Magnetic nanoparticles encapsulated into biodegradable microparticles steered with an upgraded magnetic resonance imaging system for tumor chemoembolization Pierre Pouponneau a, b , Jean-Christophe Leroux b, c , Sylvain Martel a, * a NanoRobotics Laboratory, Canada Research Chair in Micro/Nanosystem Development, Fabrication and Validation, Department of Computer and Software Engineering and Institute of Biomedical Engineering, E ´ cole Polytechnique de Montreal (EPM), C.P. 6079, Succursale Centre-ville, Montre´al, Que ´bec H3C 3A7, Canada b Canada Research Chair in Drug Delivery, Faculty of Pharmacy, Universite´ de Montre ´al, Montreal, P.O. Box 6128, Dowtown Station, Montreal, Que´bec H3C 3J7, Canada c Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zu ¨rich, Wolfgang-Pauli-Str. 10, HCI H 301, 8093 Zu ¨rich, Switzerland article info Article history: Received 23 July 2009 Accepted 2 August 2009 Available online xxx Keywords: Magnetism Nanoparticle Microencapsulation MRI (magnetic resonance imaging) Embolization abstract In this work, therapeutic magnetic micro carriers (TMMC) guided in real time by a magnetic resonance imaging (MRI) system are proposed as a mean to improve drug delivery to tumor sites. MRI steering constraints and physiological parameters for the chemoembolization of liver tumors were taken into account to design magnetic iron–cobalt nanoparticles encapsulated into biodegradable poly(D,L-lactic-co- glycolic acid) (PLGA) microparticles with the appropriate saturation magnetization (M s ). FeCo nanoparticles displayed a diameter of 182 nm and an M s of 209 emu g 1 . They were coated with a multilayered graphite shell to minimize the reduction of M s during the encapsulation steps. FeCo–PLGA microparticles, with a mean diameter of 58 mm and an M s of 61 emu g 1 , were steered in a phantom mimicking the hepatic artery and its bifurcation, with a flow in the same order of magnitude as that of the hepatic artery flow. The steering efficiency, defined as the amount of FeCo–PLGA microparticles in the targeted bifurcation channel divided by the total amount of FeCo–PLGA microparticles injected, reached 86%. The data presented in this paper confirms the feasibility of the steering of these TMMC. Ó 2009 Elsevier Ltd. All rights reserved. 1. Introduction Hepatocellular carcinoma (HCC), the most frequent primary liver cancer, remains the third cause of cancer-related death [1–3]. The survival rate for 70% of HCC patients relies on the efficacy of palliative treatments [1,2,4]. Trans arterial chemoembolization (TACE), consisting of the injection of chemotherapeutic drugs fol- lowed by obstruction of the feeding hepatic arteries supplying the tumor with an embolizing agent, is considered as the mainstay of palliative treatment for unresectable HCC [4–6]. Despite an increase in patients’ survival rate, TACE efficacy is limited by the lack of tumor targeting resulting in four main drawbacks: i) a fraction of the injected dose reaches the systemic circulation inducing unwanted cytotoxic effects [7]; ii) the antitumor drug attacks healthy liver cells [4,8]; iii) the procedure remains painful for the patient because healthy blood vessels are embolized [8]; iv) hepatic artery damages can occur during TACE, which can interfere with the catheterization at the next session and compromise the success of the treatment [9]. To minimize TACE drawbacks, we propose the development of therapeutic magnetic micro carriers (TMMC) based on magnetic nanoparticles, which could be steered in real time with an upgraded magnetic resonance imaging (MRI) system from the hepatic artery to HCC nodules and thus to produce a chemo- embolization confined to the tumor area (Fig. 1A). TMMC consist of biodegradable microparticles co-encapsulating an antitumor drug and magnetic nanoparticles required for the MRI steering and tracking (Fig. 1B). After the embolization of tumor blood vessels due to the size of TMMC, the drug will be released as the polymer degrades (Fig. 1A). Thus, the concentration of the drug in the systemic circulation should be reduced and the antitumor effect should be increased by the sustainable release of the drug over time [7,10]. For the steering in the blood vessels, an MRI system upgraded with custom gradient coils placed in its tunnel will be used. The permanent magnetic field of the MRI system saturates the magnetization of nanoparticles [11]. Gradient coils will generate the magnetic force required for the transversal displace- ment of TMMC in the blood flow to reach the targeted blood vessel (Fig. 1A) and the MRI system will track the position of TMMC. * Corresponding author. NanoRobotics Laboratory, Department of Computer and Software Engineering and Institute of Biomedical Engineering, E ´ cole Polytechnique de Montreal (EPM), C.P. 6079, Succursale Centre-ville, Montre ´ al, Que ´bec H3C 3A7, Canada. Tel.: þ1 514 340 4711x5098; fax: þ1 514 340 5280. E-mail address: sylvain.martel@polymtl.ca (S. Martel). Contents lists available at ScienceDirect Biomaterials journal homepage: www.elsevier.com/locate/biomaterials ARTICLE IN PRESS 0142-9612/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.biomaterials.2009.08.005 Biomaterials xxx (2009) 1–6 Please cite this article in press as: Pouponneau P, et al., Magnetic nanoparticles encapsulated into biodegradable microparticles steered with an..., Biomaterials (2009), doi:10.1016/j.biomaterials.2009.08.005