放射性核素光学成像及黑色素瘤的分子影像学研究
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摘要
分子影像学是一门新兴的交叉学科,涉及到影像学、分子材料学(包括纳米材料)、分子生物学(包括信号传导通路、受体、抗体、配体等)、基因研究等。目前已有多种影像学技术应用于分子影像学研究,如放射性核素成像(nuclear imaging),光学成像(optical imaging,OI),超声成像(ultrosonic imaging)和核磁共振成像(Magnetic resonance imaging, MRI)等。放射性核素成像手段主要包括正电子发射计算机断层成像(position emission tomography, PET)和单光子发射计算机断层成像(single photon emission computed tomography, SPECT)。放射性核素成像首先将放射性药物引入患者体内,在体外检测放射性药物发射出的高能量高穿透性的伽玛射线,从而研究药物在体内的分布。通过与高分辨率的计算机断层扫描技术(X-ray computed tomography)相结合,PET或SPECT可以在显示深部组织的分子影像学特征的同时,高分辨率地显示组织的解剖结构,目前已广泛地应用于临床。光学成像主要包括生物发光成像(bioluminescent imaging)、荧光成像(fluorescence imaging)等,应用于分子及细胞生物学研究和活体(in vivo)表面成像。由于目前通过美国食品药品管理局(Food and Drug Admistraton, FDA)认证的光学探针只有吲哚菁绿(indocyanine green, ICG),光学成像在临床应用较少。多数活体光学成像只初步用于小动物的实验成像。光学成像相比放射性核素成像价格较低廉,且允许具有不同光谱特征的探针进行多通道成像。
本文在国际上率先综合了核医学示踪剂和光学成像系统。使用光学系统的高敏感CCD相机检测放射性探针以韧致辐射(Bremsstrahlung radiation)或契伦科夫辐射(Cerenkov radiation)产生的低能量光子,证明了核医学探针应用于光学成像的可行性,拓展了光学成像在临床的应用前景,并为直接监测钇-90 (yttrium-90,90Y)等目前难以监测的放射性治疗用核素提供了有效手段。
一般而言,多聚肽比单体拥有更好的受体亲和力和活性。本研究以多聚黑色素细胞刺激激素(a-Melanocyte-Stimulating Hormone,简称a-MSH)类似肽和黑色素瘤为模型,利用正电子发射计算机断层扫描技术(Positron emission tomography,简称PET),对多聚肽的受体亲和力和体内肿瘤靶向能力进行了系统的比较研究。
用多肽固相合成法合成了MSH类似肽单体(MSH1),二聚体(MSH2)和四聚体(MSH4),并分别与金属螯合剂DOTA联接(DOTA-MSH1, DOTA-MSH2, DOTA-MSH4)。通过B16/F10鼠黑色素瘤细胞测定三种多肽及联接DOTA后的半数抑制浓度(IC50),评价其受体亲和力。标记64Cu后,进行PET扫描成像,观察其体内分布和肿瘤显像效果。并在不同时间点处死小鼠,取血、肿瘤及各主要器官,测量其每克组织注射百分剂量率(%ID/g)。多肽的各步反应均使用反相高效液相色谱法(RP-HPLC)进行纯化并利用电喷雾质谱(ESI-MS)进行鉴定。DOTA-MSH4在体外实验中具有最高的受体亲和力[IC50=1.00nM(95%可信区间0.83-1.21nM)],但在体内实验中肿瘤摄取量最低(1小时=0.6l±0.02%ID/g；2小时=1.82±0.85%ID/g；4小时=2.98±0.24%ID/g),且在肾脏大量蓄积(1小时=12.91±1.86%ID/g；2小时=20.89±3.98%ID/g；4小时=24.98±2.17%ID/g)。相比之下,DOTA-MSH2有着中等的受体亲和力[IC50=2.06nM(95%可信区间1.48-2.88nM)],却有更高的肿瘤摄取量(1小时=5.65±1.13%ID/g；2小时=5.23±0.5%ID/g 0；4小时=5.39±0.84%ID/g),且在肾脏中的蓄积少于DOTA-MSH4(1小时=18.23±2.50%ID/g；2小时=16.84±3.57%ID/g；4小时=16.44±1.66%ID/g). DOTA-MSH1受体亲和力最低[IC50=3.10nM(95%可信区间2.34-4.10nM)],有着中等的肿瘤摄取量(1小时=2.81+1.49%ID/g；2小时=3.74±1.57%ID/g；4小时=4.20±0.69%ID/g)和较低的肾脏蓄积(1小时=11.79±4.54%ID/g；2小时=11.24±3.95%ID/g；4小时=9.90±1.25%ID/g)。最后,对DOTA-MSH2进行的体内竞争抑制实验显示其具有良好的肿瘤特异性。高受体亲和力的DOTA-MSH4却有着较差的显像效果。在本实验测试的三种多肽探针中,DOTA-MSH2被证明是最佳的黑色素瘤PET显像剂。
Molecular imaging is a relatively new yet fast growing research discipline. Practical molecular imaging enables researchers to study diseases non-invasively in living subjects at the molecular level. Numerous studies have demonstrated that molecular imaging techniques play a central role in the era of personalized medicine. A variety of imaging modalities have been developed that provide functional and anatomical information of diseases in living small animals and patients. Such modalities include positron emission tomography (PET), single photon emission computed tomography (SPECT), optical imaging (OI, bioluminescence and fluorescence), magnetic resonance imaging (MRI), ultrasound (US), and computed tomography (CT).
