Analysis of metabolites of Cu-64 labeled DOTA PEGylated star-like copolymeric nanoparticles

Objectives Core-shell PEGylated star-like copolymers conjugated with DOTA have been developed as an in vivo imaging and drug delivery nanosystem. ⁶⁴Cu labeled star-like copolymers with surface-bound 5 kDa PEG exhibit characteristics desirable for PET imaging, these include long blood retention and low liver and splenic uptake. The aim of this work was to assess the dose dependent effects on biodistribution and the metabolic fate of the Cu-64.

Methods Dose dependence of ⁶⁴Cu-star-like copolymers were evaluated using biodistribution techniques in rats and mice (dose: 0.75–300 µg/kg). The metabolic fate in rat blood and liver was estimated using size-exclusion chromatography.

Results Blood retention of ⁶⁴Cu-star-like copolymers was prolonged with increasing dose and saturated at doses ≥75 µg/kg. In contrast, uptake in liver and spleen, decreased dramatically at higher doses. The metabolism studies revealed >90 % of nanoparticles were intact in the blood at 24 h pi, with only one metabolite, ⁶⁴Cu-ceruloplasmin observed. Two metabolites, corresponding to ⁶⁴Cu-superoxide dismutase and ⁶⁴Cu-metallothionein, were observed in the liver.

Conclusions ⁶⁴Cu-star-like copolymers were metabolically stable in the circulation. The nanoparticle biodistribution was dose-dependent, with a marked decrease in liver and spleen uptake at doses ≥75 µg/kg. There appears to be a saturable uptake system (mononuclear phagocyte system (MPS)) involved in the clearance of these nanoparticles. These findings aid in the development of the nanoparticles as a platform for molecular imaging and drug delivery.

Research Support This material is based upon work supportedby the NIH as a Program of Excellence in Nanotechnology (HL080729).