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 language | English (US) |
|---|---|
| Journal | European Journal of Nuclear Medicine and Molecular Imaging |
| DOIs | |
| State | Accepted/In press - Jan 1 2019 |
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Keywords
- Lutetium
- Metastatic
- Prostate cancer
- Prostate-specific membrane antigen
- β-Particle
ASJC Scopus subject areas
- Radiology Nuclear Medicine and imaging
Cite this
177Lu-labeled low-molecular-weight agents for PSMA-targeted radiopharmaceutical therapy. / Ray, Sangeeta; Kumar, Vivek; Lisok, Ala; Chen, Jian; Minn, Il; Brummet, Mary Elizabeth; Boinapally, Srikanth; Cole, Michael; Ngen, Ethel; Wharram, Bryan; Brayton, Cory; Hobbs, Robert; Pomper, Martin Gilbert.
In: European Journal of Nuclear Medicine and Molecular Imaging, 01.01.2019.Research output: Contribution to journal › Article
}
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
UR - http://www.scopus.com/inward/record.url?scp=85070257183&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85070257183&partnerID=8YFLogxK
U2 - 10.1007/s00259-019-04434-0
DO - 10.1007/s00259-019-04434-0
M3 - Article
C2 - 31399803
AN - SCOPUS:85070257183
JO - European Journal of Nuclear Medicine and Molecular Imaging
JF - European Journal of Nuclear Medicine and Molecular Imaging
SN - 1619-7070
ER -