Abstract
Atherosclerosis is a major cardiovascular disease worldwide, that could benefit from innovative nanomedicine imaging tools and treatments. In this perspective, we here studied, by fluorescence imaging in ApoE-/- mice, the biodistribution of non-functionalized and RXP470.1-targeted nanostructured lipid carriers (NLC) loaded with DiD dye. RXP470.1 specifically binds to MMP12, a metalloprotease that is over-expressed by macrophages residing in atherosclerotic plaques. Physico-chemical characterizations showed that RXP-NLC (about 105 RXP470.1 moieties/particle) displayed similar features as non-functionalized NLC in terms of particle diameter (about 60-65 nm), surface charge (about −5 — −10 mV), and colloidal stability. In vitro inhibition assays demonstrated that RXP-NLC conserved a selectivity and affinity profile, which favored MMP-12. In vivo data indicated that NLC and RXP-NLC presented prolonged blood circulation and accumulation in atherosclerotic lesions in a few hours. Twenty-four hours after injection, particle uptake in atherosclerotic plaques of the brachiocephalic artery was similar for both nanoparticles, as assessed by ex vivo imaging. This suggests that the RXP470.1 coating did not significantly induce an active targeting of the nanoparticles within the plaques. Overall, NLCs appeared to be very promising nanovectors to efficiently and specifically deliver imaging agents or drugs in atherosclerotic lesions, opening avenues for new nanomedicine strategies for cardiovascular diseases.
Highlights
Lipid-core nanocarriers have been developed since the 1990s, initiated by the groups of Müller [1,2] and Gasco [3]
To obtain RXP-Nanostructured lipid carriers (NLC), RXP470.1 pseudo-peptide containing a maleimide group (RXP470.1-PEG2 NH2 -Mal (4), see Supplementary Information for detailed synthesis) was coupled through thioether linkage to DiD-loaded NLC previously functionalized with thiol-protected groups (NLC-S-S-Pyr)
The deprotection of the 2-pyridil-dithio functions was performed in the presence of DTT (Figure 1a) before grafting of RXP470.1-maleimide pseudo-peptide (Figure 1b) to yield the RXP470-modified
Summary
Lipid-core nanocarriers (typically 50–300 nm diameter) have been developed since the 1990s, initiated by the groups of Müller [1,2] and Gasco [3]. They are colloidal dispersions comprising of lipid core nanodroplets stabilized in aqueous buffer by a single layer of surfactants (e.g., phospholipids, poly(ethylene glycol)-based (PEGylated) surfactants, amphiphilic saccharides). From originally pure solid lipid core nanoparticles, the addition of liquid lipids to design nanostructured lipid carriers has improved drug payload and colloidal stability of the objects, with better control over the release of active ingredients [4]. Lipid nanoparticles including NLC can be characterized by a set of physicochemical techniques providing morphological, structural, core crystallinity, colloidal stability, and drug payload information [10], which can be used to tailor drug release kinetics [11]
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