An Albumin-Binding PSMA Ligand with Higher Tumor Accumulation for PET Imaging of Prostate Cancer

Abstract

Prostate-specific membrane antigen (PSMA) is an ideal target for the diagnosis and treatment of prostate cancer. Due to the short half-life in blood, small molecules/peptides are rapidly cleared by the circulatory system. Prolonging the half-life of PSMA probes has been considered as an effective strategy to improve the tumor detection. Herein, we reported a 64Cu-labeled PSMA tracer conjugating with maleimidopropionic acid (MPA), 64Cu-PSMA-CM, which showed an excellent ability to detect PSMA-overexpressing tumors in delayed time. Cell experiments in PSMA-positive 22Rv1 cells, human serum albumin binding affinity, and micro-PET imaging studies in 22Rv1 model were performed to investigate the albumin binding capacity and PSMA specificity. Comparisons with 64Cu-PSMA-BCH were performed to explore the influence of MPA on the biological properties. 64Cu-PSMA-CM could be quickly prepared within 30 min. The uptake of 64Cu-PSMA-CM in 22Rv1 cells increased over time and it could bind to HSA with a high protein binding ratio (67.8 ± 1.5%). When compared to 64Cu-PSMA-BCH, 64Cu-PSMA-CM demonstrated higher and prolonged accumulation in 22Rv1 tumors, contributing to high tumor-to-organ ratios. These results showed that 64Cu-PSMA-CM was PSMA specific with a higher tumor uptake, which demonstrated that MPA is an optional strategy for improving the radioactivity concentration in PSMA-expressing tumors and for developing the ligands for PSMA radioligand therapy.

Investigation of the Effect on the Albumin Binding Moiety for the Pharmacokinetic Properties of 68Ga-, 205/206Bi-, and 177Lu-Labeled NAPamide-Based Radiopharmaceuticals

“…Based on the evaluation of the decay-corrected PET scans, a notable difference was encountered between the two 68 Ga-labeled probes with respective SUV mean values being 0.43 ± 0.09 and 1.31 ± 0.24 for [ 68 Ga]Ga-DOTA-NAPamide and [ 68 Ga]Ga-DOTA-IPB-NAPamide (p ≤ 0.05). This is in line with previous literature data, according to which using different albumin-binding unit such as 4-(p-iodo-phenyl)-butanoic acid moiety (IPB) to lengthen the half-life of small, tumor-specific molecules (for example PSMA) results in elevated uptake in malignant lesions [18,19].…”

Theranostic Small-Molecule Prodrug Conjugates for Targeted Delivery and Controlled Release of Toll-like Receptor 7 Agonists

“…Without incorporating an albumin-binding moiety [52], the relatively slow in vivo clearance and tissue-distribution profiles of the T-SMPDCs could be advantageous for the therapeutic applications of the prodrug conjugates because the prolonged high plasma concentration facilitates the targeted accumulation and unidirectional internalization to reach the intended intracellular target protein.…”

86Y-Labeled Albumin-Binding Fibroblast Activation Protein Inhibitor for Late-Time-Point Cancer Diagnosis

“…The concept of albumin conjugation to alter drug distribution was first verified in the chemotherapy agent paclitaxel and has recently been applied in multiple drugs (e.g., the glucagon-like peptide-1 [GLP-1] analogue liraglutide) as well as radiopharmaceuticals, including PSMA and FAPI. − ,− Albumin binders, including truncated Evans blue, butyric acid derivative, and fatty acid derivative, have been tested to modify FAPI-02 and FAPI-04 to improve tumor accumulation and retention. − In addition, multimerization serves as an alternative strategy to improve tumor uptake with two FAP-targeting moieties linked with one chelating agent (DOTA). , These molecules exhibited prolonged tissue distribution with tumor activity peaking at 4–24 h and persisted 3–4 days after administration. Undoubtedly, the prolonged circulation favored therapeutic radionuclides for a better treatment effect (the half-life of 90 Y, 177 Lu, 225 Ac ranged from 2.6 to 10 days), yet the elevated normal organ uptake (e.g., liver, kidney, bone marrow) also resulted in unnecessary radiation dose, which has been reported in clinical investigations and may lead to side effects. − The prolonged tissue distribution and delayed tumor peak activity may also limit the 68 Ga-based diagnosis, as the radiopharmaceuticals remained in the circulation rather than absorbed by the tumor within a few decay periods, and the tumor activity as well as the tumor-to-background ratio may not be satisfied.…”