PEGylation, increasing specific activity and multiple dosing as strategies to improve the risk-benefit profile of targeted radionuclide therapy with 177Lu-DOTA-bombesin analogues
PEGylation, increasing specific activity and multiple dosing as strategies to improve the risk-benefit profile of targeted radionuclide therapy with 177Lu-DOTA-bombesin analogues
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DOI：
10.1186/2191-219x-2-24
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发表时间：
2012-01-01
期刊：
影响因子：
3.2
通讯作者：
Schibli, Roger
中科院分区：
文献类型：
--
作者：
Daepp, Simone;Mueller, Cristina;Schibli, Roger
背景资料：放射性标记的蛙皮素（BN）结合物是有前途的放射性示踪剂，用于乳腺和前列腺肿瘤的成像和治疗，其中BN 2/胃泌素释放肽受体过表达。我们描述了Lu-177-DOTA-PEG（5 k）-Lys-B类似物的比活性对其治疗效果的影响，并将其与非PEG化对应物进行了比较。稳定的DOTA-BN（7-14）的衍生[Cha（13），具有5 kDa的线性PEG分子（PEG（5 k））的Nle（14）]类似物通过β（3）hLys-β Ala-的E-氨基的PEG化来进行。BN序列和DOTA螯合剂之间的β Ala间隔区。用Lu-177对非PEG化和PEG化类似物进行放射性标记。在人前列腺癌PC-3细胞中进行体外评价，并在携带PC-3肿瘤异种移植物的裸鼠中进行体内研究。PEG化BN类似物和各种剂量方案的不同的具体活动进行了评估，关于其therapeutic effictiveness.Results：BN类似物的特异性和BN 2/GRP受体的结合亲和力仅略有减少PEG化。聚乙二醇化类似物的体外结合动力学较慢，因为在4小时后达到稳态条件。PEG化将BN缀合物在人血浆中的体外稳定性提高了5.6倍。非PEG化BN类似物已经显示出有利的药代动力学，即快速血液清除和肾排泄，但PEG化进一步改善了体内行为。注射后1小时，PEG（5 k）-BN衍生物的肿瘤摄取高于非PEG化类似物的肿瘤摄取（3.43 +/- 0.63%对1.88 +/-0.4%ID/g）。此外，增加的肿瘤保留导致在感染后24小时肿瘤蓄积增加两倍，以及增加的肿瘤与非靶标比率（肿瘤与肾脏，0.6对0.4;肿瘤与肝脏，8.8对5.9，24 h p.i.）。在治疗研究中，两种Lu-177标记的BN类似物均显着抑制肿瘤生长。对于以两个部分施用的高比活性的聚乙二醇化衍生物，治疗功效最高第0天和第7天（2 x 20 MBq = 40 MBq）（73%肿瘤生长抑制，治疗后3周）。PEG化和增加比活性增强Lu-177标记的BN-100的药代动力学性质。的放射性药物，并提供了一个有针对性的放射性核素治疗方案，具有有益的抗肿瘤效果和有利的风险，在同一时间。
Background: Radiolabelled bombesin (BN) conjugates are promising radiotracers for imaging and therapy of breast and prostate tumours, in which BN2/gastrin-releasing peptide receptors are overexpressed. We describe the influence of the specific activity of a Lu-177-DOTA-PEG(5k)-Lys-B analogue on its therapeutic efficacy and compare it with its non-PEGylated counterpart.Methods: Derivatisation of a stabilised DOTA-BN(7-14)[Cha(13),Nle(14)] analogue with a linear PEG molecule of 5 kDa (PEG(5k)) was performed by PEGylation of the E-amino group of a beta(3)hLys-beta Ala-beta Ala spacer between the BN sequence and the DOTA chelator. The non-PEGylated and the PEGylated analogues were radiolabelled with Lu-177. In vitro evaluation was performed in human prostate carcinoma PC-3 cells, and in vivo studies were carried out in nude mice bearing PC-3 tumour xenografts. Different specific activities of the PEGylated BN analogue and various dose regimens were evaluated concerning their therapeutic efficacy.Results: The specificity and the binding affinity of the BN analogue for BN2/GRP receptors were only slightly reduced by PEGylation. In vitro binding kinetics of the PEGylated analogue was slower since steady-state condition was reached after 4 h. PEGylation improved the stability of BN conjugate in vitro in human plasma by a factor of 5.6. The non-PEGylated BN analogue showed favourable pharmacokinetics already, i.e. fast blood clearance and renal excretion, but PEGylation improved the in vivo behaviour further. One hour after injection, the tumour uptake of the PEG(5k)-BN derivative was higher compared with that of the non-PEGylated analogue (3.43 +/- 0.63% vs. 1.88 +/- 0.4% ID/g). Moreover, the increased tumour retention resulted in a twofold higher tumour accumulation at 24 h p.i., and increased tumour-to-non-target ratios (tumour-to-kidney, 0.6 vs. 0.4; tumour-to-liver, 8.8 vs. 5.9, 24 h p.i.). In the therapy study, both Lu-177-labelled BN analogues significantly inhibited tumour growth. The therapeutic efficacy was highest for the PEGylated derivative of high specific activity administered in two fractions (2 x 20 MBq = 40 MBq) at day 0 and day 7 (73% tumour growth inhibition, 3 weeks after therapy).Conclusions: PEGylation and increasing the specific activity enhance the pharmacokinetic properties of a Lu-177-labelled BN-based radiopharmaceutical and provide a protocol for targeted radionuclide therapy with a beneficial anti-tumour effectiveness and a favourable risk-profile at the same time.