JHU-2545 preferentially shields salivary glands and kidneys during PSMA-targeted imaging.
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-...
| Publicado en: | European Journal of Nuclear Medicine & Molecular Imaging Vol. 52; no. 5; pp. 1631 - 1642 |
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| Autores principales: | , , , , , , , , , , , , , , , |
| Formato: | Journal Article |
| Publicado: |
Springer Nature
Apr2025
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=183974329&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 183974329 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 16197070 NPC jtl: European Journal of Nuclear Medicine & Molecular Imaging issn: 16197070 maglogo: N pubinfo: dt: Apr2025 vid: 52 iid: 5 pid: 237 pub: Springer Nature place: New York, New York artinfo: ui: 183974329 182034922 10.1007/s00259-024-07044-7 183974329 ppf: 1631 ppct: 11 formats: fmt: – @attributes: type: T – @attributes: type: P tig: atl: JHU-2545 preferentially shields salivary glands and kidneys during PSMA-targeted imaging. aug: au: 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. affil: https://ror.org/00za53h95 Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, 21205, Baltimore, MD, USA sug: ab: 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. Key points: Question: Is there a method of limiting PSMA radioligand uptake into salivary glands and kidneys to potentially mitigate associated toxicity without hindering tumor uptake/efficacy? Pertinent findings: JHU-2545, a prodrug of the PSMA inhibitor 2-PMPA, was found to preferentially deliver 2-PMPA to salivary glands and kidneys relative to tumor xenografts in rodent models, leading to blunted uptake of PSMA radioligands in non-tumor tissues. Implications for patient care: If replicated in clinical studies, JHU-2545 could reduce radiation doses to salivary glands and kidneys and possibly mitigate associated toxicities in prostate cancer patients receiving PSMA radioligand therapy. pubtype: Academic Journal doctype: Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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