Chan Jennifer W, Lewis Daniel R, Petersen Latrisha K, Moghe Prabhas V, Uhrich Kathryn E
Department of Biomedical Engineering, Rutgers University, 599 Taylor Road, Piscataway, NJ 08854, USA.
Department of Chemical and Biochemical Engineering, Rutgers University, 98 Brett Road, Piscataway, NJ 08854, USA.
Biomaterials. 2016 Apr;84:219-229. doi: 10.1016/j.biomaterials.2015.12.033. Epub 2016 Jan 4.
While the development of second- and third-generation drug-eluting stents (DES) have significantly improved patient outcomes by reducing smooth muscle cell (SMC) proliferation, DES have also been associated with an increased risk of late-stent thrombosis due to delayed re-endothelialization and hypersensitivity reactions from the drug-polymer coating. Furthermore, DES anti-proliferative agents do not counteract the upstream oxidative stress that triggers the SMC proliferation cascade. In this study, we investigate biocompatible amphiphilic macromolecules (AMs) that address high oxidative lipoprotein microenvironments by competitively binding oxidized lipid receptors and suppressing SMC proliferation with minimal cytotoxicity. To determine the influence of nanoscale assembly on proliferation, micelles and nanoparticles were fabricated from AM unimers containing a phosphonate or carboxylate end-group, a sugar-based hydrophobic domain, and a hydrophilic poly(ethylene glycol) domain. The results indicate that when SMCs are exposed to high levels of oxidized lipid stimuli, nanotherapeutics inhibit lipid uptake, downregulate scavenger receptor expression, and attenuate scavenger receptor gene transcription in SMCs, and thus significantly suppress proliferation. Although both functional end-groups were similarly efficacious, nanoparticles suppressed oxidized lipid uptake and scavenger receptor expression more effectively compared to micelles, indicating the relative importance of formulation characteristics (e.g., higher localized AM concentrations and nanotherapeutic stability) in scavenger receptor binding as compared to AM end-group functionality. Furthermore, AM coatings significantly prevented platelet adhesion to metal, demonstrating its potential as an anti-platelet therapy to treat thrombosis. Thus, AM micelles and NPs can effectively repress early stage SMC proliferation and thrombosis through non-cytotoxic mechanisms, highlighting the promise of nanomedicine for next-generation cardiovascular therapeutics.
虽然第二代和第三代药物洗脱支架（DES）的发展通过减少平滑肌细胞（SMC）增殖显著改善了患者预后，但DES也与晚期支架血栓形成风险增加有关，这是由于再内皮化延迟以及药物聚合物涂层引起的超敏反应。此外，DES抗增殖剂无法对抗触发SMC增殖级联反应的上游氧化应激。在本研究中，我们研究了具有生物相容性的两亲性大分子（AM），其通过竞争性结合氧化脂质受体并以最小的细胞毒性抑制SMC增殖来应对高氧化脂蛋白微环境。为了确定纳米级组装对增殖的影响，由含有膦酸酯或羧酸酯端基、糖基疏水结构域和亲水聚乙二醇结构域的AM单体制备了胶束和纳米颗粒。结果表明，当SMC暴露于高水平的氧化脂质刺激时，纳米治疗剂可抑制脂质摄取、下调清道夫受体表达并减弱SMC中清道夫受体基因转录，从而显著抑制增殖。尽管两种功能性端基同样有效，但与胶束相比，纳米颗粒更有效地抑制氧化脂质摄取和清道夫受体表达，这表明与AM端基功能相比，制剂特性（如更高的局部AM浓度和纳米治疗稳定性）在清道夫受体结合中的相对重要性。此外，AM涂层显著防止血小板粘附于金属，证明了其作为抗血小板疗法治疗血栓形成的潜力。因此，AM胶束和纳米颗粒可通过非细胞毒性机制有效抑制早期SMC增殖和血栓形成，突出了纳米医学在下一代心血管治疗中的前景。
