Prostate-specific membrane antigen
(PSMA), also known as glutamate
carboxypeptidase II (GCPII), is a suitable target for specific delivery
of antitumor drugs and diagnostic agents due to its overexpression
in prostate cancer cells. In the current work, we describe the design,
synthesis, and biological evaluation of novel low-molecular PSMA ligands
and conjugates with fluorescent dyes FAM-5, SulfoCy5, and SulfoCy7. In vitro evaluation of synthesized PSMA ligands on the activity
of PSMA shows that the addition of aromatic amino acids into a linker
structure leads to a significant increase in inhibition. The conjugates
of the most potent ligand with FAM-5 as well as SulfoCy5 demonstrated
high affinities to PSMA-expressing tumor cells in vitro. In vivo biodistribution in 22Rv1 xenografts in
Balb/c nude mice of PSMA-SulfoCy5 and PSMA-SulfoCy7 conjugates with a novel PSMA ligand demonstrated good visualization
of PSMA-expressing tumors. Also, the conjugate PSMA-SulfoCy7 demonstrated the absence of any explicit toxicity up to 87.9 mg/kg.
Prostate
cancer is the second most common type of cancer among
men. Its main method of treatment is chemotherapy, which has a wide
range of side effects. One of the solutions to this challenge is targeted
delivery to prostate cancer cells. Here we synthesized a novel small-molecule
PSMA-targeted conjugate based on the monomethyl auristatin E. Its
structure and conformational properties were investigated by NMR spectroscopy.
Cytotoxicity, intracellular reactive oxygen species induction, and
stability under liver microsomes and P450-cytochrome species were
investigated for this conjugate. The conjugate demonstrated 77–85%
tumor growth inhibition levels on 22Rv1 (PSMA (+)) xenografts, compared
with a 37% inhibition level on PC-3 (PSMA (−)) xenografts,
in a single dose of 0.3 mg/kg and a sufficiently high therapeutic
index of 21. Acute, chronic, and subchronic toxicities and pharmacokinetics
have shown that the synthesized conjugate is a promising potential
agent for the chemotherapy of prostate cancer.
This review demonstrates the progress in the synthesis of radioiodinated compounds over the past decade. The possibilities and limitations of radiopharmaceuticals with different iodine isotopes, as well as the synthesis of low and high molecular weight compounds containing radioiodine, are discussed. An analysis of synthesis strategies, substrate frameworks, isolation methods, and metabolic stability, and the possibility of industrial production of radioiodinated organic derivatives which can find applications in the synthesis of drugs and diagnostics are presented.
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