Rational Design of Lovastatin-Loaded Spherical Reconstituted High Density Lipoprotein for Efficient and Safe Anti-Atherosclerotic Therapy.
Cuiping JiangZitong QiYuqi TangHengbo JiaZhuoting LiWenli ZhangJianping LiuPublished in: Molecular pharmaceutics (2019)
Reconstituted high density lipoprotein (rHDL) is a biomimetic nanoparticle with plaque targeting and anti-atherosclerotic efficacy. In this work, we report on a strategy to rational design of lovastatin (LOV)-loaded spherical rHDL (LOV-s-rHDL) for efficient and safe anti-atherosclerotic therapy. Briefly, three LOV-s-rHDLs were formulated with LOV/s-rHDL at ratios of 8:1, 10:1, and 15:1 upon their respective median-effect values ( Dm). The combined inhibitory effect between LOV and s-rHDL of different LOV-s-rHDL formulations on DiI-labeled oxLDL internalization was systemically investigated in RAW 264.7 cells based on the median-effect principle. Median-effect analysis demonstrated that the optimized LOV-s-rHDL was formulated with a ratio of 10:1 ( Dm LOV: Dm s-rHDL), in which LOV and s-rHDL carrier showed the best synergistic effect, presumably ascribed to their inhibitory effect on CD36 and SR-A expression according to the Western blot analysis. In vivo pharmacodynamics studies showed that the optimized LOV-s-rHDL displayed the most pronounced anti-atherosclerotic effect on decreasing plaque area and reducing the MMP level following an 8-week dosing regimen. In vivo atherosclerotic plaque targeting analysis revealed that s-rHDL had potent plaque targeting efficacy, probably owing to the interaction between apoA-I and scavenger receptor B-I. Furthermore, we observed that the optimized LOV-s-rHDL exhibited a favorable safety profile as evidenced by the results of a hemolysis assay, cell cytotoxicity study, and in vivo safety test. Collectively, the rational design of the biomimetic LOV-s-rHDL based on the median-effect analysis provides an efficient strategy to achieve a synergistic and safe anti-atherosclerotic therapy.
Keyphrases
- high density
- coronary artery disease
- cancer therapy
- stem cells
- drug delivery
- type diabetes
- poor prognosis
- randomized controlled trial
- high resolution
- oxidative stress
- cell therapy
- signaling pathway
- glycemic control
- cell proliferation
- positron emission tomography
- case control
- cell cycle arrest
- single molecule
- high speed