PEG spacers of different length influence the biological profile of bombesin-based radiolabeled antagonists

蛙皮素 体内分布 化学 亲脂性 体内 内化 多塔 药代动力学 体外 PEG比率 放射性核素治疗 放射性配体 受体 立体化学 药理学 螯合作用 生物化学 核医学 医学 生物技术 有机化学 财务 神经肽 经济 生物
作者
Mazen Jamous,Maria Luisa Tamma,Eleni Gourni,Beatrice Waser,Jean Claude Reubi,Helmut R. Maëcke,Rosalba Mansi
出处
期刊:Nuclear Medicine and Biology [Elsevier BV]
卷期号:41 (6): 464-470 被引量:39
标识
DOI:10.1016/j.nucmedbio.2014.03.014
摘要

The gastrin-releasing peptide receptor (GRPR) was shown to be expressed with high density on several types of cancers. Radiolabeled peptides for imaging and targeted radionuclide therapy have been developed. In this study, we evaluated the potential of statine-based bombesin antagonists, conjugated to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) through oligoethyleneglycol spacers, labeled with 177Lu and we determined the effect of polyethyleneglycol (PEG) spacer length on in vitro and in vivo properties. The bombesin antagonists were synthesized on solid phase using Fmoc chemistry; the spacers Fmoc-dPEGx-OH (x = 2, 4, 6 and 12) and the DOTA(tBu)3 were coupled using a standard procedure. The peptides were labeled with 177Lu and evaluated in vitro (lipophilicity, serum stability, internalization and binding affinity assays). Biodistribution studies were performed in PC-3 tumor-bearing nude mice. The solid-phase synthesis was straightforward with an overall yield ranging from 30% to 35% based on the first Fmoc cleavage. The hydrophilicity increased with spacer length (logD: − 1.95 vs − 2.22 of PEG2 and PEG12 analogs, respectively). There is a tendency of increased serum stability by increasing the spacer length (T1/2 = 246 ± 4 and 584 ± 20 for PEG2 and PEG6 analogs, respectively) which seems to reverse with the PEG12 analog. The IC50 values are similar with the only significant difference of the PEG12 analog. The 177Lu-labeled PEG4 and PEG6 conjugates showed similar pharmacokinetic with high tumor uptake and excellent tumor-to-kidney ratios (7.8 and 9.7 at 4 h for the PEG4 and PEG6 derivatives, respectively). The pancreas uptake was relatively high at 1 h but it shows fast washout (0.46% ± 0.02% IA/g and 0.29% ± 0.08% IA/g already at 4 h). Among all the studied analogs the PEG4 and PEG6 showed significantly better properties. The very high tumor-to-non-target organ ratios, in particular tumor-to-kidney ratios, already at early time point will be important in regard to safety concerning kidney toxicity.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
念姬发布了新的文献求助10
1秒前
CatC完成签到,获得积分10
1秒前
英俊的汉堡完成签到,获得积分10
2秒前
lucky完成签到,获得积分10
3秒前
5秒前
6秒前
bkagyin应助鱼咬羊采纳,获得10
6秒前
Leeny发布了新的文献求助10
7秒前
8秒前
8秒前
飞行中的鱼完成签到,获得积分20
9秒前
牛牛眉目发布了新的文献求助10
10秒前
菲晗子完成签到,获得积分20
10秒前
茜茜哎科研应助湛湛采纳,获得10
10秒前
zx发布了新的文献求助10
12秒前
13秒前
14秒前
土豪的雪巧完成签到,获得积分10
15秒前
雨的前世完成签到,获得积分10
18秒前
18秒前
Sun发布了新的文献求助10
19秒前
gulllluuuukk完成签到,获得积分10
19秒前
可可西里完成签到,获得积分10
19秒前
20秒前
茜茜哎科研应助傅勃霖采纳,获得10
20秒前
20秒前
Lee发布了新的文献求助10
21秒前
22秒前
22秒前
牛牛眉目发布了新的文献求助10
23秒前
yang发布了新的文献求助10
25秒前
蛋挞完成签到 ,获得积分10
26秒前
李爱国应助zx采纳,获得10
26秒前
bunny完成签到,获得积分20
27秒前
新威宝贝完成签到,获得积分10
29秒前
29秒前
xr完成签到 ,获得积分10
29秒前
张雷应助yangyl采纳,获得10
30秒前
AXEDW完成签到 ,获得积分10
32秒前
csy完成签到,获得积分10
35秒前
高分求助中
A new approach to the extrapolation of accelerated life test data 1000
Cognitive Neuroscience: The Biology of the Mind 1000
Technical Brochure TB 814: LPIT applications in HV gas insulated switchgear 1000
Immigrant Incorporation in East Asian Democracies 500
Nucleophilic substitution in azasydnone-modified dinitroanisoles 500
不知道标题是什么 500
A Preliminary Study on Correlation Between Independent Components of Facial Thermal Images and Subjective Assessment of Chronic Stress 500
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 3966366
求助须知:如何正确求助?哪些是违规求助? 3511778
关于积分的说明 11159852
捐赠科研通 3246372
什么是DOI,文献DOI怎么找? 1793416
邀请新用户注册赠送积分活动 874427
科研通“疑难数据库(出版商)”最低求助积分说明 804388