TY - JOUR
T1 - 177Lu-labeled low-molecular-weight agents for PSMA-targeted radiopharmaceutical therapy
AU - Banerjee, Sangeeta Ray
AU - Kumar, Vivek
AU - Lisok, Ala
AU - Chen, Jian
AU - Minn, Il
AU - Brummet, Mary
AU - Boinapally, Srikanth
AU - Cole, Michael
AU - Ngen, Ethel
AU - Wharram, Bryan
AU - Brayton, Cory
AU - Hobbs, Robert F.
AU - Pomper, Martin G.
PY - 2019/11/1
Y1 - 2019/11/1
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
VL - 46
SP - 2545
EP - 2557
JO - European Journal of Nuclear Medicine and Molecular Imaging
JF - European Journal of Nuclear Medicine and Molecular Imaging
SN - 1619-7070
IS - 12
ER -