Abstract 2065: Magnetic resonance imaging with an iron oxide nanoparticle demonstrates the preclinical feasibility of predicting intratumoral uptake and activity of MM-398, a nanoliposomal irinotecan (nal-IRI)

Sustained intratumoral delivery of cytotoxic agents is a major challenge for effective cancer treatment, and motivated the development of MM-398, a stable nanoliposomal irinotecan (nal-IRI) with an extended plasma half-life and greater tumor deposition than free irinotecan. By using a systems pharmacology approach, we have previously shown that tumor deposition of nal-IRI and the subsequent conversion of irinotecan to the active metabolite, SN-38, by carboxylesterases are important determinants for nal-IRI activity in vivo. Ferumoxytol (FMX) is a 30nm iron-oxide, super-paramagnetic nanoparticle, known to be taken up by macrophages (as is nal-IRI), and for exhibiting magnetic resonance imaging properties. Since the size of a nanoparticle affects the rate of transcapillary transport significantly, we hypothesized that nal-IRI tumor biodistribution may be predicted by FMX-based MRI (Fe-MRI). Biodistribution and imaging studies were performed in mice bearing cell-line derived (A2780, HT29, A549) and patient-derived (pancreatic adenocarcinoma) tumor xenografts. The protocol consisted of a baseline MRI scan, i.v. injection of FMX (20mg/kg), and then i.v. injection of fluorescently labeled nal-IRI (10mg/kg) 24hr later. Mice were sacrificed 24hr and 72hr after nal-IRI injection, and irinotecan and SN-38 concentrations were determined in plasma, tumor, and tissues by HPLC analysis. The presence of FMX did not interfere with nal-IRI PK or biodistribution. Cellular distribution of liposomes within tumors was also not affected by FMX at up to 50mg/kg as measured by flow cytometry. Furthermore, immunohistochemistry showed that both liposomes and FMX were co-localized with tumor-associated macrophages. The drug metabolite measurements from tissue samples showed that the xenograft tumor models display wide ranges of nal-IRI deposition capacity (irinotecan concentrations at 24hr: ∼2,104 to 20,096ng/g). A2780 tumors displayed highest concentration of both iron (3.92 μg/ml) and irinotecan (9,466 ng/g) at 72hr after nal-IRI injection, whereas A549 tumors displayed lowest levels of both iron (0.23 μg/ml ) and irinotecan (436 ng/g). We observed a correlation between the tumor Fe-MRI signal and intratumoral levels of irinotecan 72hr after nal-IRI injection (R2=0.9, p