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GG2.09 - A Nanohybrid System Based on Holotransferrin and Maghemite Nanoparticles as a Promising Theranostic Device 
April 7, 2015   4:15pm - 4:30pm

Magnetic Nanoparticles are extensively used in theranostics: hyperthermia, enhancement of contrast in MRI, etc. The main problem with nanoparticles is their delivery to the target cells [1]. To this purpose, the overexpression of transferrin-receptor 1 in cancer cells makes transferrin a potential vehicle for nanoparticles [2]. Transferrin solubilizes Fe3+ in sera and when iron-loaded, it is recognized by receptor-1, which is anchored in the plasma membrane [3]. This Triggers the receptor-mediated endocytosis of the two proteins [4,5]. We develop here a "Trojan horse" system based on this endocytosis of the holotransferrine-receptor adduct to intracellular delivery of maghemite nanoparticles. Different sizes of maghemite (Fe2O3) superparamagnetic nanoparticles (5, 10 and 15 nm) were synthesized, coated with 3-aminopropyltriethoxysilane (APTES) and coupled to holotransferrin (TFe2) by amide bonds. Each nanoparticle (NP) carried a known number of holotransferrins (TFe2-NP). This transferrin construct was tested in vitro and remains active after grafting and interacts with its receptor rapidly (50 �s) with an overall dissociation constant (11 nM) [6]. HeLa cells were incubated for several time intervals with rhodamine-labeled TFe2-NP and NPs. Confocal fluorescence microscopy showed that NPs do not cross the plasma membrane within 1 hour, whereas the constructs holotransferrine-maghemite are internalized in the cytosol in endosomes in less than 15 minutes (below). Furthermore, preliminary magnetophoresis results showed, in Lymphocyte T cells, that the rate of internalization of NPs grafted onto holotransferrine is three times larger than that of raw NPs in a culture media containing: 0, 10 and 55 % FCS. These very promising results seem to exclude the formation of a protein corona and validate our strategy. This hypothesis was also confirmed by molecular modeling. Thus, this nanohybrid system constitutes an interesting model for theranostic devices able to follow the main iron-acquisition pathway. References [1] A. Salvati, A.S. Pitek, M.P. Monopoli et al., Nat. Nanotechnol., 8 (2013) 137. [2] T.R. Daniels, et al., Biochim. Biophys. Acta, 1820 (2012) 291. [3] R.R. Crichton, Iron Metabolism: From Molecular Mechanisms to Clinical Consequences. Third Edition ed. West Sussex: J.Wiley & Sons (2009). [4] A. Dautry-Varsat, A. Ciechanover, H.F. Lodish, Proc. Natl. Acad. Sci. USA, 80 (1983) 2258. [5] M. Hemadi, P.H. Kahn, G. Miquel, et al., Biochemistry, 43 (2004) 1736. [6] H. Piraux, J. Hai, P. Verbeke et al., Biochim. Biophys. Acta., 1830 (2013) 4254.

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