Epidemiological results revealed that there is an inverse correlation between high-density lipoprotein (HDL) cholesterol levels and risks of atherosclerotic cardiovascular disease (ASCVD). probe with HDL nanoparticles when applied to ASCVD, as well as gaps in technology and knowledge required for putting the HDL-targeted therapeutics into full gear. = 47Modest regression of Tedizolid (TR-701) coronary plaque in the individual[56]MDCO-216reconstituted apoAI Milano/POPC complex = 1:1.15 weekly, 20 mg/kg(= 59) placebo (= 67) in statin-treated patientsFailed to produce an incremental plaque regression in statin therapy[62]CER-001reconstituted human apoAI to SPM and DPPG (32:1) = 1:2.710 weekly, 3 mg/kg, in addition to statinsCER-001 (= 135) or placebo (= 137) in patients with ACSFailed to promote regression of coronary atherosclerosis[65]CER-001recombinant human apoAI to SPM and DPPG (32:1) = 1:2.76 weekly, 12 mg/kgplacebo = 113, CER-001 = 100Failed to reduce coronary atherosclerosis on IVUS[64]CSL-111human apoAI with soybean phosphatidylcholine (CSL-111)4 weekly, 40 mg/kg, 80 mg/kg= 111Significant improvement in the plaque characterization index[69]CSL-112plasma-derived apoAI to mixed PCs isolated from soybean = 1:1.4weekly infusions of CSL-112Results to be concluded in 2022CSL-112 are feasible, well tolerated[71] Open in a separate window POPC: palmitoyl-oleoyl phosphatidyl choline; SPM: sphingomyelin; DPPG: dipalmitoylphosphatidyl glycerol; IVUS: intravascular ultrasonography; ACS: acute coronary syndrome; PCs: phosphatidylcholines. 11. rHDL Nanoparticles as a Drug Delivery Vehicle The application of rHDL nanoparticles for delivering therapeutic compounds for the treatment of cancer has been studied extensively [76,77,78]. Recent studies show that rHDL nanoparticle serve as a drug delivery system to deliver compounds efficiently into macrophages and atherosclerotic plaques [79]. To investigate the immunomodulatory drugs for atherosclerosis, several nanoparticles were developed to increase the specificity of the drug delivery. rHDLs were efficiently used to deliver a liver X receptors (LXR) agonist GW3965 to atherosclerotic plaques of Apoe?/? mice [80]. Importantly, rHDLs loaded with GW3965 completely abolished the liver toxicity of GW3965 in a one-week intensive treatment regimen in atherosclerotic mice. The long-term treatment with rHDLs significantly reduced atherosclerotic plaques in Apoe?/? mice [81]. Statins have potent anti-inflammatory functions, but these cannot be fully exploited with oral statin therapy owing to a low systemic bioavailability. Interestingly, an injectable rHDL nanoparticle was synthesized to deliver simvastatin, and the effect of simvastatin-rHDL on atherosclerotic plaques was examined in mice. This study demonstrates that statin-loaded reconstituted HDL nanoparticles improved inflammation in atherosclerotic plaque [82]. More interestingly, nanoparticle-based delivery of simvastatin inhibited plaque macrophage proliferation in Apoe?/? mice with advanced atherosclerotic plaques [83]. rHDL nanoparticles increased the plasma half-life of statins to 20 h. In addition, a recent study showed that rHDL-mediated targeted delivery of the LXR agonist promoted atherosclerosis regression [84]. Arachidonic acid (AA) was engineered into the rHDL complex to increase the efficacy of statins. AA-LT-rHDL (arachidonic acid-lovastatin-rHDL) exhibited lower reactivity with LCAT and more potent inhibition effects on foam cell formation Tedizolid (TR-701) in the presence of LCAT because of less undesired LT leakage during the remodeling of rHDLs induced by LCAT and more cellular drug uptake [85]. In addition, increasing AA concentration in AA-LT-rHDL particles reduced intracellular lipid deposition, decreased intracellular cholesterol esters content, and DiI-oxLDL uptake, and inhibited the expressions of pro-inflammatory cytokines TNF- and IL-6 [85]. Together, these results proved that AA modification prevented the reactivity of LT-rHDL with LCAT, thereby inhibiting the undesired drug leakage during rHDL remodeling induced by LCAT. To better fulfill the targeted-delivery of rHDL, it might be interesting to determine whether the efficacy of the incorporation of AA into LT-rHDL is better than LT-rHDL for the Rabbit polyclonal to TXLNA treatment of atherosclerosis in mice. It would also be intriguing to investigate whether the polyunsaturated fatty acids, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), have better efficacy than AA in preventing LCAT-induced degradation of rHDL. 12. Delivery of Oligonucleotides Using rHDL Nanoparticles HDLs are highly heterogeneous and transport a large variety of lipids, proteins, and microRNAs [86]. Anti-sense nucleotides and Tedizolid (TR-701) siRNA(s) are widely used to modulate gene expression and are being considered for therapeutics of atherosclerosis [87,88,89]. One of the major issues is that.