～（99m）Tc标记Bombesin & ～（177）Lu标记RGD多肽放射性药物的研究
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摘要
本论文研究了蛙皮素BN和RGD多肽的放射性标记物在肿瘤受体显像中的应用，考察了不同协同配体和双功能螯合剂对放射性标记物的化学性质、药代动力学和生物特性的影响。
首先，已经报道的放射性核素标记的蛙皮素BN多用于前列腺癌的诊断和治疗，而Cassano等的研究表明HT29结肠癌肿瘤细胞也过度表达GRP受体，为了开发此靶点的受体显像剂，我们尝试以~(99m)Tc标记连有双功能螯合剂HYNIC的蛙皮素类似物BN(7-14)NH_2片段(HYNIC-β-Ala-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH_2)用于结肠癌的诊断显像。在其~(99m)Tc标记方法中，分别以TPPTS(三苯基膦三间磺酸钠盐)、IsoNIC(异烟酸)和PDA(2，5-二羧酸吡啶)作为协同配体得到三种三重配体标记物[~(99m)Tc(HYNIC-BN)(Tricine)(TPPTS)]、[~(99m)Tc(HYNIC-BN)(Tricine)(IsoNIC)]和[~(99m)Tc(HYNIC-BN)(Tricine)(PDA)]。研究发现，三种标记物都能获得高标记率，且都有良好的体外稳定性；通过荷HT29结肠癌裸鼠体内分布和代谢实验发现，亲水性最好的标记物[~(99m)Tc(HYNIC-BN)(Tricine)(TPPTS)]具有最佳的体内代谢分布特征，表现在其胃肠道放射性浓聚少，肾清除快，能显著地降低腹腔正常组织的放射性本底。选其用于荷瘤鼠的γ显像，我们得到了肿瘤定位显影非常清晰的γ显像图。以上实验数据表明，不同的协同配体能对HYNIC-BN的~(99m)Tc标记物的生物性质产生了显著性的影响。而γ显像结果则证明，~(99m)Tc标记的BN多肽示踪剂可应用于结肠癌显像，其中[~(99m)Tc(HYNIC-BN)(Tricine)(TPPTS)]将是一种候选的有潜力的结肠癌受体显像剂。
其次，我们用~(177)Lu标记三种不同双功能螯合剂偶联的RGD多肽E[c(RGDfK)]_2，并对其体内外性质进行评价。三种标记物~(177)Lu-DTPA-Bz-E[c(RGDFK)]_2、~(177)Lu-DOTA-E[c(RGDFK)]_2和~(177)Lu-DOTA-Bz-E[c(RGDFK)]_2均可获得满意的标记率和放化纯，且在生理盐水和胎牛血清(FBS)体系中均有良好的稳定性。三种标记物的脂水分配系数LogP_(o/w)没有显著性差异，这与它们的HPLC保留时间相一致。三种化合物DTPA-Bz-E[c(RGDFK)]_2、DOTA-E[c(RGDFK)]_2和DOTA-Bz-E[c(RGDFK)]_2与U87MG细胞表达的整合素α_vβ_3结合的IC_(50)值分别为3.23±0.78 nM、2.35±0.75nM和5.88±0.35nM，表明它们与整合素α_vβ_3结合能力没有显著性差异。三种标记物因为双功能螯合剂不同而有不同的~(177)Lu螯合结构、带有不同的分子电荷和不同的供电原子，但它们在荷U87MG神经胶质瘤裸鼠体内的生物分布和体内代谢特征很类似。选取~(177)Lu-DOTA-Bz-E[c(RGDFK)]_2进行荷瘤裸鼠的γ显像，得到了令人满意的显像效果。实验证明环状E[c(RGDfK)]_2二聚体结构是其~(177)Lu标记物生物性质的决定性因素，而本实验中的三种双功能螯合剂没有引起标记物生物活性的显著性差异，本研究为进一步研制靶向整合素α_vβ_3的肿瘤治疗剂奠定了基础。
In this study, the bombesin (BN) and RGD (Arg-Gly-Asp) peptides were labeled with ~(99m)Tc and ~(177)Lu, respectively, for tumor molecular imaging. We evaluated the impact of coligands and bifunctional chelators (BFCs) on the chemical and biological properties as well as pharmacokinetics of these radiotracers.
