Pharmacie sans ordonnance livraison rapide 24h: acheter viagra en ligne en France.
Microsoft word - isrms abstract_barge.doc
Targeting tumor cells with Gd(III) chelates through the glutamine transporting system
A. Barge1,2, L. Tei2,3, S. Geninatti Crich2,4, R. Stefanìa4, M. Forsterova4, S. Lanzardo2,4, A. Ciampa4, G. Cravotto1, and S. Aime2,4
1Department of Drug Science and Technology, University of Torino, Torino, Italy, Italy, 2CIM - Center for Molecular Imaging,
Torino, Italy, 3DISAV, Università del Piemonte Orientale, Alessandria, Italy, 4Department of Chemistry IFM, University of
Torino, Torino, Italy.
The development of new Gd-based contrast agents (CAs) with high contrast ability and targeting capability is the key step for the
set-up of innovative magnetic resonance-molecular imaging (MRMI) protocols. In fact, in MRMI procedures, one has to visualize
epitopes that are present at very low concentration (typically in the 50-100 nM range) and therefore it is necessary to design proper
methods to amplify the response upon recognition of the target of interest.
We have recently exploited the glutamine transporting system as a route to deliver a large number of Gd(III) contrast agents to the
tumor cells. It is well known that proliferating cells consume more glucose and amino acids (and their derivatives) than their
benign counterparts. Transport of glucose and amino acids into cells is mediated by specific membrane proteins called
transporters, which are responsible for the translocation of the substrate from one side of the membrane to the other. The increased
expression or up-regulation of these transporters correlates with the greater transport of glucose and amino acids and it is strictly
related to the cells growth. We have chosen glutamine as it is the most abundant amino acid in the body (0.5-0.8 mM in serum)
and is the physiological non-toxic ammonium vehicle between different mammalian tissues; therefore glutamine is the main
source of nitrogen for tumor cells which transport glutamine at a faster rate than normal cells1. Methods.
Extensive synthetic chemistry has bbeen necessary to synthetize the compounds reported in fig.1. In particular novel systems for
efficient conjugation have been synthetized, namely DOTAMAC6OH and DOTAMAC6NH2 . The latter compound has been used
in the synthesis of DOTAMA/Gln multimers both in solid phase and in solution. Gln phospholipid was synthesized by conjugation
of activated PEG 2000 spaced phospholipid with Gln, GdHPDO3A loaded liposome was prepared using this Gln phospholipid as
targeting unit. All Gd-complexes were tested in vitro
on HTC, C6 and Hepatocytes cell lines and the best compounds also in vivo
on A/J mice grafted with the
murine neuroblastoma cell line Neuro-2a and in Her-2/neu transgenic mice developing multiple mammary carcinoma Results.
Several glutamine and Gd chelate containing systems have been prepared (Fig.1). Namely: a) Gd-DOTA monoamide derivatives
in which the glutamine residue is conjugated through different functionalities; b) Gd-DOTA monoamide derivatives endowed with
a different spacer between the chelate and the glutamine moieties; c) Multi-valent systems containing more glutamine residues per
Gd complex; d) A Gd-loaded liposome functionalized with glutamine vectors on its outer surface.
A thorough investigation on different cell lines has allowed to assess the main determinants of cellular uptake through the
glutamine transporter system. Important parameters appear to be the length of the spacer between the glutamine and the chelate
moiety and the way through which the glutamine residue is conjugated to the imaging reporter. No advantage has been found with
the use of the glutamine multimeric system. Finally the liposome works very well “in vitro” but not yet “in vivo”. Conclusions.
This work has allowed the identification of the determinants of cellular binding and uptake through the glutamine transporters.
The latter target appears very promising for the MRI visualization of tumor cells.
Figure 1: New DOTAMA derivatives bringing glutamine as vector References
1) Medina, M.A.; Sanchez-Jimenez, F.; Marquez, J.; Rodriguez Quesada, A.; Nunez de Castro, I. Mol Cell Biochem
, 113, 1-
15; Souba, W.W. Ann Surg
, 218, 715-28
2) Crich SG, Cabella C, Barge A, Belfiore S, Ghirelli C, Lattuada L, Lanzardo S, Mortillaro A, Tei L, Visigalli M, Forni G, Aime
, 49, 4926-4936
5th Annual Columbus CANstruction® Competition It starts with one can. To feed the hungry. To lift the spirit. To change the world.® architects, engineers, artists or designers What design & build structures made entirely Where Fair Oaks Mall, Columbus, Indiana CANstruction®, a charity committed to ending hunger, is using
REMS Presszangen Mini Zubehör für REMS Mini-Press ACC 3UHVV¿WWLQJ6\VWHPH IU *DVLQVWDOODWLRQHQ GUIHQ QXU PLW GHQ LQ GHU 7DEHOOH JHOE KLQWHUOHJWHQ 3UHVV]DQJHQ JHSUHVVW ZHUGHQ Nationale Regelwerke beachten. 1) Nur Presszangen ab Kennzeichnung „108“ (1. Quartal 2008), „208“ (2. Quartal 2008) usw. einsetzbar. Die Kennzeichnung ist auf jeder Pressbacke gestempelt. 2) Zur Aufnahme geeig