OI has rapidly gained popularity in molecular imaging. It is an inexpensive imaging technique due to the low costs of detection devices. The technique is easy to learn and use and interpretation of the images is generally straightforward. Imaging in the near-infrared (NIR) region has advantages of improved tissue penetration and low tissue autofluorescence which enhances target to background ratios. While OI generally detects low energy light (visible or near-infrared light) emitted from bioluminescence or fluorescence probes, radioactive molecular probes are traditionally imaged with PET, SPECT or gamma (y) cameras that detect high energy y rays. We hypothesized that radionuclide radiation in the low energy window of light (1.2-3.1 eV, 400-1000 nm) could be imaged using OI techniques and be especially valuable for molecular OI. Thus we examined a variety of radionuclides with different types of emission properties (β+,β- orγ) using a commercially available OI instrument for in vitro and in vivo optical imaging.
In this research, we have evaluated three radionuclides (18F,131I, and 90Y) for small animal radioactive OI because of their important roles in nuclear medicine.18F is the most often used PET radionuclide, and 131I and 90Y are two most widely used radionuclides for radiotherapy. In vivo optical images with reasonable sensitivity can be quickly obtained for all three radionuclides. These encouraging results suggest that the radioactive OI can be a powerful tool for fast preliminary evaluation of 18F,131I, and 90Y labeled compounds. This will be important for 90Y based agents development, since it has been relatively difficult to obtain in vivo information for an 90Y agent through non-invasive imaging method.
Compared to conventional fluorescence and bioluminescence imaging, radioactive OI has some unique properties. It has wide emission spectrum as demonstrated here, so that a radioactive probe can be monitored at different wavelengths. More importantly, radioactive OI does not require excitation light, which is a significant advantage over traditional OI. The radioactive OI signal generated by a radioactive probe is constitutive, which is very different from fluorescence and bioluminescence probes. The radioactive OI can be performed by monitoring spectral windows that differ from typical FLuc spectrum. Therefore, it is possible to perform BLI and radioactive OI in the same animal with proper emission filters.
The results presented here bridge the subfields of imaging by visualizing radioactive probes with OI. Our study demonstrates the feasibility of molecular imaging of living subjects using OI modalities in conjunction with a wide diversity of radioactive probes. It provides a new molecular imaging strategy and will likely have significant impact on both small animal and clinical imaging.
