title: RGD peptide functionalized and reconstituted high-density lipoprotein nanoparticles as a versatile and multimodal tumor targeting molecular imaging probe.
abstract: High density lipoprotein (HDL), an endogenous nanoparticle, transports fat throughout the body and is capable of transferring cholesterol from atheroma in the vessel wall to the liver. In the present study, we utilized HDL as a multimodal nanoparticle platform for tumor targeting and imaging via nonspecific accumulation and specific binding to angiogenically activated blood vessels. We reconstituted HDL (rHDL) with amphiphilic gadolinium chelates and fluorescent dyes. To target angiogenic endothelial cells, rHDL was functionalized with alphavbeta3-integrin-specific RGD peptides (rHDL-RGD). Nonspecific RAD peptides were conjugated to rHDL nanoparticles as a control (rHDL-RAD). It was observed in vitro that all 3 nanoparticles were phagocytosed by macrophages, while alphavbeta3-integrin-specific rHDL-RGD nanoparticles were preferentially taken up by endothelial cells. The uptake of nanoparticles in mouse tumors was evaluated in vivo using near infrared (NIR) and MR imaging. All nanoparticles accumulated in tumors but with very different accumulation/binding kinetics as observed by NIR imaging. Moreover, confocal microscopy revealed rHDL-RGD to be associated with tumor endothelial cells, while rHDL and rHDL-RAD nanoparticles were mainly found in the interstitial space. This study demonstrates the ability to reroute HDL from its natural targets to tumor blood vessels and its potential for multimodal imaging of tumor-associated processes.
authors.affiliation: Translational and Molecular Imaging Institute, Department of Radiology and Medicine, Mt. Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Peter A
authors.initials: PA
authors.lastname: Jarzyna
authors.forename: Geralda A F
authors.initials: GA
authors.lastname: van Tilborg
authors.forename: Van Anh
authors.initials: VA
authors.lastname: Nguyen
authors.forename: David P
authors.initials: DP
authors.lastname: Cormode
authors.forename: Ahmed
authors.initials: A
authors.lastname: Klink
authors.forename: Arjan W
authors.initials: AW
authors.lastname: Griffioen
authors.forename: Gwendalyn J
authors.initials: GJ
authors.lastname: Randolph
authors.forename: Edward A
authors.initials: EA
authors.lastname: Fisher
authors.forename: Willem J M
authors.initials: WJ
authors.lastname: Mulder
authors.forename: Zahi A
authors.initials: ZA
authors.lastname: Fayad
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000737:chemistry; D008264:Macrophages / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D057054:Molecular Imaging; D015335:Molecular Probes; D053758:Nanoparticles; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000175:diagnosis* / Q000378:metabolism; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism; D010587:Phagocytosis; D012512:Sarcoma, Ewing / Q000098:blood supply* / Q000378:metabolism; D019265:Spectroscopy, Near-Infrared; D014018:Tissue Distribution; D014471:Umbilical Veins / Q000166:cytology
chemical_list: D039302:Integrin alphaVbeta3; D008075:Lipoproteins, HDL; D015335:Molecular Probes; D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid