MR and fluorescent imaging of low-density lipoprotein receptors

Hui Li, Brian D. Gray, Ian Corbin, Corinna Lebherz, Hoon Choi, Sissel Lund-Katz, James M. Wilson, Jerry D. Glickson, Rong Zhou

Research output: Contribution to journalArticle

72 Scopus citations

Abstract

Over-expression of low-density lipoprotein receptors (LDLRs) occurs in many types of malignancies and is related to the requirement for lipids for rapid proliferation of the tumors. On the other hand, LDLRs that are unable to bind LDL are found on hepatocytes of patients with familial hypercholesterolemia (FH), a genetic disease that leads to premature atherosclerosis and death. The highly selective binding of LDL to LDLR makes these particles ideal carriers of therapeutic and diagnostic contrast agents into the targeted cells. The objectives of this paper are to examine whether a prototype contrast agent (PTIR267) with dual detection properties is suitable for labeling of LDL particles for in vivo detection of LDLR by magnetic resonance imaging (MRI) and for in vitro monitoring of cellular localization by confocal fluorescence microscopy. PTIR267 is a lipophilic GdDTPA derivative conjugated to a fluorescent dye. The conjugated dye molecule makes the probe sufficiently water soluble to allow labeling of LDL by a brief incubation of LDL with PTIR267 dissolved in PBS at 37°C (mole ratio LDL: PTIR267 = 0.09:1). The molar relaxivity of PTIR267 in saline is 26 mM -1s -1. Specific LDLR-mediated uptake of PTIR267-labeled LDL was demonstrated in vitro by confocal fluorescence imaging of B16 melanoma cells using confocal fluorescence imaging. In vivo uptake of PTIR267-labeled LDL by a subcutaneously implanted B16 melanoma in mice leads to 30% decrease in longitudinal relaxation time (T 1) in the tumor. In vivo uptake of PTIR267-labeled LDL leads to 70% decrease in T 1 in a normal C57BL/6 mouse liver; however, in the liver of LDL receptor gene knockout (LDLr-/-) mice with C57BL/6 background, only 12% decrease in T 1 is observed. The dual fluorescence and MR imaging properties of PTIR267, combined with the ease of LDL labeling, suggest that it will be a useful tool for optimization of LDLR-targeted cancer diagnosis or therapy and for monitoring the efficacy of gene therapy of FH.

Original languageEnglish (US)
Pages (from-to)1251-1259
Number of pages9
JournalAcademic radiology
Volume11
Issue number11
DOIs
StatePublished - Nov 1 2004

Keywords

  • B16 melanoma
  • Low-density lipoprotein
  • MR imaging
  • PTIR267
  • cancer
  • confocal fluorescent microscopy
  • familial hypercholesterolemia
  • gadolinium
  • low-density lipoprotein receptor

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

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  • Cite this

    Li, H., Gray, B. D., Corbin, I., Lebherz, C., Choi, H., Lund-Katz, S., Wilson, J. M., Glickson, J. D., & Zhou, R. (2004). MR and fluorescent imaging of low-density lipoprotein receptors. Academic radiology, 11(11), 1251-1259. https://doi.org/10.1016/j.acra.2004.08.007