Nedelcovych Michael T, Dash Ranjeet P, Wu Ying, Choi Eun Yong, Lapidus Rena S, Majer Pavel, Jančařík Andrej, Abou Diane, Penet Marie-France, Nikolopoulou Anastasia, Amor-Coarasa Alex, Babich John, Thorek Daniel L, Rais Rana, Kratochwil Clemens, Slusher Barbara S
Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA.
Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA.
Eur J Nucl Med Mol Imaging. 2025 Apr;52(5):1631-1641. doi: 10.1007/s00259-024-07044-7. Epub 2025 Jan 2.
Prostate-specific membrane antigen (PSMA) radioligand therapy is a promising treatment for metastatic castration-resistant prostate cancer (mCRPC). Several beta or alpha particle-emitting radionuclide-conjugated small molecules have shown efficacy in late-stage mCRPC and one, [[177Lu]Lu]Lu-PSMA-617, is FDA approved. In addition to tumor upregulation, PSMA is also expressed in kidneys and salivary glands where specific uptake can cause dose-limiting xerostomia and potential for nephrotoxicity. The PSMA inhibitor 2-(phosphonomethyl)pentanedioic acid (2-PMPA) can prevent kidney uptake in mice, but also blocks tumor uptake, precluding its clinical utility. Preferential delivery of 2-PMPA to non-malignant tissues could improve the therapeutic window of PSMA radioligand therapy.
A tris(isopropoxycarbonyloxymethyl) (TrisPOC) prodrug of 2-PMPA, JHU-2545, was synthesized to enhance 2-PMPA delivery to non-malignant tissues. Mouse pharmacokinetic experiments were conducted to compare JHU-2545-mediated delivery of 2-PMPA to plasma, kidney, salivary glands, and C4-2 prostate tumor xenograft. Imaging studies were conducted in rats and mice to measure uptake of PSMA PET tracers in kidney, salivary glands, and prostate tumor xenografts with and without JHU-2545 pre-treatment.
JHU-2545 resulted in approximately 3- and 53-fold greater exposure of 2-PMPA in rodent salivary glands (18.0 ± 0.97 hnmol/g) and kidneys (359 ± 4.16 hnmol/g) versus prostate tumor xenograft (6.79 ± 0.19 h*nmol/g). JHU-2545 also blocked rodent kidneys and salivary glands uptake of the PSMA PET tracers [68Ga]Ga-PSMA-11 and [18 F]F-DCFPyL by up to 85% with little effect on tumor.
JHU-2545 pre-treatment may enable greater cumulative administered doses of PSMA radioligand therapy, possibly improving safety and efficacy.
前列腺特异性膜抗原（PSMA）放射性配体疗法是转移性去势抵抗性前列腺癌（mCRPC）一种很有前景的治疗方法。几种发射β或α粒子的放射性核素偶联小分子已在晚期mCRPC中显示出疗效，其中一种，[[177Lu]Lu]Lu-PSMA-617已获美国食品药品监督管理局（FDA）批准。除肿瘤上调外，PSMA也在肾脏和唾液腺中表达，其特异性摄取可导致剂量限制性口干症和肾毒性可能性。PSMA抑制剂2-(膦酰甲基)戊二酸（2-PMPA）可防止小鼠肾脏摄取，但也会阻断肿瘤摄取，从而排除了其临床应用价值。将2-PMPA优先递送至非恶性组织可改善PSMA放射性配体疗法的治疗窗口。
合成了2-PMPA的三(异丙氧基羰氧基甲基)（TrisPOC）前药JHU-2545，以增强2-PMPA向非恶性组织的递送。进行小鼠药代动力学实验，比较JHU-2545介导的2-PMPA向血浆、肾脏、唾液腺和C4-2前列腺肿瘤异种移植瘤的递送情况。在大鼠和小鼠中进行成像研究，以测量在有和没有JHU-2545预处理的情况下，PSMA PET示踪剂在肾脏、唾液腺和前列腺肿瘤异种移植瘤中的摄取情况。
与前列腺肿瘤异种移植瘤（6.79±0.19 hnmol/g）相比，JHU-2545使2-PMPA在啮齿动物唾液腺（18.0±0.97 hnmol/g）和肾脏（359±4.16 h*nmol/g）中的暴露量分别增加约3倍和53倍。JHU-2545还可使啮齿动物肾脏和唾液腺对PSMA PET示踪剂[68Ga]Ga-PSMA-11和[18F]F-DCFPyL的摄取减少多达85%，而对肿瘤影响很小。
JHU-2545预处理可能使PSMA放射性配体疗法的累积给药剂量更高，可能改善安全性和疗效。
