The feasibility, performance, and radiation safety of an experimental generator were evaluated to efficiently produce ²¹²Pb intended for radiopharmaceuticals. Methods: The generator consisted of a flask with a removable cap containing a source of ²²⁴Ra or ²²⁸Th absorbed on quartz wool. Gaseous ²²⁰Rn emanated from the decaying source, which subsequently decayed to ²¹²Pb, which was adsorbed on the flask’s interior surface. The ²¹²Pb was collected by washing the flask with 0.5–1 mL of 0.1 M HCl. Results: The generator collector flask trapped 62%–68% of the ²¹²Pb, of which more than 87% (tested up to 26 MBq) could be harvested. The obtained ²¹²Pb solution had a high purity (>99.98%) and could be used for the preparation of radioconjugates with more than 97% radiochemical purity. Future designs of the generator should aim to further reduce the risk of radon and γ-energy exposure to operators. Conclusion: The presented technology is a promising method for easy and convenient ²¹²Pb production. Visual Abstract

Radium-224-labeled CaCO₃ microparticles have been developed to treat peritoneal carcinomatosis. The microparticles function as carriers of ²²⁴Ra, facilitating intraperitoneal retention of the alpha-emitting radionuclide. It was necessary to control the size of microparticles in suspension over time and introduce a sterilization process for the clinical use of the radiopharmaceutical. Ethylenediamine tetra(methylene phosphonic acid) (EDTMP) was investigated as a stabilizing additive. The possibility of encapsulating the radiolabeled microparticles with an outer surface layer of CaCO₃ for the improved retention of radioactivity by the carrier was studied. This work evaluated these steps of optimization and their effect on radiochemical purity, the biodistribution of radionuclides, and therapeutic efficacy. An EDTMP concentration of >1% (w/w) relative to CaCO₃ stabilized the particle size for at least one week. Without EDTMP, the median particle size increased from ~5 µm to ~25 µm immediately after sterilization by autoclaving, and the larger microparticles sedimented rapidly in suspension. The percentage of adsorbed ²²⁴Ra progeny ²¹²Pb increased from 56% to 94% at 2.4–2.5% (w/w) EDTMP when the ²²⁴Ra-labeled microparticles were layer-encapsulated. The improved formulation also resulted in a suitable biodistribution of radionuclides in mice, as well as a survival benefit for mice with intraperitoneal ovarian or colorectal tumors.

Lead-212 is recognized as a promising radionuclide for targeted alpha therapy for tumors. Many studies of ²¹²Pb-labeling of various biomolecules through bifunctional chelators have been conducted. Another approach to exploiting the cytotoxic effect is coupling the radionuclide to a microparticle acting as a carrier vehicle, which could be used for treating disseminated cancers in body cavities. Calcium carbonate may represent a suitable material, as it is biocompatible, biodegradable, and easy to synthesize. In this work, we explored ²¹²Pb-labeling of various CaCO₃ microparticles and developed a protocol that can be straightforwardly implemented by clinicians. Vaterite microparticles stabilized by pamidronate were effective as ²¹²Pb carriers; labeling yields of ≥98% were achieved, and ²¹²Pb was strongly retained by the particles in an in vitro stability assessment. Moreover, the amounts of ²¹²Pb reaching the kidneys, liver, spleen, and skeleton of mice following intraperitoneal (i.p.) administration were very low compared to i.p. injection of unbound ²¹²Pb²⁺, indicating that CaCO₃-bound ²¹²Pb exhibited stability when administered intraperitoneally. Therapeutic efficacy was observed in a model of i.p. ovarian cancer for all the tested doses, ranging from 63 to 430 kBq per mouse. Lead-212-labeled CaCO₃ microparticles represent a promising candidate for treating intracavitary cancers.