Osteopontin-Targeted and PPARδ-Agonist-Loaded Nanoparticles Efficiently Reduce Atherosclerosis in Apolipoprotein E^–/– Mice

Abstract

Atherosclerosis is the leading cause of vascular pathologies and acute cardiovascular events worldwide. Early theranostics of atherosclerotic plaque formation is critical for the prevention of associated cardiovascular complications. Osteopontin (OPN) expression in vascular smooth muscle cells (VSMCs) has been reported as a promising molecular target for the diagnosis and treatment of atherosclerotic plaques. The PPARδ agonist GW1516 has been shown to inhibit VSMC migration and apoptosis. However, GW1516 has low aqueous solubility and poor oral bioavailability, which are major obstacles to its broad development and application. In this study, GW1516@NP-OPN, which is anti-OPN-targeted and loaded with the PPARδ agonist GW1516, was synthesized using a nanoprecipitation method. The uptake of GW1516@NP-OPN was examined using fluorescence microscopy and flow cytometry assay in VSMC in vitro models. Using the Transwell assay and acridine orange/ethidium bromide staining methods, we observed that the inhibition of VSMCS migration and apoptosis was significantly higher in cells treated with GW1516@NP-OPN than those treated with free GW1516. The western blot assay further confirmed that GW1516@NP-OPN can increase FAK phosphorylation and TGF-βprotein expression. The effect of NPs was further tested in vivo. The atherosclerotic lesion areas were greatly decreased by GW1516@NP-OPN compared with the free drug treatment in apolipoprotein E –/– mice models. Consequently, our results showed that GW1516@NP-OPN stabilizes the PPARδ agonist aqueous formulation, improves its anti-plaque formation activities in vivo and in vitro, and can therefore be recommended for further development as a potential anti-atherosclerotic nanotherapy.

Nanomaterials Responsive to Endogenous Biomarkers for Cardiovascular Disease Theranostics

“…Importantly, the biomarker OPN can provide guidance for imaging-guided treatment. [136,137] For example, Cao and coworkers reported a theranostic nanoprobe (TPZ/IR780@HSA-OPN, TIHO) consisting of hypoxia-activatable tirapazamine (TPZ) as a foam cell inhibitor, IR780 as a photosensitizer, and human serum albumin (HSA)-OPN targeting peptide (HSA-OPN) as the skeleton for imaging and treatment of vulnerable plaques (Figure 9F). [138] OPN was expressed specifically in ox-LDL-stimulated foamy macrophages (Figure 9G).…”

Advances in the treatment of atherosclerosis with ligand‐modified nanocarriers

“…designed and constructed nanoparticles (GW1516@NP‐OPN) coupled with anti‐OPN antibodies, which encapsulated agonists of PPARδ receptors GW1516, and demonstrated efficiently suppressing the migration and apoptosis of VSMCs induced by ox‐LDL. [ 148 ] Suggestively, the experimental results show that antibody modification affects drug release from the nanoparticle system. Conjugation of anti‐OPN antibody leads to higher micelle density and covalent binding of micelles to antibody may alter the hydrophilic end structure and increase the size of the interstitial space leading to slower drug release from OPN‐targeted NPs than non‐targeted NPs.…”

Osteopontin: A Bone-Derived Protein Involved in Rheumatoid Arthritis and Osteoarthritis Immunopathology

“…Moreover, OPN is secreted by hepatic lipid-associated macrophages implicated in non-alcoholic fatty liver disease related to obesity [ 58 ]. On the other hand, it has been observed that OPN is expressed in vascular smooth muscle cells in different stages of atherosclerosis, and angiotensin-II induces its expression [ 59 , 60 ].…”