Magnetic resonance imaging detection of tumor cells by targeting low-density lipoprotein receptors with Gd-loaded low-density lipoprotein particles.

Gd-DO3A-diph and Gd-AAZTAC17 are lipophilic magnetic resonance imaging (MRI) agents that display high affinity for low-density lipoprotein (LDL) particles. However, on binding to LDL, Gd-DO3A-diph shows a decreased hydration that results in a lower enhancement of water proton relaxation rate. Conversely, Gd-AAZTAC17 displays a strong relaxation enhancement at the imaging fields. Each LDL particle can load up to 100 and 400 UNITS of Gd-DO3A-diph and Gd-AAZTAC17, respectively. Their LDL adducts are taken up by human hepatoblastoma G2 (HepG2) and melanoma B16 tumor cells when added to the incubation medium. T(1) measurements of the labeled cells indicate that Gd-AAZTAC17 is significantly more efficient than Gd-DO3A-diph. Furthermore, it has been found that HepG2 hepatoma cells can internalize higher amounts of Gd-AAZTAC17 than B16 cells and the involvement of LDL receptors (LDLRs) has been demonstrated in competition assays with free LDL. Gd-AAZTAC17/LDL adduct proved to be an efficient probe in the magnetic resonance (MR) visualization of subcutaneous tumors in animal models obtained by injecting B16 melanoma cells into the right flank of mice. Finally, confocal microscopy validation of the distribution of LDL-based probes in the tumor has been obtained by doping the Gd-AAZTAC17/LDL adduct with a fluorescent phospholipid moiety.

[1]  K. Fung,et al.  Circumvention of multidrug resistance and reduction of cardiotoxicity of doxorubicin in vivo by coupling it with low density lipoprotein. , 2002, Life sciences.

[2]  E. Reddi,et al.  Role of delivery vehicles for photosensitizers in the photodynamic therapy of tumours. , 1997, Journal of photochemistry and photobiology. B, Biology.

[3]  M. Botta,et al.  1H and 17O-NMR relaxometric investigations of paramagnetic contrast agents for MRI. Clues for higher relaxivities , 1999 .

[4]  J. Bulte,et al.  Magnetic resonance imaging of cell surface receptors using targeted contrast agents. , 2004, Current pharmaceutical biotechnology.

[5]  F. Wuest,et al.  Labeling of low-density lipoproteins using the 18F-labeled thiol-reactive reagent N-[6-(4-[18F]fluorobenzylidene)aminooxyhexyl]maleimide. , 2007, Nuclear medicine and biology.

[6]  G. Schonfeld,et al.  Regulation of low density lipoprotein receptor gene expression in HepG2 and Caco2 cells by palmitate, oleate, and 25-hydroxycholesterol. , 1995, Journal of lipid research.

[7]  Britton Chance,et al.  Carbocyanine labeled LDL for optical imaging of tumors1 , 2004 .

[8]  Shelton D Caruthers,et al.  Nanotechnological applications in medicine. , 2007, Current opinion in biotechnology.

[9]  Z. Fayad,et al.  Magnetic resonance imaging of atherosclerosis by targeting extracellular matrix deposition with Gadofluorine M. , 2007, Contrast media & molecular imaging.

[10]  V. Fuster,et al.  MRI to detect atherosclerosis with gadolinium‐containing immunomicelles targeting the macrophage scavenger receptor , 2006, Magnetic resonance in medicine.

[11]  Raymond A. Firestone.  Low-Density Lipoprotein as a Vehicle for Targeting Antitumor Compounds to Cancer Cells , 1994 .

[12]  C. Yuan,et al.  Development of a lipoprotein based molecular imaging MR contrast agent for the noninvasive detection of early atherosclerotic disease , 2004, The International Journal of Cardiovascular Imaging.

[13]  M. Botta,et al.  Ternary Gd(III)L-HSA adducts: evidence for the replacement of inner-sphere water molecules by coordinating groups of the protein. Implications for the design of contrast agents for MRI , 2000, JBIC Journal of Biological Inorganic Chemistry.

[14]  K. Wasan,et al.  Potential role of the low-density lipoprotein receptor family as mediators of cellular drug uptake. , 2004, Advanced drug delivery reviews.

