Specific penetration and accumulation of a homing peptide within atherosclerotic plaques of apolipoprotein E-deficient mice

Abstract

The ability to selectively deliver compounds into atherosclerotic plaques would greatly benefit the detection and treatment of atherosclerotic disease. We describe such a delivery system based on a 9-amino acid cyclic peptide, LyP-1. LyP-1 was originally identified as a tumor-homing peptide that specifically recognizes tumor cells, tumor lymphatics, and tumor-associated macrophages. As the receptor for LyP-1, p32, is expressed in atherosclerotic plaques, we tested the ability of LyP-1 to home to plaques. Fluorescein-labeled LyP-1 was intravenously injected into apolipoprotein E (ApoE)-null mice that had been maintained on a high-fat diet to induce atherosclerosis. LyP-1 accumulated in the plaque interior, predominantly in macrophages. More than 60% of cells released from plaques were positive for LyP-1 fluorescence. Another plaque-homing peptide, CREKA, which binds to fibrinfibronectin clots and accumulates at the surface of plaques, yielded fewer positive cells. Tissues that did not contain plaque yielded only traces of LyP-1 + cells. LyP-1 was capable of delivering intravenously injected nanoparticles to plaques; we observed abundant accumulation of LyP-1-coated superparamagnetic iron oxide nanoparticles in the plaque interior, whereas CREKAnanoworms remained at the surface of the plaques. Intravenous injection of 4-[ cell-penetrating peptide | p32/gC1qR/hyaluronic acid binding protein1 | plaque-associated macrophages | in vivo imaging

Hyaluronic acid-decorated reconstituted high density lipoprotein targeting atherosclerotic lesions

“…Recently, researchers have discovered multiple potential targets preferentially presented on atherosclerotic progress, including some specific inflammatory cells and a number of particular cell surface receptors, etc. Several atherosclerotic lesions-targeted ligands have been developed hitherto, which contain phage display technology-derived special peptides targeting for vascular cellular adhesion molecule-1 (VCAM-1) [4], dextran sulfate for scavenge receptor type-A (SR-A) [5], phosphatidylserine for cluster of differentiation 36 (CD36) [6] and LyP-1 peptide for cell face p32 abundant in foam cell [7], etc. However, those atherosclerotic lesions-targeted ligands were almost exploited in atherosclerotic lesions imaging, but not involved in the lesions-targeted drug delivery for efficient treatment of atherosclerosis yet.…”

Transtumoral targeting enabled by a novel neuropilin-binding peptide

“…LyP-1 homes to tumor lymphatics, tumor cells and tumor macrophages by specifically binding to its receptor p32, a mitochondrial protein expressed on the surface of these cells (Laakkonen et al, 2002;Fogal et al, 2008). LyP-1 also homes to atherosclerotic plaques and penetrates into their interior (Hamzah et al, 2011;Uchida et al, 2011). The presence of the cryptic CendR motif suggests the possibility of secondary binding to NRP1 (and perhaps to NRP2 in the lymphatics) and involvement of the CendR pathway.…”

Hybrid Nanotechnologies for Detection and Synergistic Therapies for Breast Cancer

“…[ 55 ] A major advantage of the CendR system is that by allowing effective extravasation and tissue penetration, a CendR peptide makes more of the target tissue (such as a tumor) available for a therapeutic agent than would be the case with targeting elements that lack the CendR properties. The ability of CendR peptides to promote tissue entry and accumulation of compounds that are not conjugated with the peptide (by-stander effect) provides additional unique advantages: First, it is not necessary to create a new chemical entity to target a drug by CendR peptide co-administration, as is the case when a drug is coupled to a targeting element.…”

“…LyP-1, which has been shown to be a tumor-penetrating peptide that depends on the CendR mechanism, [ 46 ] also homes to atherosclerotic plaques, penetrating into the plaque interior. [ 55 ] Iron oxide NPs and protein cage NPs have been show to enter plaques when coated with LyP-1. [ 55 , 82 ] Moreover, peptides in a panel of heart-homing peptides, which were also found to penetrate into extravascular heart tissue, contain CendR sequences, [ 20 ] and likely also use the CendR…”