Multivalent peptides have been explored as a useful strategy to construct molecular imaging probes and drug delivery carriers. It is generally accepted that multivalency has advantages over monovalency for improving binding affinity, activity and even in vivo performance of biomolecule. The alpha-melanocyte-stimulating hormone (a-MSH) receptor (melanocortin type 1 receptor, or MC1R) has been found to be over-expressed in most murine and human melanoma. a-MSH analogs tagged with radionuclides have been demonstrated to be a class of promising agents for melanoma imaging and/or peptide receptor-targeted radionuclide therapy.Herein by using multivalent a-melanocyte stimulating hormone (a-MSH) analogs, B16F10 melanoma-bearing mice and microPET imaging technology, we systematically investigated the influence of multivalent effect on a-MSH analogs'binding affinity and in vivo melanoma targeting profiles.
Three a-MSH analogs named as MSH1, MSH2 and MSH4 were designed and synthesized, which contained one, two or four valency of an a-MSH core sequence, His-d, Phe-Arg-Trp, respectively (Fig. a). a-MSH analog tetramer was constructed using the multiple antigenic peptide (MAP) scaffold.1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was conjugated to the lysine residue of peptides for radiolabeling with a PET radioisotope,64Cu. In vitro binding affinity assays were performed with B16F10 melanoma cell line. After radiolabeling with 64Cu, the in vivo performances of the peptides were evaluated in subcutaneous B16F10 melanoma xenografted mice by micro-PET imaging followed by biodistribution studies.
In the receptor competition binding assays, DOTA-MSH4 showed highest binding affinity (IC50= 1.00 nM) which is consistent with its highest ligand density. However, in vivo study demonstrated poor performance of MSH4 as an imaging agent due to its lowest tumor uptake and highest kidney accumulation, In comparison, DOTA-MSH2 displayed medium affinity (IC50=2.06 nM), yet highest tumor uptake and lowest kidney accumulation (Fig. b). Further blocking study of DOTA-MSH2 confirmed its tumor targeting specificity in vivo.
Multivalency effects have complex impact to peptides' in vivo behaviors. Eventhough MSH tetramer shows the higher binding affinities in vitro, the better in vivo tumor targeting ability is achieved by MSH dimer. Cu-64 labeled dimeric DOTA-MSH2 has been identified as an ideal melanoma PET imaging probe.
本文在国际上率先综合了核医学示踪剂和光学成像系统。使用光学系统的高敏感CCD相机检测放射性探针以韧致辐射(Bremsstrahlung radiation)或契伦科夫辐射(Cerenkov radiation)产生的低能量光子,证明了核医学探针应用于光学成像的可行性,拓展了光学成像在临床的应用前景,并为直接监测钇-90 (yttrium-90,90Y)等目前难以监测的放射性治疗用核素提供了有效手段。
一般而言,多聚肽比单体拥有更好的受体亲和力和活性。本研究以多聚黑色素细胞刺激激素(a-Melanocyte-Stimulating Hormone,简称a-MSH)类似肽和黑色素瘤为模型,利用正电子发射计算机断层扫描技术(Positron emission tomography,简称PET),对多聚肽的受体亲和力和体内肿瘤靶向能力进行了系统的比较研究。
用多肽固相合成法合成了MSH类似肽单体(MSH1),二聚体(MSH2)和四聚体(MSH4),并分别与金属螯合剂DOTA联接(DOTA-MSH1, DOTA-MSH2, DOTA-MSH4)。通过B16/F10鼠黑色素瘤细胞测定三种多肽及联接DOTA后的半数抑制浓度(IC50),评价其受体亲和力。标记64Cu后,进行PET扫描成像,观察其体内分布和肿瘤显像效果。并在不同时间点处死小鼠,取血、肿瘤及各主要器官,测量其每克组织注射百分剂量率(%ID/g)。多肽的各步反应均使用反相高效液相色谱法(RP-HPLC)进行纯化并利用电喷雾质谱(ESI-MS)进行鉴定。DOTA-MSH4在体外实验中具有最高的受体亲和力[IC50=1.00nM(95%可信区间0.83-1.21nM)],但在体内实验中肿瘤摄取量最低(1小时=0.6l±0.02%ID/g；2小时=1.82±0.85%ID/g；4小时=2.98±0.24%ID/g),且在肾脏大量蓄积(1小时=12.91±1.86%ID/g；2小时=20.89±3.98%ID/g；4小时=24.98±2.17%ID/g)。相比之下,DOTA-MSH2有着中等的受体亲和力[IC50=2.06nM(95%可信区间1.48-2.88nM)],却有更高的肿瘤摄取量(1小时=5.65±1.13%ID/g；2小时=5.23±0.5%ID/g 0；4小时=5.39±0.84%ID/g),且在肾脏中的蓄积少于DOTA-MSH4(1小时=18.23±2.50%ID/g；2小时=16.84±3.57%ID/g；4小时=16.44±1.66%ID/g). DOTA-MSH1受体亲和力最低[IC50=3.10nM(95%可信区间2.34-4.10nM)],有着中等的肿瘤摄取量(1小时=2.81+1.49%ID/g；2小时=3.74±1.57%ID/g；4小时=4.20±0.69%ID/g)和较低的肾脏蓄积(1小时=11.79±4.54%ID/g；2小时=11.24±3.95%ID/g；4小时=9.90±1.25%ID/g)。最后,对DOTA-MSH2进行的体内竞争抑制实验显示其具有良好的肿瘤特异性。高受体亲和力的DOTA-MSH4却有着较差的显像效果。在本实验测试的三种多肽探针中,DOTA-MSH2被证明是最佳的黑色素瘤PET显像剂。
