Abstract
Metastatic castration-resistant prostate cancer (mCRPC) is a progressive and incurable disease with poor prognosis for patients. Despite introduction of novel therapies, the mortality rate remains high. An attractive alternative for extension of the life of mCRPC patients is PSMA-based targeted radioimmunotherapy. In this paper, we extended our in vitro study of 223Ra-labeled and PSMA-targeted NaA nanozeolites [223RaA-silane-PEG-D2B] by undertaking comprehensive preclinical in vitro and in vivo research. The toxicity of the new compound was evaluated in LNCaP C4-2, DU-145, RWPE-1 and HPrEC prostate cells and in BALB/c mice. The tissue distribution of 133Ba- and 223Ra-labeled conjugates was studied at different time points after injection in BALB/c and LNCaP C4-2 tumor-bearing BALB/c Nude mice. No obvious symptoms of antibody-free and antibody-functionalized nanocarriers cytotoxicity and immunotoxicity was found, while exposure to 223Ra-labeled conjugates resulted in bone marrow fibrosis, decreased the number of WBC and platelets and elevated serum concentrations of ALT and AST enzymes. Biodistribution studies revealed high accumulation of 223Ra-labeled conjugates in the liver, lungs, spleen and bone tissue. Nontargeted and PSMA-targeted radioconjugates exhibited a similar, marginal uptake in tumour lesions. In conclusion, despite the fact that NaA nanozeolites are safe carriers, the intravenous administration of NaA nanozeolite-based radioconjugates is dubious due to its high accumulation in the lungs, liver, spleen and bones.
Highlights
Metastatic castration-resistant prostate cancer is a progressive and incurable disease with poor prognosis for patients [1]
The lessons learned from 20 years of experience with PSMA vectors labeled with beta emitters have shown that this type of therapy was associated with ≥50% reduction in PSA level
We aimed to extent our previous findings, which revealed that the radiobioconjugate 223RaA-silane-PEG-D2B was very stable in human blood serum in vitro, bound and internalized into PSMA-expressing LNCaP C4-2 cells, as well as demonstrating potent radiotoxicity in LNCaP C4-2 cells [24]
Summary
Metastatic castration-resistant prostate cancer (mCRPC) is a progressive and incurable disease with poor prognosis for patients [1]. Despite several options for the treatment of mCRPC, such as taxanes-based chemotherapy, second-generation antiandrogens, poly-(ADP-ribose)-polymerase (PARP) inhibitors, immunotherapy with sipuleucel-T and therapy with the bone-seeking radium-223 dichloride (Xofigo®), the median survival is ~30 months with a 30% 5-year survival rate. An attractive alternative concept for extension of the life of mCRPC patients with acceptable side effects is the PSMA-based targeted radionuclide therapy (TRT). The lessons learned from 20 years of experience with PSMA vectors labeled with beta emitters have shown that this type of therapy was associated with ≥50% reduction in PSA level. The therapy allowed for efficient treatment of large tumors but has been suboptimal for the eradication of small cell clusters. The limitations of beta-emitter-based therapies may be linked to insufficient dose delivery to the tumor and the low linear-energy transfer of β-particles [4,5]
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