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)
Authors: Kalra Ashish V. , Spernyak Joseph , Kim Jaeyeon , Sengooba Arnold , Klinz Stephan , Paz Nancy , Cain Jason , Kamoun Walid , Straubinger Ninfa , Qu Yang , Trueman Sheryl , Bayever Eliel , Nielsen Ulrik , Drummond Daryl , Fitzgerald Jonathan , Straubinger Robert 
Published: May 2015

Abstract
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&lt;0.001). Furthermore, in vivo activity studies confirmed that xenograft models having higher intratumoral levels of irinotecan and SN-38 at 72hr showed greater tumor growth inhibition.
In summary, preclinical studies demonstrate the potential of utilizing Fe-MRI as a potential diagnostic tool to identify patients with higher tumor permeability. Based on encouraging preclinical data, a pilot study in patients with advanced solid tumors with extensive Fe-MRI scanning and paired tumor biopsies (NCT # 01770353) is being conducted.
Citation Format: Ashish V. Kalra, Joseph Spernyak, Jaeyeon Kim, Arnold Sengooba, Stephan Klinz, Nancy Paz, Jason Cain, Walid Kamoun, Ninfa Straubinger, Yang Qu, Sheryl Trueman, Eliel Bayever, Ulrik Nielsen, Daryl Drummond, Jonathan Fitzgerald, Robert Straubinger. 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). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2065. doi:10.1158/1538-7445.AM2014-2065