Molecular imaging is a relatively new yet fast growing research discipline. Practical molecular imaging enables researchers to study diseases non-invasively in living subjects at the molecular level. Numerous studies have demonstrated that molecular imaging techniques play a central role in the era of personalized medicine. A variety of imaging modalities have been developed that provide functional and anatomical information of diseases in living small animals and patients. Such modalities include positron emission tomography (PET), single photon emission computed tomography (SPECT), optical imaging (OI, bioluminescence and fluorescence), magnetic resonance imaging (MRI), ultrasound (US), and computed tomography (CT).
OI has rapidly gained popularity in molecular imaging. It is an inexpensive imaging technique due to the low costs of detection devices. The technique is easy to learn and use and interpretation of the images is generally straightforward. Imaging in the near-infrared (NIR) region has advantages of improved tissue penetration and low tissue autofluorescence which enhances target to background ratios. While OI generally detects low energy light (visible or near-infrared light) emitted from bioluminescence or fluorescence probes, radioactive molecular probes are traditionally imaged with PET, SPECT or gamma (y) cameras that detect high energy y rays. We hypothesized that radionuclide radiation in the low energy window of light (1.2-3.1 eV, 400-1000 nm) could be imaged using OI techniques and be especially valuable for molecular OI. Thus we examined a variety of radionuclides with different types of emission properties (β+,β- orγ) using a commercially available OI instrument for in vitro and in vivo optical imaging.
In this research, we have evaluated three radionuclides (18F,131I, and 90Y) for small animal radioactive OI because of their important roles in nuclear medicine.18F is the most often used PET radionuclide, and 131I and 90Y are two most widely used radionuclides for radiotherapy. In vivo optical images with reasonable sensitivity can be quickly obtained for all three radionuclides. These encouraging results suggest that the radioactive OI can be a powerful tool for fast preliminary evaluation of 18F,131I, and 90Y labeled compounds. This will be important for 90Y based agents development, since it has been relatively difficult to obtain in vivo information for an 90Y agent through non-invasive imaging method.
Compared to conventional fluorescence and bioluminescence imaging, radioactive OI has some unique properties. It has wide emission spectrum as demonstrated here, so that a radioactive probe can be monitored at different wavelengths. More importantly, radioactive OI does not require excitation light, which is a significant advantage over traditional OI. The radioactive OI signal generated by a radioactive probe is constitutive, which is very different from fluorescence and bioluminescence probes. The radioactive OI can be performed by monitoring spectral windows that differ from typical FLuc spectrum. Therefore, it is possible to perform BLI and radioactive OI in the same animal with proper emission filters.
The results presented here bridge the subfields of imaging by visualizing radioactive probes with OI. Our study demonstrates the feasibility of molecular imaging of living subjects using OI modalities in conjunction with a wide diversity of radioactive probes. It provides a new molecular imaging strategy and will likely have significant impact on both small animal and clinical imaging.
