Nanoparticles loaded with the DNA methyltransferase inhibitor SGI-1027 decrease murine atherosclerosis and inflammation in cultured human macrophages

Aim: The DNA of the atheroma is hypermethylated relative to adjacent healthy vascular tissue. A significant portion of hypermethylated loci in the atheroma DNA map to genes related to macrophage function. Reversing macrophage DNA methylation to physiological levels by targeting DNA methyltransferase (DNMT) activity may therefore slow atherogenesis. Here, the anti-inflammatory and anti-atherogenic activity of macrophage-targeted DNMT inhibitor SGI-1027 were tested. Methods: SGI-1027 was encapsulated into human serum albumin (HSA) nanoparticle (HSANP) functionalized with the PP1 peptide, a macrophage scavenger receptor 1 ligand, fused to a FLAG epitope (S-HSANP-FLAGPP1). Results: Nanoparticle physico-chemical characteristics predicted good marginalization towards the vascular wall, although SGI-1027 encapsulation efficiency was relatively low (~23%). S-HSANP-FLAGPP1 were rapidly internalized compared to non-functionalized and, surprisingly, functionalized void controls, and induced a shift towards an anti-inflammatory profile of secreted cytokines in human THP-1 macrophages. S-HSANP-FLAGPP1 colonized the atheroma and induced a significant ~44% reduction of atherosclerosis burden in the aortic tree of apolipoprotein E (ApoE)-null mice compared to controls. A reduction in aortic root atherosclerosis was observed, although primarily induced by HSANP irrespective of loading or functionalization. No alteration of body weight, non-vascular tissue gross histology, plasma glucose, triglyceride or cholesterol were observed. HSA whether free or structured in nanoparticles, induced a 3–4-fold increase in high-density lipoprotein (HDL) compared to vehicle. Conclusions: Unexpectedly, effects that were likely non-epigenetic and induced by HSA per se were observed. HSANP loaded with SGI-1027 were anti-atherogenic but in an anatomical location-dependent fashion. SGI-1027 displayed a novel anti-inflammatory activity in non-proliferating THP-1 cells, implying that those effects are likely unrelated to DNMT inhibition. HSA elevated HDL per se, thus underlining a possible additional advantage of HSA-based nanocarriers.