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.
Crich
Simonetta Geninatti
SG
Department of Chemistry IFM, and Center for Molecular Imaging, University of Torino, Torino, Italy.
Lanzardo
Stefania
S
Alberti
Diego
D
Belfiore
Simona
S
Ciampa
Anna
A
Giovenzana
Giovanni B
GB
Lovazzano
Clara
C
Pagliarin
Roberto
R
Aime
Silvio
S
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000737:chemistry / Q000473:pathology; D045744:Cell Line, Tumor / Q000737:chemistry / Q000637:transplantation; D003124:Colorimetry; D003287:Contrast Media / Q000032:analysis*; D004337:Drug Carriers; D006801:Humans; D008051:Lipid Bilayers; D008077:Lipoproteins, LDL / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008113:Liver Neoplasms / Q000737:chemistry / Q000473:pathology; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008546:Melanoma, Experimental / Q000737:chemistry / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal / Q000379:methods; D009368:Neoplasm Transplantation; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods*; D009942:Organometallic Compounds / Q000032:analysis* / Q000138:chemical synthesis / Q000493:pharmacokinetics; D010316:Particle Size; D011485:Protein Binding; D011973:Receptors, LDL / Q000032:analysis* / Q000187:drug effects; D013047:Specific Pathogen-Free Organisms
D003287:Contrast Media; D004337:Drug Carriers; C526378:Gd-AA2TAC17; C526379:Gd-DO3A-diph; D008051:Lipid Bilayers; D008077:Lipoproteins, LDL; D009942:Organometallic Compounds; D011973:Receptors, LDL