Abstract
Prostate-specific membrane antigen (PSMA) is an attractive target for the diagnosis and therapy of prostate cancer as it is specifically overexpressed in prostate cancer cells. Improving the circulation of radioligands in the blood is considered as an effective strategy that can improve tumor burden, which benefits detection of small lesions and improves the effect of PSMA radioligand therapy (PRLT). In this study, we introduced maleimidopropionic acid (MPA) to a PSMA-targeted tracer and developed Al18F-PSMA-CM, which targets human serum albumin (HSA) binding and PSMA. Al18F-PSMA-CM is evaluated in vitro and in vivo for stability, PSMA specificity, and biodistribution in 22Rv1 tumor-bearing mice. Al18F-PSMA-CM was prepared with a radiochemical purity of >99% and specific activity of 11.22–18.70 MBq/nmol. Al18F-PSMA-CM was stable in vitro and in vivo and prolonged circulation in blood with a binding ratio of 47 ± 3.2% and Kd value of 3.08 ± 0.45 nM to HSA. The uptake of Al18F-PSMA-CM in PSMA(+) 22Rv1 cells was increased in 2 h, and the uptake was blocked by a PSMA inhibitor, ZJ-43. The Kd value of Al18F-PSMA-CM to PSMA was 8.46 ± 0.24 nM. Al18F-PSMA-CM was accumulated in kidneys and 22Rv1 tumors [74.76 ± 15.42 and 6.16 ± 0.74 ID%/g at 2 h post injection (p.i.)], which were decreased by −80.0 and −84.3% when co-injected with ZJ-43. Al18F-PSMA-CM showed high PSMA specificity and accumulated in 22Rv1 tumors with increasing uptake in 4 h. MPA moiety showed the ability to prolong the half-life of tracers, and the MPA-conjugated tracer showed the potential to improve tumor uptake. MPA may be a choice to develop radiopharmaceuticals for PRLT of prostate cancer.
Highlights
Prostate cancer (PCa) is the most common cancer in males in the world, especially in western countries
Prostate-specific membrane antigen (PSMA) is an attractive target for the diagnosis and therapy of PCa as it is overexpressed in most PCa and metastasis cells (Sweat et al, 1998; Rybalov et al, 2014)
The non-decayed radiochemical yield of Al18F-PSMA-CM was calculated as 34.2 ± 5.2% with a radiochemical purity of >99% and a specific activity of 15.2 ± 2.9 GBq/μmol
Summary
Prostate cancer (PCa) is the most common cancer in males in the world, especially in western countries. As chemotherapy and other systemic treatment options had associated toxicities or offer only a modest survival benefit, prostate-specific membrane antigen (PSMA) radioligand therapy (PRLT) has become an emerging treatment for metastatic CRPC (mCRPC) (Petrylak et al, 2004; de Bono et al, 2010; Scher et al, 2012; Parker et al, 2013). The most studied radioligands were 177Lu/225AcPSMA-617 or 177Lu/225Ac-PSMA-I&T; they are small molecules with rapid blood clearance, which limited the achievement of therapeutic concentration in tumor tissues (Umbricht et al, 2018). Enhancing the blood halflife of radioligands meets the need for desirable accumulation of radioactivity in tumor cells. Some studies demonstrated that prolonging the half-life can increase the uptake of radiotracers in PSMA-expressing tumors and can show better therapeutic effects (Choy et al, 2017; Benesova et al, 2018)
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