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A peptide targeted contrast agent specific to fibrin-fibronectin complexes for cancer molecular imaging with MRI.

ABSTRACT: A peptide targeted contrast agent, CLT1-(Gd-DTPA), was synthesized for molecular imaging of fibronectin-fibrin complexes in tumor tissue with magnetic resonance imaging (MRI). The T(1) and T(2) relaxivities of CLT1-(Gd-DTPA) were 4.22 and 4.45 mM(-1) s(-1) at 3 T, respectively. The targeted contrast agent specifically bound to tumor tissue and resulted in significant tumor contrast enhancement at a dose of 0.1 mmol Gd/kg for at least 60 min in mice bearing HT-29 human colon carcinoma xenografts as shown in dynamic MR images. In contrast, a control nontargeted contrast agent, Gd(DTPA-BMA), was cleared rapidly with little tumor enhancement 60 min postinjection. Tumor enhancement with CLT1-(Gd-DTPA) was significantly reduced after coinjection with a 3-fold excess of free CLT1 peptide. The preliminary study has shown that CLT1-(Gd-DTPA) can specifically bind to the fibrin-fibronectin complexes in tumor tissues, resulting in significant tumor enhancement. The targeted contrast agent has a potential for cancer molecular imaging with MRI.

SUBMITTER: Ye F

PROVIDER: S-EPMC2651601 | biostudies-other | 2008 Dec

REPOSITORIES: biostudies-other

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Project description:This study sought to develop magnetic resonance contrast agents based on high-density lipoprotein (HDL) nanoparticles to noninvasively visualize intraplaque macrophages and collagen content in mouse atherosclerotic plaques.Macrophages and collagen are important intraplaque components that play central roles in plaque progression and/or regression. In a Reversa mouse model, plaque regression with compositional changes (from high macrophage, low collagen to low macrophage, high collagen) can be induced.This study labeled HDL nanoparticles with amphiphilic gadolinium chelates to enable target-specific imaging of intraplaque macrophages. To render HDL nanoparticles specific for the extracellular matrix, labeled HDL nanoparticles were functionalized with collagen-specific EP3533 peptides (EP3533-HDL) via poly(ethylene glycol) spacers embedded in the HDL lipid layers. The association of nanoparticles with collagen was examined in vitro by optical methods. The in vivo magnetic resonance efficacy of these nanoparticles was evaluated in a Reversa mouse model of atherosclerosis regression. Ex vivo confocal microscopy was applied to corroborate the in vivo findings and to evaluate the fate of the different HDL nanoparticles.All nanoparticles had similar sizes (10 ± 2 nm) and longitudinal relaxivity r1 (9 ± 1 s(-1) mmol/l(-1)). EP3533-HDL showed strong association with collagen in vitro. After 28 days of plaque regression in Reversa mice, EP3533-HDL showed significantly increased (p < 0.05) in vivo magnetic resonance signal in aortic vessel walls (normalized enhancement ratio [NERw] = 85 ± 25%; change of contrast-to-noise ratio [?CNRw] = 17 ± 5) compared with HDL (NERw = -7 ± 23%; ?CNRw = -2 ± 4) and nonspecific control EP3612-HDL (NERw = 4 ± 24%; ?CNRw = 1 ± 6) at 24 h after injection. Ex vivo confocal images revealed the colocalization of EP3533-HDL with collagen. Immunohistostaining analysis confirmed the changes of collagen and macrophage contents in the aortic vessel walls after regression.This study shows that the HDL nanoparticle platform can be modified to monitor in vivo plaque compositional changes in a regression environment, which will facilitate understanding plaque regression and the search for therapeutic interventions.

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A peptide targeted contrast agent specific to fibrin-fibronectin complexes for cancer molecular imaging with MRI.

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