Copolymer-Based Hepatocyte Asialoglycoprotein Receptor Targeting Agent for SPECT

Abstract

Poly(vinylbenzyl-O-β-D-galactopyranosyl-D-gluconamide) (PVLA) can be specifically internalized by hepatocytes via the asialoglycoprotein receptor. In this study, we synthesized and characterized galactose-carrying copolymers with hydrazinonicotinamide chains as bifunctional groups to radiolabel PVLA with (99m)Tc for SPECT targeting specific hepatocytes. Poly(N-p-vinylbenzyl-[O-β-D-galactopyranosyl-(1→4)-D-gluconamide]-co-N-p-vinylbenzyl-6-[2-(4-dimethylamino)benzaldehydehydrazono]nicotinate) (P(VLA-co-VNI)) was first prepared via copolymerization of N-p-vinylbenzyl-O-β-D-galactopyranosyl-D-gluconamide with 5% (mol) of N-p-vinylbenzyl-(4-dimethylaminobenzaldehyde hydrazono)nicotinamide. The copolymer was labeled with (99m)Tc using tricine as a coligand. Then (99m)Tc[P(VLA-co-VNI)](tricine)(2) was evaluated by in vivo metabolic stability and biodistribution in normal mice. SPECT was performed in normal New Zealand White rabbits and rabbits with liver cancer. (99m)Tc[P(VLA-co-VNI)](tricine)(2) was prepared in high labeling yield (>95%) and radiochemical purity (>99%), with good stability. The results of biodistribution in mice demonstrated that the liver uptake was 125.33 ± 10.99 percentage injected dose per gram at 10 min after injection and could be blocked significantly by preinjecting free neogalactosylalbumin or P(VLA-co-VNI). SPECT images with high quality were obtained at 15, 30, 60, and 120 min after injection of the radiotracer. Significant radioactivity defect was observed in the liver cancer model. The bifunctional coupling agent hydrazinonicotinamide was introduced to PVLA via copolymerization and labeled with (99m)Tc. The promising biologic properties of (99m)Tc[P(VLA-co-VNI)](tricine)(2) afford potential applications for the assessment of hepatocyte function in the future.