有明显差异,且以T_2*值的变化更为敏感。普鲁士蓝染色证明肿瘤血管内皮细胞见蓝色铁颗粒存在,病理学结果与MR图像得到相互印证。以上结果提示RGD-PLA-USPIO有望成为针对肿瘤血管生成的特异性MR探针。
第四部分在细胞水平研究了柠檬酸和右旋糖酐包被的氧化铁纳米粒子对HUVEC细胞增殖、迁移、侵袭、分化能力的影响,观察了细胞骨架结构的改变。结果显示两种不同包被包被材料的氧化铁纳米粒子均可以抑制HUVECs增殖、迁移和侵袭,这种抑制能力呈浓度依赖性,且柠檬酸包被的氧化铁纳米粒子较右旋糖酐包被的氧化铁纳米粒子具有更高的细胞毒性。氧化铁纳米粒子可以显著遏制内皮细胞分化成管腔样结构的能力,在荧光显微镜下观察发现细胞骨架重新分布,粘着斑形成减少,细胞粘附能力减弱。由于细胞的粘附是贴壁细胞存活、生长、迁移、侵袭、分化等其他一切细胞生物活动的基础,经氧化铁纳米粒子处理后细胞出现的去粘附造成了其增殖、迁移、侵袭、分化能力的障碍。这种障碍很可能与铁催化的自由基损伤反应相关。
总结以上实验,本研究成功构建以整合素α_vβ_3为分子靶的特异性MR探针RGD-PLA-USPIO,结果表明RGD-PLA-USPIO可以有效在MR图像上显示活化肿瘤血管内皮整合素α_vβ_3的表达。HUVECs与柠檬酸或右旋糖酐包被的氧化铁纳米粒子孵育后,细胞的增殖、迁移、侵袭和分化能力等均受到不同程度的抑制。
Integrin is often significantly up-regulated in activated endothelial cells during tumor angiogenesis. The arginine-glycine-aspartic acid (RGD) peptide sequence is a specific recognition motif toαvβ3 integrin. Development of RGD peptide labeled, high specific MR probe for molecular imaging of tumor angiogenesis is capable to facilitate early dectection and may help monitor tumor vascular change during anti-angiogenesis therapy. In this study, a RGD labeled, Poly lactic acid (PLA) coated ultrasmall paramagnetic iron oxide (USPIO) (referred to as RGD-PLA-USPIO) were developed and the ability to detect tumor angiogenesis was investigated in vitro and in vivo. Pronounced signal decrease in T2*-weighted magnetic resonance image (MRI) and heterogeneous arrangement of neovasculature of tumor tissue were clearly identified in Vx-2 tumor model. The results demonstrate the efficiency of RGD-PLA-USPIO to visualizeαvβ3 integrin in activated tumor endothelial cells. In addition, the influence of dextran and citric acid coated IONPs on the behavior and function of human umbilical vein endothelial cells'(HUVECs) was discussed in concerned of viability, cytoskeleton, migration/invasion and differentiation. The thesis consists of four major sections.
ⅠPLA-USPIO were prepared in situ by a modified co-precipitation method by sonification in Ethanol-Water solution. Spherical particle shape was determined by TEM and FTIR showed plenty of carboxyl groups on the surface of PLA-USPIO for better binding or conjugation with specific ligands. PLA-USPIO prolonged circulation time through decreased uptake by RES. Furthermore, PLA-USPIO generated significant signal reduction in T2WI and T2*WI and T2* relaxation time measurement was more sensitive to the magnetic field inhomogeneity induced by USPIO.
II RGD-PLA-USPIO was prepared by crosslink reaction. The specific affinity of RGD-PLA-USPIO to integrin was identified by B16F10, SPC-Aland HUVECs binding tests and it was indicated that binding capacity was dependent with the level of integrin in cells. TEM confirmed the existence of RGD-PLA-USPIO in cytoplasm. MR scan of HUVECs incubated with RGD-PLA-USPIO exhibited a dose-dependent signal decrease in T2WI, which facilitated the utility of RGD-PLA-USPIO as a MR probe.
III Vx-2 adenocarcinoma is highly malignant and is considered to be an ideal tumor model with significant integrin expressed in tumor endothelial cells. Compared with PLA-USPIO injection, Vx-2 tumor rabbits receiving RGD-PLA-USPIO revealed a marked decrease in T2*WI and T2WI, although not exclusively, asymmetrically located along the tumor periphery. The signal decease was typically seen in a patchy distribution adjacent to blood vessels and along the lateral tumor border as small spots. The T2 and T2* relaxation times of tumor accordingly decreased with the signal change in images and T2* relaxation time was more sensitive due to a susceptibility effect. Prussian blue stain of the Vx-2 tumor visualized blue granule in tumor endothelium and corroborated angiogenesis observed with MR images. Generally, RGD-PLA-USPIO hold promise to be uitilized as novel MR probe for in vivo detection of tumor angiogenesis.
