109Pd/109mAg in-vivo generator in the form of nanoparticles for combined β- - Auger electron therapy of hepatocellular carcinoma

Abstract

Background Convenient therapeutic protocols for hepatocellular carcinoma (HCC) are often ineffective due to late diagnosis and high tumor heterogeneity, leading to poor long-term outcomes. However, recently performed studies suggest that using nanostructures in liver cancer treatment may improve therapeutic effects. Inorganic nanoparticles represent a unique material which tend to accumulate in the liver when introduced in-vivo. Typically, this is a major drawback that prevents the therapeutic use of nanoparticles in medicine. However, in HCC tumours, this may be advantageous because nanoparticles may accumulate in the target organ, where the leaky vasculature of HCC causes their accumulation in tumour cells via the EPR effect. On the other hand, recent studies have shown that combining low- and high-LET radiation emitted from the same radionuclide, such as ¹⁶¹Tb, can increase the effectiveness of radionuclide therapy. Therefore, to improve the effectiveness of radionuclide therapy for hepatocellular carcinoma, we suggest utilizing radioactive palladium nanoparticles in the form of ¹⁰⁹Pd/^109mAg in-vivo generator that emits simultaneously β⁻ particles and Auger electrons. Results Palladium nanoparticles with a size of 5 nm were synthesized using ¹⁰⁹Pd produced through neutron irradiation of natural palladium or enriched ¹⁰⁸Pd. Unlike the ¹⁰⁹Pd-cyclam complex where the daughter radionuclide diffuses away from the molecules, ^109mAg remains within the nanoparticles after the decay of ¹⁰⁹Pd. In vitro cell studies using radioactive ¹⁰⁹Pd nanoparticles revealed that the nanoparticles accumulated inside cells, reaching around 50% total uptake. The ¹⁰⁹Pd-PEG nanoparticles exhibited high cytotoxicity, even at low levels of radioactivity (6.25 MBq/mL), resulting in almost complete cell death at 25 MBq/mL. This cytotoxic effect was significantly greater than that of PdNPs labeled with β⁻ (¹³¹I) and Auger electron emitters (¹²⁵I). The metabolic viability of HCC cells was found to be correlated with cell DNA DSBs. Also successful radioconjugate anticancer activity was observed in three-dimensional tumor spheroids, resulting in a significant treatment response. Conclusion The results obtained indicate that nanoparticles labeled with ¹⁰⁹Pd can be effectively used for combined β⁻ - Auger electron targeted radionuclide therapy of HCC. Due to the decay of both components (β⁻ and Auger electrons), the ¹⁰⁹Pd/^109mAg in-vivo generator presents a unique potential in this field.