Multivalent peptides have been explored as a useful strategy to construct molecular imaging probes and drug delivery carriers. It is generally accepted that multivalency has advantages over monovalency for improving binding affinity, activity and even in vivo performance of biomolecule. The alpha-melanocyte-stimulating hormone (a-MSH) receptor (melanocortin type 1 receptor, or MC1R) has been found to be over-expressed in most murine and human melanoma. a-MSH analogs tagged with radionuclides have been demonstrated to be a class of promising agents for melanoma imaging and/or peptide receptor-targeted radionuclide therapy.Herein by using multivalent a-melanocyte stimulating hormone (a-MSH) analogs, B16F10 melanoma-bearing mice and microPET imaging technology, we systematically investigated the influence of multivalent effect on a-MSH analogs'binding affinity and in vivo melanoma targeting profiles.
Three a-MSH analogs named as MSH1, MSH2 and MSH4 were designed and synthesized, which contained one, two or four valency of an a-MSH core sequence, His-d, Phe-Arg-Trp, respectively (Fig. a). a-MSH analog tetramer was constructed using the multiple antigenic peptide (MAP) scaffold.1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was conjugated to the lysine residue of peptides for radiolabeling with a PET radioisotope,64Cu. In vitro binding affinity assays were performed with B16F10 melanoma cell line. After radiolabeling with 64Cu, the in vivo performances of the peptides were evaluated in subcutaneous B16F10 melanoma xenografted mice by micro-PET imaging followed by biodistribution studies.
In the receptor competition binding assays, DOTA-MSH4 showed highest binding affinity (IC50= 1.00 nM) which is consistent with its highest ligand density. However, in vivo study demonstrated poor performance of MSH4 as an imaging agent due to its lowest tumor uptake and highest kidney accumulation, In comparison, DOTA-MSH2 displayed medium affinity (IC50=2.06 nM), yet highest tumor uptake and lowest kidney accumulation (Fig. b). Further blocking study of DOTA-MSH2 confirmed its tumor targeting specificity in vivo.
Multivalency effects have complex impact to peptides' in vivo behaviors. Eventhough MSH tetramer shows the higher binding affinities in vitro, the better in vivo tumor targeting ability is achieved by MSH dimer. Cu-64 labeled dimeric DOTA-MSH2 has been identified as an ideal melanoma PET imaging probe.
引文
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[1]Massoud TF, Gambhir SS. Molecular imaging in living subjects:seeing fundamental biological processes in a new light. Genes Dev.2003; 17:545-80.
[2]Alford R, Ogawa M, Choyke PL, Kobayashi H. Molecular probes for the in vivo imaging of cancer. MolBiosyst.2009; 5:1279-91.
[3]Woods RP, Cherry SR, Mazziotta JC. Rapid automated algorithm for aligning and reslicing PET images. J Comput Assist Tomogr.1992; 16:620-33.
[4]Phelps ME. Inaugural article:positron emission tomography provides molecular imaging of biological processes. Proc Natl Acad Sci U S A.2000; 97:9226-33.
[5]Amano S, Inoue T, Tomiyoshi K, Ando T, Endo K. In vivo comparison of PET and SPECT radiopharmaceuticals in detecting breast cancer. J Nucl Med.1998; 39: 1424-7.
[6]Weissleder R. Scaling down imaging:molecular mapping of cancer in mice. Nat Rev Cancer.2002; 2:11-8.
[7]Madsen MT. Recent advances in SPECT imaging. J Nucl Med.2007; 48:661-73.
[8]Weissleder R, Mahmood U. Molecular imaging. Radiology.2001; 219:316-33.
[9]Weissleder R, Ntziachristos V. Shedding light onto live molecular targets. Nat Med.2003; 9:123-8.
[10]Gibson AP, Hebden JC, Arridge SR. Recent advances in diffuse optical imaging. Phys Med Biol.2005; 50:R1-43.
[11]Liu H, Ren G, Miao Z, Zhang X, Tang X, Han P, et al. Molecular Optical Imaging with Radioactive Probes. PLoS ONE.2010; 5:e9470.