[15]  Eliana Gianolio,et al.  Insights into the use of paramagnetic Gd(III) complexes in MR‐molecular imaging investigations , 2002, Journal of magnetic resonance imaging : JMRI.

[16]  K. Fung,et al.  Low density lipoprotein as a targeted carrier for doxorubicin in nude mice bearing human hepatoma HepG2 cells. , 2001, Life sciences.

[17]  R. Frants,et al.  Heparan sulphate proteoglycans are involved in the lipoprotein lipase-mediated enhancement of the cellular binding of very low density and low density lipoproteins. , 1992, Biochemical and biophysical research communications.

[18]  M. Brown,et al.  Receptor-mediated endocytosis: insights from the lipoprotein receptor system. , 1979, Proceedings of the National Academy of Sciences of the United States of America.

[19]  V. Lorusso,et al.  Cellular labeling with Gd(III) chelates: only high thermodynamic stabilities prevent the cells acting as 'sponges' of Gd3+ ions. , 2006, Contrast media & molecular imaging.

[20]  M. Botta,et al.  Gd(III)-BASED CONTRAST AGENTS FOR MRI , 2005 .

[21]  M. Neeman,et al.  Magnetic resonance imaging visualization of hyaluronidase in ovarian carcinoma. , 2005, Cancer research.

[22]  Hui Li,et al.  Ligand conjugated low-density lipoprotein nanoparticles for enhanced optical cancer imaging in vivo. , 2007, Journal of the American Chemical Society.

[23]  R Weissleder,et al.  Molecular imaging. , 2009, Radiology.

[24]  G. Cravotto,et al.  How to determine free Gd and free ligand in solution of Gd chelates. A technical note. , 2006, Contrast media & molecular imaging.

[25]  Britton Chance,et al.  Low-density lipoprotein reconstituted by pyropheophorbide cholesteryl oleate as target-specific photosensitizer. , 2002, Bioconjugate chemistry.

[26]  Klaas Nicolay,et al.  Lipid‐based nanoparticles for contrast‐enhanced MRI and molecular imaging , 2006, NMR in biomedicine.

[27]  S. Laurent,et al.  Paramagnetic liposomes containing amphiphilic bisamide derivatives of Gd-DTPA with aromatic side chain groups as possible contrast agents for magnetic resonance imaging , 2005, European Biophysics Journal.

[28]  Eliana Gianolio,et al.  [Gd-AAZTA]-: a new structural entry for an improved generation of MRI contrast agents. , 2004, Inorganic chemistry.

[29]  H. Oppelaar,et al.  Receptor-mediated uptake of low-density lipoprotein by B16 melanoma cells in vitro and in vivo in mice. , 1996, British Journal of Cancer.

[30]  R. Sharma,et al.  Evaluation of potential tracer ability of (99m)Tc-labeled acetylated LDL for scintigraphy of LDL-scavenger receptor sites of macrophageal origin. , 2001, Nuclear medicine and biology.

[31]  E. Gianolio,et al.  Relaxometric and modelling studies of the binding of a lipophilic Gd-AAZTA complex to fatted and defatted human serum albumin. , 2007, Chemistry.

[32]  Zahi A. Fayad,et al.  Molecular, cellular and functional imaging of atherothrombosis , 2004, Nature Reviews Drug Discovery.

[33]  J. Glickson,et al.  Near-infrared optical imaging of B16 melanoma cells via low-density lipoprotein-mediated uptake and delivery of high emission dipole strength tris[(porphinato)zinc(II)] fluorophores. , 2005, Bioconjugate chemistry.

[34]  Peter Caravan,et al.  Strategies for increasing the sensitivity of gadolinium based MRI contrast agents. , 2006, Chemical Society reviews.

[35]  Rong Zhou,et al.  Low-density lipoprotein nanoparticles as magnetic resonance imaging contrast agents. , 2006, Neoplasia.

[36]  Hui Li,et al.  Rerouting lipoprotein nanoparticles to selected alternate receptors for the targeted delivery of cancer diagnostic and therapeutic agents. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[37]  R. Zhou,et al.  MR and fluorescent imaging of low-density lipoprotein receptors. , 2004, Academic radiology.