IV The biological effects of citrate and dextran coated IONP on HUVECs were investigated in terms of cell proliferation, cytoskeleton, migration/invasion and differentiation. Cell proliferation, migration and invasion were inhibited in a dose dependent manner and citrate-IONP had more toxic effects than dextran-IONP. The capacity of HUVECs to form vascular network on Matrigel diminished after exposure to IONPs. Cytoskeletal structures were greatly disrupted, as evidenced by diminished vinculin spots, and disorganized actin fiber and tubulin networks. Cell attachment is necessary to mediate the survival of anchorage-dependent cells and critical for efficient cell growth, migration, invasion and differentiation. The detachment after exposure to IONPs induced the dysfunction of HUVECs and the iron catalyzed free radical damage might attribute to it.
In general, we have reported the development of RGD-PLA-USPIO as anαvβ3 integrin targeted MR probe and the results demonstrate RGD-PLA-USPIO can efficiently visiualize the expression ofαvβ3 integrin on tumor vascularature. Additionally, HUVECs proliferation, migration/invasion and differentiation is greatly inhibited after incubation with citrate and dextran-coated iron oxide nanoparticles.
第一部分采用改良共沉淀法(乙醇水溶液为溶剂的超声共沉淀法)制备PLA-USPIO,以透射电镜(TEM)和傅里叶变换红外光谱(FTIR)表征,显示经PLA包覆的USPIO呈球形结构,且表面富有羧基,为进一步偶联配体或其他靶分子提供了条件。PLA-USPIO具有较好的弛豫效能,在T_2和T_2*图像可以呈现明显的信号改变。将PLA-USPIO静脉注射后,可以有效的减少网状巨噬细胞系统(RES)对USPIO的摄取,延长在血液循环中停留的时间。通过计算USPIO注射前后T_2*和T_2弛豫时间改变,发现T_2*WI和T_2*值的测量对USPIO引起的磁场不均一更为敏感。
第二部分将RGD与PLA-USPIO经crosslink反应偶联制备RGD-PLA-USPIO探针。RGD-PLA-USPIO与B16F10、SPC-Al和HUVECs的结合实验证明,探针与整合素特异性结合的能力,并且其结合的多少与细胞表达整合素水平高低相关。透射电镜结果进一步证实了细胞内纳米氧化铁颗粒的存在。RGD-PLA-USPIO与HUVECs孵育后行MR扫描显示浓度相关性T2WI信号降低,提示RGD-PLA-USPIO作为对比剂所构建的MR探针具有应用于MR成像的可能性。
第三部分Vx-2肿瘤恶性度高,病理组织学证实肿瘤内小血管α_vβ_3整合素表达强阳性,是研究肿瘤血管生成的理想模型。将体外实验验证后的RGD-PLA-USPIO探针在VX-2肿瘤进行活体成像,以PLA-USPIO作为对照,结果表明RGD-PLA-USPIO可特异性降低VX-2肿瘤组织T_2*WI和T_2WI信号强度,在肿瘤周边富血管区域呈点片状信号降低。注射RGD-PLA-USPIO前后的T_2和T_2*弛豫时间变化量与PLA-USPIO相比有明显差异,且以T_2*值的变化更为敏感。普鲁士蓝染色证明肿瘤血管内皮细胞见蓝色铁颗粒存在,病理学结果与MR图像得到相互印证。以上结果提示RGD-PLA-USPIO有望成为针对肿瘤血管生成的特异性MR探针。
第四部分在细胞水平研究了柠檬酸和右旋糖酐包被的氧化铁纳米粒子对HUVEC细胞增殖、迁移、侵袭、分化能力的影响,观察了细胞骨架结构的改变。结果显示两种不同包被包被材料的氧化铁纳米粒子均可以抑制HUVECs增殖、迁移和侵袭,这种抑制能力呈浓度依赖性,且柠檬酸包被的氧化铁纳米粒子较右旋糖酐包被的氧化铁纳米粒子具有更高的细胞毒性。氧化铁纳米粒子可以显著遏制内皮细胞分化成管腔样结构的能力,在荧光显微镜下观察发现细胞骨架重新分布,粘着斑形成减少,细胞粘附能力减弱。由于细胞的粘附是贴壁细胞存活、生长、迁移、侵袭、分化等其他一切细胞生物活动的基础,经氧化铁纳米粒子处理后细胞出现的去粘附造成了其增殖、迁移、侵袭、分化能力的障碍。这种障碍很可能与铁催化的自由基损伤反应相关。
总结以上实验,本研究成功构建以整合素α_vβ_3为分子靶的特异性MR探针RGD-PLA-USPIO,结果表明RGD-PLA-USPIO可以有效在MR图像上显示活化肿瘤血管内皮整合素α_vβ_3的表达。HUVECs与柠檬酸或右旋糖酐包被的氧化铁纳米粒子孵育后,细胞的增殖、迁移、侵袭和分化能力等均受到不同程度的抑制。
Integrin is often significantly up-regulated in activated endothelial cells during tumor angiogenesis. The arginine-glycine-aspartic acid (RGD) peptide sequence is a specific recognition motif toαvβ3 integrin. Development of RGD peptide labeled, high specific MR probe for molecular imaging of tumor angiogenesis is capable to facilitate early dectection and may help monitor tumor vascular change during anti-angiogenesis therapy. In this study, a RGD labeled, Poly lactic acid (PLA) coated ultrasmall paramagnetic iron oxide (USPIO) (referred to as RGD-PLA-USPIO) were developed and the ability to detect tumor angiogenesis was investigated in vitro and in vivo. Pronounced signal decrease in T2*-weighted magnetic resonance image (MRI) and heterogeneous arrangement of neovasculature of tumor tissue were clearly identified in Vx-2 tumor model. The results demonstrate the efficiency of RGD-PLA-USPIO to visualizeαvβ3 integrin in activated tumor endothelial cells. In addition, the influence of dextran and citric acid coated IONPs on the behavior and function of human umbilical vein endothelial cells'(HUVECs) was discussed in concerned of viability, cytoskeleton, migration/invasion and differentiation. The thesis consists of four major sections.
