Purpose

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.

Methods

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.

Results

JHU-2545 resulted in approximately 3- and 53-fold greater exposure of 2-PMPA in rodent salivary glands (18.0 ± 0.97 h*nmol/g) and kidneys (359 ± 4.16 h*nmol/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.

Conclusions

JHU-2545 pre-treatment may enable greater cumulative administered doses of PSMA radioligand therapy, possibly improving safety and efficacy.

中文翻译：

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JHU-2545 在 PSMA 靶向成像期间优先保护唾液腺和肾脏

 目的

前列腺特异性膜抗原 （PSMA） 放射配体疗法是治疗转移性去势抵抗性前列腺癌 （mCRPC） 的一种很有前途的治疗方法。几种 β 或 α 粒子发射放射性核素偶联的小分子已在晚期 mCRPC 中显示出疗效，其中一种 [[177Lu]Lu]Lu-PSMA-617 已获得 FDA 批准。除了肿瘤上调外，PSMA 还在肾脏和唾液腺中表达，其中特异性摄取可导致剂量限制性口干症和潜在的肾毒性。PSMA 抑制剂 2-（膦酰甲基）戊二酸 （2-PMPA） 可以防止小鼠的肾脏摄取，但也阻断肿瘤摄取，从而排除其临床应用。优先将 2-PMPA 递送至非恶性组织可改善 PSMA 放射配体治疗的治疗窗口。

 方法

合成了 2-PMPA 的三（异丙氧羰基氧基甲基）（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 递送至血浆、肾脏、唾液腺和 C4-2 前列腺肿瘤异种移植物。在大鼠和小鼠中进行影像学研究，以测量肾脏、唾液腺和前列腺肿瘤异种移植物中 PSMA PET 示踪剂的摄取，有和没有 JHU-2545 预处理。

 结果

与前列腺肿瘤异种移植物 （6.79 ±至 0.19 h*nmol/g） 相比，JHU-2545 导致啮齿动物唾液腺 （18.0 ± 0.97 h*nmol/g） 和肾脏 （359 ± 4.16 h*nmol/g） 中 2-PMPA 暴露量分别高出约 3 倍和 53 倍。JHU-2545 还阻断了啮齿动物肾脏和唾液腺对 PSMA PET 示踪剂 [68Ga]Ga-PSMA-11 和 [18 F]F-DCFPyL 的摄取高达 85%，对肿瘤几乎没有影响。

 结论

JHU-2545 预处理可能使 PSMA 放射配体治疗的累积给药剂量更大，从而可能提高安全性和有效性。