Design and Evaluation of 223Ra-Labeled and Anti-PSMA Targeted NaA Nanozeolites for Prostate Cancer Therapy–Part I

Abstract

Prostate cancer is the second most frequent malignancy in men worldwide. Unfortunately, current therapies often lead to the onset of metastatic castration-resistant prostate cancer (mCRPC), causing significant mortality. Therefore, there is an urgent need for new and targeted therapies that are advantageous over the current ones. Recently, the PSMA-targeted radioligand therapy of mCRPC has shown very promising results. In line with this, we described the synthesis of a new radioimmunoconjugate, 223RaA-silane-PEG-D2B, for targeted mCRPC therapy. The new compound consists of a NaA zeolite nanocarrier loaded with the α-particle emitting Ra-223 radionuclide, functionalized with the anti-PSMA D2B antibody. Physicochemical properties of the synthesized compound were characterized by standard methods (HR-SEM, TEM, XRD, FTIR, EDS, NTA, DLS, BET, TGA). The targeting selectivity, the extent of internalization, and cytotoxicity were determined in LNCaP C4-2 (PSMA+) and DU-145 (PSMA-) cells. Our results supported the 223RaA-silane-PEG-D2B synthesis and revealed that the final product had a diameter ca. 120 nm and specific activity 0.65 MBq/1mg. The product was characterized by a high yield of stability (>95% up to 12 days). The conjugation reaction resulted in approximately 50 antibodies/nanoparticle. The obtained radioimmunoconjugate bound specifically and internalized into PSMA-expressing LNCaP C4-2 cells, but not into PSMA-negative DU-145 cells. 223RaA-silane-PEG-D2B demonstrated also potent cytotoxicity in LNCaP C4-2 cells. These promising results require further in vivo evaluation of 223RaA-silane-PEG-D2B with regard to its toxicity and therapeutic efficacy.

Preclinical and Clinical Status of PSMA-Targeted Alpha Therapy for Metastatic Castration-Resistant Prostate Cancer

“…Unfortunately, 223 Ra, like other alkaline earth metals, forms very weak complexes [160,161]. To overcome this limitation, several nanomaterials, hydroxyapatites, polyoxopalladates, nanozeolites, barium sulfate, and titanium dioxide nanoparticles have been tested for stable incorporation of radium and linking to the targeting vector [84,[162][163][164][165][166]. So far, only one paper has been published investigating the encapsulation of 223 Ra into functionalized nanozeolites for PSMA-TAT [84].…”

“…To overcome this limitation, several nanomaterials, hydroxyapatites, polyoxopalladates, nanozeolites, barium sulfate, and titanium dioxide nanoparticles have been tested for stable incorporation of radium and linking to the targeting vector [ 84 , 162 , 163 , 164 , 165 , 166 ]. So far, only one paper has been published investigating the encapsulation of 223 Ra into functionalized nanozeolites for PSMA-TAT [ 84 ]. NaA zeolite is one of the synthetic, non-toxic microporous crystalline aluminosilicate zeolites that can accommodate a wide variety of various molecules, including radionuclides [ 165 , 167 ].…”

“…NaA zeolite is one of the synthetic, non-toxic microporous crystalline aluminosilicate zeolites that can accommodate a wide variety of various molecules, including radionuclides [ 165 , 167 ]. Czerwińska et al [ 84 ] modified NaA nanozeolite with silane-PEG (polyethylene glycol) and functionalized it with anti-PSMA D2B antibody as a carrier of 223 Ra and its daughter radionuclides for PSMA-TAT. The obtained 120 nm 223 RaA–silane-PEG-PSMA D2B bioconjugate was highly stable (<2% of 223 Ra and <6% of the daughter radionuclides were released up to 12 days) [ 84 ].…”

“…Czerwińska et al [ 84 ] modified NaA nanozeolite with silane-PEG (polyethylene glycol) and functionalized it with anti-PSMA D2B antibody as a carrier of 223 Ra and its daughter radionuclides for PSMA-TAT. The obtained 120 nm 223 RaA–silane-PEG-PSMA D2B bioconjugate was highly stable (<2% of 223 Ra and <6% of the daughter radionuclides were released up to 12 days) [ 84 ]. The radioimmunoconjugate bound specifically and internalized into PSMA-expressing C4-2 cells, but not into PSMA-negative DU-145 cells.…”

“…The radioimmunoconjugate bound specifically and internalized into PSMA-expressing C4-2 cells, but not into PSMA-negative DU-145 cells. Treatment of C4-2 cells with 20 kBq/mL of the radioimmunoconjugate resulted in an 80% reduction in metabolic activity [ 84 ]. Further preclinical studies in vivo are needed to validate the therapeutic efficacy and toxicity of 223 RaA-silane-PEG-D2B.…”