Preclinical Development of PNT6555, a Boronic Acid–Based, Fibroblast Activation Protein-α (FAP)–Targeted Radiotheranostic for Imaging and Treatment of FAP-Positive Tumors

成纤维细胞活化蛋白 化学 硼酸 癌症研究 癌症 组合化学 医学 内科学
作者
Sarah E. Poplawski,Robin Hallett,Mark H. Dornan,Kyle E. Novakowski,Shuang Pan,Anthony P. Belanger,Quang‐Dé Nguyen,Wengen Wu,Albert Felten,Yuxin Liu,Shin Hye Ahn,Valerie S. Hergott,Barry Jones,Jack H. Lai,Joe A. B. McCann,William W. Bachovchin
出处
期刊:The Journal of Nuclear Medicine [Society of Nuclear Medicine]
卷期号:65 (1): 100-108 被引量:1
标识
DOI:10.2967/jnumed.123.266345
摘要

The overexpression of fibroblast activation protein-α (FAP) in solid cancers relative to levels in normal tissues has led to its recognition as a target for delivering agents directly to tumors. Radiolabeled quinoline-based FAP ligands have established clinical feasibility for tumor imaging, but their therapeutic potential is limited due to suboptimal tumor retention, which has prompted the search for alternative pharmacophores. One such pharmacophore is the boronic acid derivative N-(pyridine-4-carbonyl)-d-Ala-boroPro, a potent and selective FAP inhibitor (FAPI). In this study, the diagnostic and therapeutic (theranostic) potential of N-(pyridine-4-carbonyl)-d-Ala-boroPro–based metal-chelating DOTA-FAPIs was evaluated. Methods: Three DOTA-FAPIs, PNT6555, PNT6952, and PNT6522, were synthesized and characterized with respect to potency and selectivity toward soluble and cell membrane FAP; cellular uptake of the Lu-chelated analogs; biodistribution and pharmacokinetics in mice xenografted with human embryonic kidney cell–derived tumors expressing mouse FAP; the diagnostic potential of 68Ga-chelated DOTA-FAPIs by direct organ assay and small-animal PET; the antitumor activity of 177Lu-, 225Ac-, or 161Tb-chelated analogs using human embryonic kidney cell–derived tumors expressing mouse FAP; and the tumor-selective delivery of 177Lu-chelated DOTA-FAPIs via direct organ assay and SPECT. Results: DOTA-FAPIs and their natGa and natLu chelates exhibited potent inhibition of human and mouse sources of FAP and greatly reduced activity toward closely related prolyl endopeptidase and dipeptidyl peptidase 4. 68Ga-PNT6555 and 68Ga-PNT6952 showed rapid renal clearance and continuous accumulation in tumors, resulting in tumor-selective exposure at 60 min after administration. 177Lu-PNT6555 was distinguished from 177Lu-PNT6952 and 177Lu-PNT6522 by significantly higher tumor accumulation over 168 h. In therapeutic studies, all 3 177Lu-DOTA-FAPIs exhibited significant antitumor activity at well-tolerated doses, with 177Lu-PNT6555 producing the greatest tumor growth delay and animal survival. 225Ac-PNT6555 and 161Tb-PNT6555 were similarly efficacious, producing 80% and 100% survival at optimal doses, respectively. Conclusion: PNT6555 has potential for clinical translation as a theranostic agent in FAP-positive cancer.
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
大幅提高文件上传限制,最高150M (2024-4-1)

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
1秒前
淡然靖柔完成签到,获得积分10
3秒前
4秒前
Dr.Mary完成签到 ,获得积分10
5秒前
平常的过客应助欧皇采纳,获得10
5秒前
乐乐应助缥缈的飞扬采纳,获得10
6秒前
段落落发布了新的文献求助10
6秒前
迅速的续发布了新的文献求助10
6秒前
9秒前
9秒前
ma发布了新的文献求助10
10秒前
吉尼太美完成签到 ,获得积分10
11秒前
YWJ关闭了YWJ文献求助
13秒前
潘善若发布了新的文献求助10
14秒前
14秒前
15秒前
16秒前
无所不能的虫虫完成签到,获得积分10
20秒前
beta1scat应助顺利的亦云采纳,获得20
21秒前
21秒前
21秒前
潘善若完成签到,获得积分10
22秒前
22秒前
迅速的续完成签到 ,获得积分10
23秒前
小白发布了新的文献求助10
26秒前
27秒前
zqw完成签到,获得积分10
29秒前
hcd12138完成签到,获得积分10
30秒前
31秒前
木头人完成签到,获得积分10
31秒前
32秒前
简单海发布了新的文献求助10
33秒前
33秒前
共享精神应助无私的白昼采纳,获得10
35秒前
球球发布了新的文献求助10
36秒前
含蓄的含羞草完成签到,获得积分10
36秒前
36秒前
简泞完成签到,获得积分10
38秒前
wwqdd发布了新的文献求助10
41秒前
jin发布了新的文献求助10
41秒前
高分求助中
Sustainability in Tides Chemistry 1500
TM 5-855-1(Fundamentals of protective design for conventional weapons) 1000
Handbook of the Mammals of the World – Volume 3: Primates 600
Gerard de Lairesse : an artist between stage and studio 500
Digging and Dealing in Eighteenth-Century Rome 500
Queer Politics in Times of New Authoritarianisms: Popular Culture in South Asia 500
Livre et militantisme : La Cité éditeur 1958-1967 500
热门求助领域 (近24小时)
化学 医学 生物 材料科学 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 基因 遗传学 催化作用 物理化学 免疫学 量子力学 细胞生物学
热门帖子
关注 科研通微信公众号,转发送积分 3064564
求助须知:如何正确求助?哪些是违规求助? 2719276
关于积分的说明 7463160
捐赠科研通 2365657
什么是DOI,文献DOI怎么找? 1254139
科研通“疑难数据库(出版商)”最低求助积分说明 608796
版权声明 596684