Department of Medical Imaging, Nuclear Medicine, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Geert Grooteplein Zuid 10, 6525GA, Nijmegen, The Netherlands.
Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands.
Eur J Nucl Med Mol Imaging. 2023 Jul;50(9):2872-2884. doi: 10.1007/s00259-023-06224-1. Epub 2023 Apr 15.
Incomplete resection of prostate cancer (PCa) results in increased risk of disease recurrence. Combined fluorescence-guided surgery with tumor-targeted photodynamic therapy (tPDT) may help to achieve complete tumor eradication. We developed a prostate-specific membrane antigen (PSMA) ligand consisting of a DOTA chelator for In labeling and a fluorophore/photosensitizer IRDye700DX (PSMA-N064). We evaluated the efficacy of PSMA-tPDT using PSMA-N064 in cell viability assays, a mouse xenograft model and in an ex vivo incubation study on fresh human PCa tissue.
In vitro, therapeutic efficacy of PSMA-N064 was evaluated using PSMA-positive LS174T cells and LS174T wild-type cells. In vivo, PSMA-N064-mediated tPDT was tested in immunodeficient BALB/c mice-bearing PSMA-positive LS174T xenografts. Tumor growth and survival were compared to control mice that received either NIR light or ligand injection only. Ex vivo tPDT efficacy was evaluated in excised fresh human PCa tissue incubated with PSMA-N064.
In vitro, tPDT led to a PSMA-specific light- and ligand dose-dependent loss in cell viability. In vivo, tPDT-induced tumor cell apoptosis, delayed tumor growth, and significantly improved survival (p = 0.004) of the treated PSMA-positive tumor-bearing mice compared with the controls. In fresh ex vivo human PCa tissue, apoptosis was significantly increased in PSMA-tPDT-treated samples compared to non-treated control samples (p = 0.037).
This study showed the feasibility of PSMA-N064-mediated tPDT in cell assays, a xenograft model and excised fresh human PCa tissue. This paves the way to investigate the impact of in vivo PSMA-tPDT on surgical outcome in PCa patients.
前列腺癌（PCa）的不完全切除会增加疾病复发的风险。结合荧光引导手术和肿瘤靶向光动力疗法（tPDT）可能有助于彻底消除肿瘤。我们开发了一种前列腺特异性膜抗原（PSMA）配体，由用于 In 标记的 DOTA 螯合剂和荧光团/光敏剂 IRDye700DX（PSMA-N064）组成。我们使用 PSMA-N064 在细胞活力测定、小鼠异种移植模型和新鲜人前列腺癌组织的离体孵育研究中评估了 PSMA-tPDT 的疗效。
在体外，使用 PSMA 阳性 LS174T 细胞和 LS174T 野生型细胞评估 PSMA-N064 的治疗效果。在体内，在携带 PSMA 阳性 LS174T 异种移植瘤的免疫缺陷 BALB/c 小鼠中测试 PSMA-N064 介导的 tPDT。将肿瘤生长和存活与仅接受 NIR 光或配体注射的对照小鼠进行比较。在离体孵育的新鲜人前列腺癌组织中评估离体 tPDT 的疗效。
在体外，tPDT 导致细胞活力的 PSMA 特异性光和配体剂量依赖性丧失。在体内，与对照组相比，tPDT 诱导的肿瘤细胞凋亡、延迟肿瘤生长并显著提高了治疗的 PSMA 阳性荷瘤小鼠的存活率（p=0.004）。在离体新鲜人前列腺癌组织中，与未处理的对照样本相比，PSMA-tPDT 处理的样本中凋亡明显增加（p=0.037）。
本研究表明 PSMA-N064 介导的 tPDT 在细胞测定、异种移植模型和离体新鲜人前列腺癌组织中具有可行性。这为研究体内 PSMA-tPDT 对前列腺癌患者手术结果的影响铺平了道路。
