Gonzalez Paulina, Debnath Sashi, Chen Yu-An, Hernandez Elizabeth, Jha Preeti, Dakanali Marianna, Hsieh Jer-Tsong, Sun Xiankai
Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Pharmaceutics. 2023 Feb 1;15(2):481. doi: 10.3390/pharmaceutics15020481.
After androgen deprivation therapy, a significant number of prostate cancer cases progress with a therapy-resistant neuroendocrine phenotype (NEPC). This represents a challenge for diagnosis and treatment. Based on our previously reported design of theranostic small-molecule prodrug conjugates (T-SMPDCs), herein we report a T-SMPDC tailored for targeted positron emission tomography (PET) imaging and chemotherapy of NEPC. The T-SMPDC is built upon a triazine core (TZ) to present three functionalities: (1) a chelating moiety (DOTA: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) for PET imaging when labeled with Ga (t = 68 min) or other relevant radiometals; (2) an octreotide (Octr) that targets the somatostatin receptor 2 (SSTR2), which is overexpressed in the innervated tumor microenvironment (TME); and (3) fingolimod, FTY720-an antagonist of sphingosine kinase 1 that is an intracellular enzyme upregulated in NEPC. Polyethylene glycol (PEG) chains were incorporated via conventional conjugation methods or a click chemistry reaction forming a 1,4-disubstituted 1,2,3-triazole (Trz) linkage for the optimization of in vivo kinetics as necessary. The T-SMPDC, DOTA-PEG-TZ(PEG-Octr)-PEG-Trz-PEG-Val-Cit-pABOC-FTY720 (PEG: PEG with n repeating ethyleneoxy units (n = 2, 3, or 4); Val: valine; Cit: citrulline; pABOC: p-amino-benzyloxycarbonyl), showed selective SSTR2 binding and mediated internalization of the molecule in SSTR2 cells. Release of FTY720 was observed when the T-SMPDC was exposed to cathepsin B, and the released FTY720 exerted cytotoxicity in cells. In vivo PET imaging showed significantly higher accumulation (2.1 ± 0.3 %ID/g; = 0.02) of [Ga]Ga-DOTA-PEG-TZ(PEG-Octr)-PEG-Trz-PEG-Val-Cit-pABOC-FTY720 in SSTR2 prostate cancer xenografts than in the SSTR2 xenografts (1.5 ± 0.4 %ID/g) at 13 min post-injection (p.i.) with a rapid excretion through the kidneys. Taken together, these proof-of-concept results validate the design concept of the T-SMPDC, which may hold a great potential for targeted diagnosis and therapy of NEPC.
雄激素剥夺治疗后，相当数量的前列腺癌病例会进展为具有治疗抵抗性的神经内分泌表型（NEPC）。这对诊断和治疗构成了挑战。基于我们之前报道的治疗诊断小分子前药缀合物（T-SMPDCs）的设计，在此我们报告一种专为NEPC的靶向正电子发射断层扫描（PET）成像和化疗量身定制的T-SMPDC。该T-SMPDC基于三嗪核心（TZ）构建，具有三种功能：（1）一个螯合部分（DOTA：1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸），当用Ga（t = 68分钟）或其他相关放射性金属标记时用于PET成像；（2）一种靶向生长抑素受体2（SSTR2）的奥曲肽（Octr），其在神经支配的肿瘤微环境（TME）中过表达；（3）芬戈莫德，FTY720 - 一种鞘氨醇激酶1的拮抗剂，鞘氨醇激酶1是一种在NEPC中上调的细胞内酶。通过常规缀合方法或点击化学反应引入聚乙二醇（PEG）链，形成1,4-二取代的1,2,3-三唑（Trz）键，以根据需要优化体内动力学。T-SMPDC，DOTA-PEG-TZ(PEG-Octr)-PEG-Trz-PEG-Val-Cit-pABOC-FTY720（PEG：具有n个重复乙氧基单元（n = 2、3或4）的PEG；Val：缬氨酸；Cit：瓜氨酸；pABOC：对氨基苄氧基羰基），显示出对SSTR2的选择性结合，并介导该分子在SSTR2细胞中的内化。当T-SMPDC暴露于组织蛋白酶B时观察到FTY720的释放，并且释放的FTY720在细胞中发挥细胞毒性作用。体内PET成像显示，注射后13分钟（p.i.）时，[Ga]Ga-DOTA-PEG-TZ(PEG-Octr)-PEG-Trz-PEG-Val-Cit-pABOC-FTY720在SSTR2前列腺癌异种移植瘤中的积累显著高于SSTR2异种移植瘤（2.1±0.3 %ID/g； = 0.02），且通过肾脏快速排泄。综上所述，这些概念验证结果验证了T-SMPDC的设计理念，其可能在NEPC的靶向诊断和治疗方面具有巨大潜力。
