(640c) Pharmacokinetic Model for the Distribution of Radiometal-Chelator-Dendrimer-PNA-IGF1 Analog Nanoparticles In Tumor-Bearing Mice

We hypothesized that overexpression of a mutated KRAS oncogene in a human pancreas cancer xenograft could be detected by external scintigraphic imaging of a KRAS peptide nucleic acid (PNA) hybridization probe, radiolabeled with a polydiaminopropanoyl (PDAP) dendrimer of ¹¹¹In ions, endocytosed into cancer cells that overexpress insulin-like growth factor 1 receptor (IGF1R) via an IGF1 peptide retro-inverso fragment, D(Cys-Ser-Lys-Cys). We assembled this molecular imaging nanoparticle (MIN) on a polymer support by solid-phase coupling starting from the C-terminus of the IGF1 peptide, purified the MIN by reverse-phase HPLC, and analyzed the MIN by mass spectrometry. The in vivo distribution of the KRAS MIN labeled with ¹¹¹In was established scintigraphically at 4 and 24 hours using human pancreas cancer xenografts in immunocompromised mice. The MIN distributed normally to the kidneys, livers, tumors, and other tissues. A two-compartment model of the tissue distribution was used to calculate an elimination rate constant of 1.64 ± 0.09/hr. The forward rate calculated for blood to tissue distribution was 0.26 ± 0.14/hr. The backward rate from tissue to blood was calculated as 0.089 ± 0.032/hr. Further it was determined that the MIN tends to reside in the vascular space of the mouse. An oligonucleotide pharmacokinetic model adapted from the literature fitted the distribution of the MIN in several tissues and in the blood by empirically adjusting the injected dose able to enter tissues and bind to its mRNA target at only 10-20% of the MIN concentration in blood. We speculate that the majority of the MIN is filtered out of the blood by the kidneys, and that a small fraction binds to the circulating insulin-like growth factor binding proteins (IGFBPs), which then aid in distributing the MIN into the different organs and tumor. This work was supported in part by NCI contract N01 CO27175 to E.W.