[12]Gobin AM, Lee MH, Halas NJ, James WD, Drezek RA, West JL. Near-infrared resonant nanoshells for combined optical imaging and photothermal cancer therapy. Nano Lett.2007; 7:1929-34.
[13]Rao J, Dragulescu-Andrasi A, Yao H. Fluorescence imaging in vivo:recent advances. Curr Opin Biotechnol.2007; 18:17-25.
[14]So MK, Xu C, Loening AM, Gambhir SS, Rao J. Self-illuminating quantum dot conjugates for in vivo imaging. Nat Biotechnol.2006; 24:339-43.
[15]Liu H, Zhang X, Xing B, Han P, Gambhir SS, Cheng Z. Radiation Luminescence Excited Quantum Dots for In Vivo Multiplexed Optical Imaging. Small. 2010, May; in press.
[16]Szentirmai O, Baker CH, Lin N, Szucs S, Takahashi M, Kiryu S, et al. Noninvasive bioluminescence imaging of luciferase expressing intracranial U87 xenografts:correlation with magnetic resonance imaging determined tumor volume and longitudinal use in assessing tumor growth and antiangiogenic treatment effect. Neurosurgery.2006; 58:365-72; discussion 65-72.
[17]Nakel W. The elementary process of Bremsstrahlung. Physics Reports-Review Section of Physics Letters.1994; 243:317-53.
[18]Cerenkov PA. Visible radiation produced by electrons moving in a medium with velocities exceeding that of light. Physical Review.1937; 52:0378-79.
[19]Ross HH. Measurement of Beta-Emitting Nuclides Using Cerenkov Radiation. Analytical Chemistry.1969; 41:1260-65.
[20]Seltzer SM, Berger MJ. Bremsstrahlung Spectra from Electron Interactions with Screened Atomic-Nuclei and Orbital Electrons. Nuclear Instruments & Methods in Physics Research Section B-Beam Interactions with Materials and Atoms.1985; 12: 95-134.
[21]Robertson R, Germanos MS, Li C, Mitchell GS, Cherry SR, Silva MD. Optical imaging of Cerenkov light generation from positron-emitting radiotracers. Phys Med Biol.2009; 54:N355-65.
[22]Oriuchi N, Higuchi T, Hanaoka H, Iida Y, Endo K. Current status of cancer therapy with radiolabeled monoclonal antibody. Ann Nucl Med.2005; 19:355-65.
[23]Klibanov AL. Ultrasound molecular imaging with targeted microbubble contrast agents. JNucl Cardiol.2007; 14:876-84.
[24]Hernot S, Klibanov AL. Microbubbles in ultrasound-triggered drug and gene delivery. Adv Drug Deliv Rev.2008; 60:1153-66.
[25]Czernin J, Allen-Auerbach M, Schelbert HR. Improvements in cancer staging with PET/CT:literature-based evidence as of September 2006. J Nucl Med.2007; 48 Suppl1:78S-88S.
[26]Louie A. Multimodality Imaging Probes:Design and Challenges. Chem Rev. 2010.
[27]Cherry SR. Multimodality imaging:beyond PET/CT and SPECT/CT. Semin Nucl Med.2009; 39:348-53.
[28]Schambach SJ, Bag S, Schilling L, Groden C, Brockmann MA. Application of micro-CT in small animal imaging. Methods.2010; 50:2-13.
[29]Benveniste H, Blackband S. MR microscopy and high resolution small animal MRI:applications in neuroscience research. Prog Neurobiol.2002; 67:393-420.
[30]Liang H, Yang Y, Yang K, Wu Y, Boone JM, Cherry SR. A microPET/CT system for in vivo small animal imaging. Phys Med Biol.2007; 52:3881-94.
[31]Strand SE, Ivanovic M, Erlandsson K, Franceschi D, Button T, Sjogren K, et al. Small animal imaging with pinhole single-photon emission computed tomography. Cancer.1994; 73:981-4.
[32]Meikle SR, Kench P, Kassiou M, Banati RB. Small animal SPECT and its place in the matrix of molecular imaging technologies. Phys Med Biol.2005; 50:R45-61.