In vivo prevention of arterial restenosis with paclitaxel-encapsulated targeted lipid-polymeric nanoparticles
In vivo prevention of arterial restenosis with paclitaxel-encapsulated targeted lipid-polymeric nanoparticles
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DOI：
10.1073/pnas.1115945108
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发表时间：
2011-11-29
影响因子：
11.1
通讯作者：
Farokhzad, Omid C.
中科院分区：
文献类型：
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作者：
Chan, Juliana M.;Rhee, June-Wha;Farokhzad, Omid C.
在最近成功的经皮冠状动脉介入治疗（PCI）治疗冠状动脉疾病（CAD），许多挑战仍然存在。特别是，来自该过程的机械损伤导致广泛的内皮剥脱，暴露下面的富含IV型胶原的基底层，这促进血管内血栓形成和平滑肌增殖。以前，我们报道了IV型胶原蛋白靶向纳米颗粒（NPs）的工程，并证明了其优先定位于动脉损伤部位。在这里，我们开发了一种全身给药的，有针对性的NP系统，以提供抗增殖剂受伤的血管。将约60 nm的脂质聚合物NP用胶原IV靶向肽进行表面官能化并装载紫杉醇。在安全性研究中，靶向的NP没有显示出毒性迹象，并且与紫杉醇相比，最大耐受剂量提高了>= 3.5倍。在使用大鼠颈动脉损伤模型的疗效研究中，在术后第0天和第5天静脉注射紫杉醇（0.3 mg/kg或1 mg/kg）。靶向NP组在2周时导致新生内膜-中膜（N/M）评分低于生理盐水、紫杉醇或非靶向NP的对照组。与假损伤组相比，用靶向NP治疗观察到动脉狭窄减少了50%。改善的耐受性、缓释和血管靶向的组合可能为CAD的管理提供安全有效的选择。
Following recent successes with percutaneous coronary intervention (PCI) for treating coronary artery disease (CAD), many challenges remain. In particular, mechanical injury from the procedure results in extensive endothelial denudation, exposing the underlying collagen IV-rich basal lamina, which promotes both intravascular thrombosis and smooth muscle proliferation. Previously, we reported the engineering of collagen IV-targeting nanoparticles (NPs) and demonstrated their preferential localization to sites of arterial injury. Here, we develop a systemically administered, targeted NP system to deliver an antiproliferative agent to injured vasculature. Approximately 60-nm lipid-polymeric NPs were surface functionalized with collagen IV-targeting peptides and loaded with paclitaxel. In safety studies, the targeted NPs showed no signs of toxicity and a >= 3.5-fold improved maximum tolerated dose versus paclitaxel. In efficacy studies using a rat carotid injury model, paclitaxel (0.3 mg/kg or 1 mg/kg) was i.v. administered postprocedure on days 0 and 5. The targeted NP group resulted in lower neointima-to-media (N/M) scores at 2 wk versus control groups of saline, paclitaxel, or nontargeted NPs. Compared with sham-injury groups, an similar to 50% reduction in arterial stenosis was observed with targeted NP treatment. The combination of improved tolerability, sustained release, and vascular targeting could potentially provide a safe and efficacious option in the management of CAD.