We attempted ~(99m)Tc-labeled bombesin analogue BN(7-14)NH_2 (HYNIC-β-Ala-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH_2) for imaging of colon cancer. A ternary ligands system was used in the ~(99m)Tc labeling of HYNIC-BN(7-14)NH_2, using tricine (Tris(hydroxymethyl)methylglycine) and water-soluble TPPTS (trisodium triphenyl-phosphine-3,3',3"-trisulfonate), IsoNIC (isonicotinic acid), and PDA (2,5-pyridine-dicarboxylicacid) as coligands. These radiotracers ~(99m)Tc(HYNIC-BN(7-14)NH_2)(tricine) (L)](L=TPPTS/IsoNIC/PDA) showed excellent labeling yield and in vitro stability. It was found that three coligands had significant impact on the properties of raiotracers. Among the three radiotracers, [~(99m)Tc(HYNIC-BN(7-14)NH_2)(tricine)(TPPTS)] had the best hydrophilicity, so that it was excreted fast from kidneys, minimizing radioactivity accumulation in intestine and stomach. The clear images of [~(99m)Tc(HYNIC-BN(7-14)NH_2) (tricine)(TPPTS)] in nude mice bearing HT29 human colon cancer xenografts were obtained at 1 h and 4 h postinjection. [~(99m)Tc(HYNIC-BN(7-14)NH_2)(tricine)(TPPTS)] is a promising candidate for diagnosis of colon cancer.
We chose different BFCs to prepared ~(177)Lu-labeled RGD dimmer, DTPA-Bz-E[c(RGDfK)]_2 (a), DOTA-E[c(RGDfK)]_2 (b), DOTA-Bz-E[c(RGDfK)]_2 (c), and evaluated their in vitro and in vivo characteristics. The radiolabeling yield of three preparations was more than 95%, with radiochemical purity (RCP) was more than 99% after purification. Receptor binding experiments were performed on U87MG human glioma cells for three compounds, with the IC_(50) values were 3.23±0.78 nM (a), 2.35±0.75 nM (b) and 5.88±0.35 nM (c), respectively. There was no significant difference on integrin a_vβ_3 binding. The stability of three radiotrcers in saline and FBS solution was excellent with RCP > 95% during 24 h after labeling. There was no significant difference in Log P_(o/w) values of three radiotracers within the experimental error, which is consistent with their similarity in HPLC retention time. In general, all three radiotracers have very similar biodistribution patterns despite their difference in the ~(177)Lu chelates with respect to the molecular charge, chelator framework and donor atoms. The selective images of U87MG xenografted tumors were obtained at 4 h postinjection for ~(177)Lu-DOTA-Bz-E[C(RGDFK)]_2. The current study validates the feasibility of ~(177)Lu-labeled RGD dimmer for the therapy of integrin a_vβ_3-positive tumors.
首先，已经报道的放射性核素标记的蛙皮素BN多用于前列腺癌的诊断和治疗，而Cassano等的研究表明HT29结肠癌肿瘤细胞也过度表达GRP受体，为了开发此靶点的受体显像剂，我们尝试以~(99m)Tc标记连有双功能螯合剂HYNIC的蛙皮素类似物BN(7-14)NH_2片段(HYNIC-β-Ala-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH_2)用于结肠癌的诊断显像。在其~(99m)Tc标记方法中，分别以TPPTS(三苯基膦三间磺酸钠盐)、IsoNIC(异烟酸)和PDA(2，5-二羧酸吡啶)作为协同配体得到三种三重配体标记物[~(99m)Tc(HYNIC-BN)(Tricine)(TPPTS)]、[~(99m)Tc(HYNIC-BN)(Tricine)(IsoNIC)]和[~(99m)Tc(HYNIC-BN)(Tricine)(PDA)]。研究发现，三种标记物都能获得高标记率，且都有良好的体外稳定性；通过荷HT29结肠癌裸鼠体内分布和代谢实验发现，亲水性最好的标记物[~(99m)Tc(HYNIC-BN)(Tricine)(TPPTS)]具有最佳的体内代谢分布特征，表现在其胃肠道放射性浓聚少，肾清除快，能显著地降低腹腔正常组织的放射性本底。选其用于荷瘤鼠的γ显像，我们得到了肿瘤定位显影非常清晰的γ显像图。以上实验数据表明，不同的协同配体能对HYNIC-BN的~(99m)Tc标记物的生物性质产生了显著性的影响。而γ显像结果则证明，~(99m)Tc标记的BN多肽示踪剂可应用于结肠癌显像，其中[~(99m)Tc(HYNIC-BN)(Tricine)(TPPTS)]将是一种候选的有潜力的结肠癌受体显像剂。
