177Lu-labeled low-molecular-weight agents for PSMA-targeted radiopharmaceutical therapy

Sangeeta Ray, Vivek Kumar, Ala Lisok, Jian Chen, Il Minn, Mary Elizabeth Brummet, Srikanth Boinapally, Michael Cole, Ethel Ngen, Bryan Wharram, Cory Brayton, Robert Hobbs, Martin Gilbert Pomper

Research output: Contribution to journalArticle

Abstract

Purpose: To develop a prostate-specific membrane antigen (PSMA)-targeted radiotherapeutic for metastatic castration-resistant prostate cancer (mCRPC) with optimized efficacy and minimized toxicity employing the β-particle radiation of 177Lu. Methods: We synthesized 14 new PSMA-targeted, 177Lu-labeled radioligands (177Lu-L1–177Lu-L14) using different chelating agents and linkers. We evaluated them in vitro using human prostate cancer PSMA(+) PC3 PIP and PSMA(−) PC3 flu cells and in corresponding flank tumor models. Efficacy and toxicity after 8 weeks were evaluated at a single administration of 111 MBq for 177Lu-L1, 177Lu-L3, 177Lu-L5 and 177Lu-PSMA-617. Efficacy of 177Lu-L1 was further investigated using different doses, and long-term toxicity was determined in healthy immunocompetent mice. Results: Radioligands were produced in high radiochemical yield and purity. Cell uptake and internalization indicated specific uptake only in PSMA(+) PC3 cells. 177Lu-L1, 177Lu-L3 and 177Lu-L5 demonstrated comparable uptake to 177Lu-PSMA-617 and 177Lu-PSMA-I&T in PSMA-expressing tumors up to 72 h post-injection. 177Lu-L1, 177Lu-L3 and 177Lu-L5 also demonstrated efficient tumor regression at 8 weeks. 177Lu-L1 enabled the highest survival rate. Necropsy studies of the treated group at 8 weeks revealed subacute damage to lacrimal glands and testes. No radiation nephropathy was observed 1 year post-treatment in healthy mice receiving 111 MBq of 177Lu-L1, most likely related to the fast renal clearance of this agent. Conclusions: 177Lu-L1 is a viable clinical candidate for radionuclide therapy of PSMA-expressing malignancies because of its high tumor-targeting ability and low off-target radiotoxic effects.

Original languageEnglish (US)
JournalEuropean Journal of Nuclear Medicine and Molecular Imaging
DOIs
StateAccepted/In press - Jan 1 2019

Fingerprint

Radiopharmaceuticals
Molecular Weight
Therapeutics
Prostatic Neoplasms
Neoplasms
Renal Agents
human glutamate carboxypeptidase II
Radiation
Lacrimal Apparatus
Castration
Chelating Agents
Radioisotopes
Testis
Injections

Keywords

  • Lutetium
  • Metastatic
  • Prostate cancer
  • Prostate-specific membrane antigen
  • β-Particle

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

Cite this

@article{2160bf4eef6d4bcaa9f5f50d82da6a27,
title = "177Lu-labeled low-molecular-weight agents for PSMA-targeted radiopharmaceutical therapy",
abstract = "Purpose: To develop a prostate-specific membrane antigen (PSMA)-targeted radiotherapeutic for metastatic castration-resistant prostate cancer (mCRPC) with optimized efficacy and minimized toxicity employing the β-particle radiation of 177Lu. Methods: We synthesized 14 new PSMA-targeted, 177Lu-labeled radioligands (177Lu-L1–177Lu-L14) using different chelating agents and linkers. We evaluated them in vitro using human prostate cancer PSMA(+) PC3 PIP and PSMA(−) PC3 flu cells and in corresponding flank tumor models. Efficacy and toxicity after 8 weeks were evaluated at a single administration of 111 MBq for 177Lu-L1, 177Lu-L3, 177Lu-L5 and 177Lu-PSMA-617. Efficacy of 177Lu-L1 was further investigated using different doses, and long-term toxicity was determined in healthy immunocompetent mice. Results: Radioligands were produced in high radiochemical yield and purity. Cell uptake and internalization indicated specific uptake only in PSMA(+) PC3 cells. 177Lu-L1, 177Lu-L3 and 177Lu-L5 demonstrated comparable uptake to 177Lu-PSMA-617 and 177Lu-PSMA-I&T in PSMA-expressing tumors up to 72 h post-injection. 177Lu-L1, 177Lu-L3 and 177Lu-L5 also demonstrated efficient tumor regression at 8 weeks. 177Lu-L1 enabled the highest survival rate. Necropsy studies of the treated group at 8 weeks revealed subacute damage to lacrimal glands and testes. No radiation nephropathy was observed 1 year post-treatment in healthy mice receiving 111 MBq of 177Lu-L1, most likely related to the fast renal clearance of this agent. Conclusions: 177Lu-L1 is a viable clinical candidate for radionuclide therapy of PSMA-expressing malignancies because of its high tumor-targeting ability and low off-target radiotoxic effects.",
keywords = "Lutetium, Metastatic, Prostate cancer, Prostate-specific membrane antigen, β-Particle",
author = "Sangeeta Ray and Vivek Kumar and Ala Lisok and Jian Chen and Il Minn and Brummet, {Mary Elizabeth} and Srikanth Boinapally and Michael Cole and Ethel Ngen and Bryan Wharram and Cory Brayton and Robert Hobbs and Pomper, {Martin Gilbert}",
year = "2019",
month = "1",
day = "1",
doi = "10.1007/s00259-019-04434-0",
language = "English (US)",
journal = "European Journal of Nuclear Medicine and Molecular Imaging",
issn = "1619-7070",
publisher = "Springer Verlag",

