Abstract
The clinical translation of theranostic 177Lu-radiopharmaceuticals based on inhibitors of the prostate-specific membrane antigen (PSMA) has demonstrated positive clinical responses in patients with advanced prostate cancer (PCa). However, challenges still remain, particularly regarding their pharmacokinetic and dosimetric properties. We developed a potential PSMA-immunotheranostic agent by conjugation of a single-chain variable fragment of the IgGD2B antibody (scFvD2B) to DOTA, to obtain a 177Lu-labelled agent with a better pharmacokinetic profile than those previously reported. The labelled conjugated 177Lu-scFvD2B was obtained in high yield and stability. In vitro, 177Lu-scFvD2B disclosed a higher binding and internalization in LNCaP (PSMA-positive) compared to PC3 (negative control) human PCa cells. In vivo studies in healthy nude mice revealed that 177Lu-scFvD2B present a favorable biokinetic profile, characterized by a rapid clearance from non-target tissues and minimal liver accumulation, but a slow wash-out from kidneys. Micro-SPECT/CT imaging of mice bearing pulmonary microtumors evidenced a slow uptake by LNCaP tumors, which steadily rose up to a maximum value of 3.6 SUV at 192 h. This high and prolonged tumor uptake suggests that 177Lu-scFvD2B has great potential in delivering ablative radiation doses to PSMA-expressing tumors, and warrants further studies to evaluate its preclinical therapeutic efficacy.
Highlights
Prostate cancer (PCa) is the second leading cause of cancer deaths for adult men in the Western world
prostate-specific membrane antigen (PSMA) is overexpressed in 95% of prostate cancers and its expression levels progressively increase in high-grade tumors and in metastatic disease, up to 1,000 times more than in normal cells[2]
The human prostate cancer LNCaP and androgen-independent bone metastasis PC-3 cell lines were obtained from the American Type Culture Collection (ATCC)
Summary
Prostate cancer (PCa) is the second leading cause of cancer deaths for adult men in the Western world. Among the several PSMA-targeting molecules that have been developed, the radiolabeled Glu-ureido-based PSMA inhibitors are gaining much interest due to their high uptake by PSMA-positive cancer cells, and low background and excellent contrast in cancer imaging, even in small metastases[3,4]. Theranostic agents such as 177Lu-PSMA-617, 177Lu-PSMA-I&T and 177Lu-iPSMA have demonstrated their ability to efficiently target PSMA-expressing tumors, with the consequent decrease of serum PSA levels in 30–60% of PCa patients[5,6]. Most 177Lu-labeled PSMA inhibitors are currently employed only as compassionate treatment for patients with end-stage metastatic castration-resistant PCa8
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