其次，我们用~(177)Lu标记三种不同双功能螯合剂偶联的RGD多肽E[c(RGDfK)]_2，并对其体内外性质进行评价。三种标记物~(177)Lu-DTPA-Bz-E[c(RGDFK)]_2、~(177)Lu-DOTA-E[c(RGDFK)]_2和~(177)Lu-DOTA-Bz-E[c(RGDFK)]_2均可获得满意的标记率和放化纯，且在生理盐水和胎牛血清(FBS)体系中均有良好的稳定性。三种标记物的脂水分配系数LogP_(o/w)没有显著性差异，这与它们的HPLC保留时间相一致。三种化合物DTPA-Bz-E[c(RGDFK)]_2、DOTA-E[c(RGDFK)]_2和DOTA-Bz-E[c(RGDFK)]_2与U87MG细胞表达的整合素α_vβ_3结合的IC_(50)值分别为3.23±0.78 nM、2.35±0.75nM和5.88±0.35nM，表明它们与整合素α_vβ_3结合能力没有显著性差异。三种标记物因为双功能螯合剂不同而有不同的~(177)Lu螯合结构、带有不同的分子电荷和不同的供电原子，但它们在荷U87MG神经胶质瘤裸鼠体内的生物分布和体内代谢特征很类似。选取~(177)Lu-DOTA-Bz-E[c(RGDFK)]_2进行荷瘤裸鼠的γ显像，得到了令人满意的显像效果。实验证明环状E[c(RGDfK)]_2二聚体结构是其~(177)Lu标记物生物性质的决定性因素，而本实验中的三种双功能螯合剂没有引起标记物生物活性的显著性差异，本研究为进一步研制靶向整合素α_vβ_3的肿瘤治疗剂奠定了基础。
In this study, the bombesin (BN) and RGD (Arg-Gly-Asp) peptides were labeled with ~(99m)Tc and ~(177)Lu, respectively, for tumor molecular imaging. We evaluated the impact of coligands and bifunctional chelators (BFCs) on the chemical and biological properties as well as pharmacokinetics of these radiotracers.
We attempted ~(99m)Tc-labeled bombesin analogue BN(7-14)NH_2 (HYNIC-β-Ala-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH_2) for imaging of colon cancer. A ternary ligands system was used in the ~(99m)Tc labeling of HYNIC-BN(7-14)NH_2, using tricine (Tris(hydroxymethyl)methylglycine) and water-soluble TPPTS (trisodium triphenyl-phosphine-3,3',3"-trisulfonate), IsoNIC (isonicotinic acid), and PDA (2,5-pyridine-dicarboxylicacid) as coligands. These radiotracers ~(99m)Tc(HYNIC-BN(7-14)NH_2)(tricine) (L)](L=TPPTS/IsoNIC/PDA) showed excellent labeling yield and in vitro stability. It was found that three coligands had significant impact on the properties of raiotracers. Among the three radiotracers, [~(99m)Tc(HYNIC-BN(7-14)NH_2)(tricine)(TPPTS)] had the best hydrophilicity, so that it was excreted fast from kidneys, minimizing radioactivity accumulation in intestine and stomach. The clear images of [~(99m)Tc(HYNIC-BN(7-14)NH_2) (tricine)(TPPTS)] in nude mice bearing HT29 human colon cancer xenografts were obtained at 1 h and 4 h postinjection. [~(99m)Tc(HYNIC-BN(7-14)NH_2)(tricine)(TPPTS)] is a promising candidate for diagnosis of colon cancer.
We chose different BFCs to prepared ~(177)Lu-labeled RGD dimmer, DTPA-Bz-E[c(RGDfK)]_2 (a), DOTA-E[c(RGDfK)]_2 (b), DOTA-Bz-E[c(RGDfK)]_2 (c), and evaluated their in vitro and in vivo characteristics. The radiolabeling yield of three preparations was more than 95%, with radiochemical purity (RCP) was more than 99% after purification. Receptor binding experiments were performed on U87MG human glioma cells for three compounds, with the IC_(50) values were 3.23±0.78 nM (a), 2.35±0.75 nM (b) and 5.88±0.35 nM (c), respectively. There was no significant difference on integrin a_vβ_3 binding. The stability of three radiotrcers in saline and FBS solution was excellent with RCP > 95% during 24 h after labeling. There was no significant difference in Log P_(o/w) values of three radiotracers within the experimental error, which is consistent with their similarity in HPLC retention time. In general, all three radiotracers have very similar biodistribution patterns despite their difference in the ~(177)Lu chelates with respect to the molecular charge, chelator framework and donor atoms. The selective images of U87MG xenografted tumors were obtained at 4 h postinjection for ~(177)Lu-DOTA-Bz-E[C(RGDFK)]_2. The current study validates the feasibility of ~(177)Lu-labeled RGD dimmer for the therapy of integrin a_vβ_3-positive tumors.
引文
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[83]177Lu-DOTA-Bz-RGD dimer和177Lu-DOTA-Bz-PEG4-RGD dimer的制备及生物评价．史继云，余子磷，贾兵，赵慧云，王凡．同位素，已接收．
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