}

TY - JOUR

T1 - 177Lu-labeled low-molecular-weight agents for PSMA-targeted radiopharmaceutical therapy

AU - Ray, Sangeeta

AU - Kumar, Vivek

AU - Lisok, Ala

AU - Chen, Jian

AU - Minn, Il

AU - Brummet, Mary Elizabeth

AU - Boinapally, Srikanth

AU - Cole, Michael

AU - Ngen, Ethel

AU - Wharram, Bryan

AU - Brayton, Cory

AU - Hobbs, Robert

AU - Pomper, Martin Gilbert

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Purpose: To develop a prostate-specific membrane antigen (PSMA)-targeted radiotherapeutic for metastatic castration-resistant prostate cancer (mCRPC) with optimized efficacy and minimized toxicity employing the β-particle radiation of 177Lu. Methods: We synthesized 14 new PSMA-targeted, 177Lu-labeled radioligands (177Lu-L1–177Lu-L14) using different chelating agents and linkers. We evaluated them in vitro using human prostate cancer PSMA(+) PC3 PIP and PSMA(−) PC3 flu cells and in corresponding flank tumor models. Efficacy and toxicity after 8 weeks were evaluated at a single administration of 111 MBq for 177Lu-L1, 177Lu-L3, 177Lu-L5 and 177Lu-PSMA-617. Efficacy of 177Lu-L1 was further investigated using different doses, and long-term toxicity was determined in healthy immunocompetent mice. Results: Radioligands were produced in high radiochemical yield and purity. Cell uptake and internalization indicated specific uptake only in PSMA(+) PC3 cells. 177Lu-L1, 177Lu-L3 and 177Lu-L5 demonstrated comparable uptake to 177Lu-PSMA-617 and 177Lu-PSMA-I&T in PSMA-expressing tumors up to 72 h post-injection. 177Lu-L1, 177Lu-L3 and 177Lu-L5 also demonstrated efficient tumor regression at 8 weeks. 177Lu-L1 enabled the highest survival rate. Necropsy studies of the treated group at 8 weeks revealed subacute damage to lacrimal glands and testes. No radiation nephropathy was observed 1 year post-treatment in healthy mice receiving 111 MBq of 177Lu-L1, most likely related to the fast renal clearance of this agent. Conclusions: 177Lu-L1 is a viable clinical candidate for radionuclide therapy of PSMA-expressing malignancies because of its high tumor-targeting ability and low off-target radiotoxic effects.

AB - Purpose: To develop a prostate-specific membrane antigen (PSMA)-targeted radiotherapeutic for metastatic castration-resistant prostate cancer (mCRPC) with optimized efficacy and minimized toxicity employing the β-particle radiation of 177Lu. Methods: We synthesized 14 new PSMA-targeted, 177Lu-labeled radioligands (177Lu-L1–177Lu-L14) using different chelating agents and linkers. We evaluated them in vitro using human prostate cancer PSMA(+) PC3 PIP and PSMA(−) PC3 flu cells and in corresponding flank tumor models. Efficacy and toxicity after 8 weeks were evaluated at a single administration of 111 MBq for 177Lu-L1, 177Lu-L3, 177Lu-L5 and 177Lu-PSMA-617. Efficacy of 177Lu-L1 was further investigated using different doses, and long-term toxicity was determined in healthy immunocompetent mice. Results: Radioligands were produced in high radiochemical yield and purity. Cell uptake and internalization indicated specific uptake only in PSMA(+) PC3 cells. 177Lu-L1, 177Lu-L3 and 177Lu-L5 demonstrated comparable uptake to 177Lu-PSMA-617 and 177Lu-PSMA-I&T in PSMA-expressing tumors up to 72 h post-injection. 177Lu-L1, 177Lu-L3 and 177Lu-L5 also demonstrated efficient tumor regression at 8 weeks. 177Lu-L1 enabled the highest survival rate. Necropsy studies of the treated group at 8 weeks revealed subacute damage to lacrimal glands and testes. No radiation nephropathy was observed 1 year post-treatment in healthy mice receiving 111 MBq of 177Lu-L1, most likely related to the fast renal clearance of this agent. Conclusions: 177Lu-L1 is a viable clinical candidate for radionuclide therapy of PSMA-expressing malignancies because of its high tumor-targeting ability and low off-target radiotoxic effects.

KW - Lutetium

KW - Metastatic

KW - Prostate cancer

KW - Prostate-specific membrane antigen

KW - β-Particle

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U2 - 10.1007/s00259-019-04434-0

DO - 10.1007/s00259-019-04434-0

M3 - Article

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JO - European Journal of Nuclear Medicine and Molecular Imaging

JF - European Journal of Nuclear Medicine and Molecular Imaging

SN - 1619-7070

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