Design and Evaluation of 223Ra-Labeled and Anti-PSMA Targeted NaA Nanozeolites for Prostate Cancer Therapy—Part II. Toxicity, Pharmacokinetics and Biodistribution

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.

Radiolabeled nanomaterials for biomedical applications: radiopharmacy in the era of nanotechnology

“…Unlike 99m Tc, 64 Cu, and 177 Lu, the stable chelation of the alkaline earth metal 223 Ra is a challenge (Abou et al 2021;Lankoff et al 2021) because of its complete electronic configuration ([Rn]7s 2 ) and the recoil energy effect. Hence, properly designed encapsulating of 223 Ra in nanomaterials such as micelles (Hilgard et al 2010) or surface sorption onto NPs might be the solution to get new 223 Ra radiopharmaceuticals for alpha-targeted therapy.…”

“…It would definitely bring novel obstacles and challenges for their systemic application, e.g., an unspecific uptake in RES, problematic active targeting, barriers crossing, toxicity, etc. (Lankoff et al 2021;Kleynhans et al 2021). However, further research is needed to elucidate the overall fate of the radiolabeled nanomaterials in vivo, such as active or passive transport to the tumor, the tumor microenvironment modification, immunogenic tumor-cell death, etc.…”

PSMA-Targeted Nanotheranostics for Imaging and Radiotherapy of Prostate Cancer

“…In addition, several other PSMA-targeted metal nanoparticle systems, such as 177 Lu-labeled lutetium oxide (Lu 2 O 3 ) NPs [ 43 , 44 ] and 223 Ra-labeled NaA zeolite NPs [ 45 , 46 ], have been developed and evaluated to treat prostate cancer. These reports also demonstrated chelator-free radiolabeling of theranostic isotopes into the respective metal NP cores.…”

“…The synthesis of lutetium oxide NPs and their radiolabeling was carried out simultaneously by adding the appropriate fraction of radioisotope 177 Lu at the time of NP formulation, whereas the radiolabeling of 223 Ra to the NaA nanozeolite was carried out by exchanging Na + for 223 Ra 2+ cation. Although these chelator free nanozeolites demonstrated promising PSMA-targeted cell uptake, they failed to show any PSMA-targeted tumor uptake with high accumulation in the lungs, liver, spleen, and bones, which could be due to the large particle size [ 46 ]. However, the lutetium oxide NPs demonstrated selective toxicity to malignant tumors without any histological changes in healthy tissues, thus supporting their potential for clinical translation [ 44 ].…”

Nanoparticle-Based Radioconjugates for Targeted Imaging and Therapy of Prostate Cancer

“…Recently, a novel NP-based radioconjugate [ 223 Ra]A-silane-PEG-D2B for targeted alpha therapy of PCa was successfully synthesised and characterised [ 50 , 59 ]. This compound consisted of a NaA zeolite NPs loaded with 223Ra, modified with silane-PEG molecules, and functionalized with anti-PSMA D2B antibody ( Figure 16 ).…”