Purpose/objective The aim of this study was to develop and investigate the properties of a magnetic iron oxide nanoparticle–ethiodised oil formulation for image-guided thermal therapy of liver cancer. Materials and methods The formulation comprises bionised nano-ferrite (BNF) nanoparticles suspended in ethiodised oil, emulsified with polysorbate 20 (BNF-lip). Nanoparticle size was measured via photon correlation spectroscopy and transmission electron microscopy. In vivo thermal therapy capability was tested in two groups of male Foxn1nu mice bearing subcutaneous HepG2 xenograft tumours. Group I (n =12) was used to screen conditions for group II (n =48). In group II, mice received one of BNF-lip (n =18), BNF alone (n =16), or PBS (n =14), followed by alternating magnetic field (AMF) hyperthermia, with either varied duration (15 or 20 min) or amplitude (0, 16, 20, or 24 kA/m). Image-guided fluoroscopic intra-arterial injection of BNF-lip was tested in New Zealand white rabbits (n =10), bearing liver VX2 tumours. The animals were subsequently imaged with CT and 3 T MRI, up to 7 days post-injection. The tumours were histopathologically evaluated for distribution of BNF-lip. Results The BNF showed larger aggregate diameters when suspended in BNF-lip, compared to clear solution. The BNF-lip formulation produced maximum tumour temperatures with AMF >20 kA/m and showed positive X-ray visibility and substantial shortening of T1 and T2 relaxation time, with sustained intratumoural retention up to 7 days post-injection. On pathology, intratumoural BNF-lip distribution correlated well with CT imaging of intratumoural BNF-lip distribution. Conclusion The BNF-lip formulation has favourable thermal and dual imaging capabilities for image-guided thermal therapy of liver cancer, suggesting further exploration for clinical applications.

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Purpose: Magnetic hyperthermia with local delivery of iron oxide nanoparticles (NP) offers a promising therapeutic alternative for primary liver cancer. Our aim was to explore the therapeutic potential of local NP injection, using a nanoparticle- ethiodized oil (lipiodol) emulsion (NLE), in xenograft HepG2 mouse models of liver cancer and in orthotopic VX2 rabbit liver cancer models. Materials/Methods: NLE comprises lipiodol (50% w/v), polysorbate 20 (Tween 20, 0.2% w/v) and biocompatible Fe3O4 nanoparticles (BNF, 49.8% w/v). In vivo mice experiments included intra-tumor injections of a) NLE (n=20), b) BNF (n=12), c) PBS (n=14) in Foxnu1 mice bearing flank xenograft HepG2 tumors with and without AMF hyperthermia exposure (15-min, 300-700 Gauss, 150 kHz, 18 hours post-injection, with core and peri-tumor temperature measurements). Mice were either euthanized at 1-7 days or observed for tumor growth delay. Rabbit experiments included intra-arterial injections of NLE (n=8) with (n=4) and without (n=4) subsequent AMF hyperthermia exposure (20 min, 300 Gauss, 150 KHz, 48 hours (n=2) or 7 days (n=2) post-injection, with core and peri-tumor temperature measurements). Rabbits were euthanized at 3 or 7 days. Rabbits were imaged at baseline and before euthanasia in a clinical 320-slice CT scanner, as well as in a clinical 3T MR scanner. Imaging analysis included CT perfusion measurements, MR T2* measurements and co-registration of lipiodol and iron content. Pathologic analysis for all studies included evaluation of tumor necrosis, lipiodol and iron distribution.. Results: In mice, average maximum tumor temperature increase was 7.4±0.5°C for NLE (n=8) and 5.4±0.3°C for NP (n=5). At 24 days, there was a 4-fold difference in tumor growth delay between PBS and NLE-AMF heated tumors. Increased tumor necrosis was observed at 7 days in the NLE group. Intra-tumor iron distribution of NLE samples showed a characteristic distribution of NLE along the vascular tumor pathways at the tumor rim. In rabbits, average maximum tumor temperature increase was 3.2±0.5°C. Similarly, increased tumor necrosis was observed at 7 days and intra-tumor iron was seen deposited at the tumor rim. While CT imaging revealed primarily lipiodol deposition, MR imaging was very sensitive in detecting iron distribution, even in non-targeted areas. Conclusion: Preliminary in vivo data of the proposed NLE formulation for magnetic hyperthermia and dual imaging show potential for intra-tumor delivery and therapy in HepG2 xenograft mice models and intra-arterial delivery and therapy in the VX2 liver cancer model, with MRI/CT capabilities. Histological analysis of NLE treated tumors confirmed intra-tumour iron deposition with increased cellular damage. Initial results are encouraging and motivate further development for clinical translation. Citation Format: Eleni Liapi, Sahar Mirpour, Madhav Seshadri, Anilchandra Attaluri, Michele Wabler, Haoming Zhou, Robert Ivkov. Multifunctional formulation for dual imaging and magnetic hyperthermia therapy of liver cancer: A preclinical feasibility study. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr B33.