ⅠPLA-USPIO were prepared in situ by a modified co-precipitation method by sonification in Ethanol-Water solution. Spherical particle shape was determined by TEM and FTIR showed plenty of carboxyl groups on the surface of PLA-USPIO for better binding or conjugation with specific ligands. PLA-USPIO prolonged circulation time through decreased uptake by RES. Furthermore, PLA-USPIO generated significant signal reduction in T2WI and T2*WI and T2* relaxation time measurement was more sensitive to the magnetic field inhomogeneity induced by USPIO.
II RGD-PLA-USPIO was prepared by crosslink reaction. The specific affinity of RGD-PLA-USPIO to integrin was identified by B16F10, SPC-Aland HUVECs binding tests and it was indicated that binding capacity was dependent with the level of integrin in cells. TEM confirmed the existence of RGD-PLA-USPIO in cytoplasm. MR scan of HUVECs incubated with RGD-PLA-USPIO exhibited a dose-dependent signal decrease in T2WI, which facilitated the utility of RGD-PLA-USPIO as a MR probe.
III Vx-2 adenocarcinoma is highly malignant and is considered to be an ideal tumor model with significant integrin expressed in tumor endothelial cells. Compared with PLA-USPIO injection, Vx-2 tumor rabbits receiving RGD-PLA-USPIO revealed a marked decrease in T2*WI and T2WI, although not exclusively, asymmetrically located along the tumor periphery. The signal decease was typically seen in a patchy distribution adjacent to blood vessels and along the lateral tumor border as small spots. The T2 and T2* relaxation times of tumor accordingly decreased with the signal change in images and T2* relaxation time was more sensitive due to a susceptibility effect. Prussian blue stain of the Vx-2 tumor visualized blue granule in tumor endothelium and corroborated angiogenesis observed with MR images. Generally, RGD-PLA-USPIO hold promise to be uitilized as novel MR probe for in vivo detection of tumor angiogenesis.
IV The biological effects of citrate and dextran coated IONP on HUVECs were investigated in terms of cell proliferation, cytoskeleton, migration/invasion and differentiation. Cell proliferation, migration and invasion were inhibited in a dose dependent manner and citrate-IONP had more toxic effects than dextran-IONP. The capacity of HUVECs to form vascular network on Matrigel diminished after exposure to IONPs. Cytoskeletal structures were greatly disrupted, as evidenced by diminished vinculin spots, and disorganized actin fiber and tubulin networks. Cell attachment is necessary to mediate the survival of anchorage-dependent cells and critical for efficient cell growth, migration, invasion and differentiation. The detachment after exposure to IONPs induced the dysfunction of HUVECs and the iron catalyzed free radical damage might attribute to it.
In general, we have reported the development of RGD-PLA-USPIO as anαvβ3 integrin targeted MR probe and the results demonstrate RGD-PLA-USPIO can efficiently visiualize the expression ofαvβ3 integrin on tumor vascularature. Additionally, HUVECs proliferation, migration/invasion and differentiation is greatly inhibited after incubation with citrate and dextran-coated iron oxide nanoparticles.
引文
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