Mesenchymal stem cells as cellular vehicles for delivery of nanoparticles to brain tumors Mathilde Roger a , Anne Clavreul a, b , Marie-Claire Venier-Julienne a , Catherine Passirani a , Laurence Sindji a , Paul Schiller c, d , Claudia Montero-Menei a , Philippe Menei a, b, * a INSERM Unit 646, Ingénierie de la Vectorisation Particulaire, 10 rue André Bocquel, Université d’Angers, 49100 Angers, France b Département de Neurochirurgie, Centre Hospitalier Universitaire d’Angers, 4 rue Larrey, 49100 Angers, France c Departments of Biochemistry/Molecular Biology and Medicine, University of Miami Miller School of Medicine, Miami, FL 33125-1693, USA d Geriatric Research, Education and Clinical Center (GRECC) and Research Service, VA Medical Center; and Departments of Medicine and Biochemistry & Molecular Biology, and Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL 33125-1693, USA article info Article history: Received 19 June 2010 Accepted 8 July 2010 Available online 5 August 2010 Keywords: Mesenchymal stem cells Nanoparticles Glioma Cellular vehicle abstract The prognosis of patients with malignant glioma remains extremely poor, despite surgery and improvements in radio- and chemo-therapies. Nanotechnologies represent great promise in glioma therapy as they protect therapeutic agent and allow its sustained release. However, new paradigms allowing tumor specific targeting and extensive intratumoral distribution must be developed to effi- ciently deliver nanoparticles (NPs). Knowing the tropism of mesenchymal stem cells (MSCs) for brain tumors, the aim of this study was to obtain the proof of concept that these cells can be used as NP delivery vehicles. Two types of NPs loaded with coumarin-6 were investigated: poly-lactic acid NPs (PLA-NPs) and lipid nanocapsules (LNCs). The results show that these NPs can be efficiently internalized into MSCs while cell viability and differentiation are not affected. Furthermore, these NP-loaded cells were able to migrate toward an experimental human glioma model. These data suggest that MSCs can serve as cellular carriers for NPs in brain tumors. Ó 2010 Elsevier Ltd. All rights reserved. 1. Introduction Malignant glioma has a poor prognosis despite aggressive treatment using surgery, radiotherapy and chemotherapy [1,2]. The difficulty with cancer treatments, especially with brain, is to achieve an effective delivery of therapeutic agents to the tumor and to the infiltrating tumor cells. Many promising treatments for glioma involve nanoparticles (NPs). NPs are defined as solid colloidal particles of matricial (nanospheres) or vesicular type (nanocapsules) ranging in size from 10 to 1000 nm. They are generally constituted of biodegradable and non-biodegradable polymers or lipids. NPs can carry multiple therapeutic agents such as drugs [3e5], radio- nucleides [6] or DNA [7,8]. The therapeutic agent can be entrapped in, adsorbed or chemically coupled onto their surface. These NPs protect the therapeutic agent from a premature degradation and allow its sustained and controlled release. Although NPs represent promising carriers for drug delivery to glioma [4,9,10], an efficient NP delivery to brain tumor is a central mandate of this treatment. The main limitation is the obstacle of the bloodebrain barrier (BBB), which separates the blood from the cerebral parenchyma [11]. Active brain-targeting strategies to cross BBB have been investigated such as the conjugation of lipid nanocapsules (LNCs) to OX26 monoclonal antibodies which can then recognise the transferrin receptor loca- lized principally on the brain capillary endothelium [12]. However, this active targeting leads to a low NP accumulation in the brain. To bypass the BBB, direct intratumoral NP delivery using convection- enhanced-delivery (CED) has been used. This method, using an external pressure gradient inducing fluid convection in the brain via a surgically implanted catheter, allows greater volume distri- bution to be achieved in comparison to diffusion alone [13,14]. A combination of nanotechnology with the CED technique showed promising results in 9L experimental glioma in rats [15,16]. How- ever, this approach presented some disadvantages such as long infusion times inducing infections, potential intracranial hyperten- sions and unpredictable drug distribution. Another alternative to enhance NP delivery in brain tumor is the use of cellular vectors that have endogenous tumor-homing activity and can thereby chaperone NP delivery in vivo. In this regard, mesenchymal stem cells also called multipotent mesenchymal stromal cells (MSCs) which have a tendency to distribute at the site of tumors could be potential candidates [17,18]. Following intra-arterial * Corresponding author. INSERM Unit 646, Ingénierie de la Vectorisation Par- ticulaire, 10 rue André Bocquel, Université d’Angers, 49100 Angers, France. Tel.: þ33241354822; fax: þ33241735853. E-mail address: phmenei@chu-angers.fr (P. Menei). Contents lists available at ScienceDirect Biomaterials journal homepage: www.elsevier.com/locate/biomaterials 0142-9612/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.biomaterials.2010.07.048 Biomaterials 31 (2010) 8393e8401