Song C, Labhasetwar V, Cui X, Underwood T, Levy R J
Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, USA.
J Control Release. 1998 Jul 31;54(2):201-11. doi: 10.1016/s0168-3659(98)00016-9.
Biodegradable nanoparticles (NP) with a spherical diameter ranging from 70 to 160 nm were investigated for potential usefulness for the local intraluminal therapy of restenosis, the disease process responsible for arterial reobstruction following angioplasty. NPs containing a water-insoluble anti-proliferative agent U-86983 (U-86, Pharmacia and Upjohn, Kalamazoo, MI) were formulated from oil-water emulsions using biodegradable polymers such as poly(lactic acid-co-glycolic acid) (PLGA), and specific additives after particle formation, to enhance arterial retention using either heparin, didodecylmethylammonium bromide (DMAB), or fibrinogen, or combinations. Femoral and carotid arteries of male mongrel dogs were isolated in situ, and were then subjected to a balloon angioplasty. A NP suspension of a predetermined concentration was then infused into the artery for various durations. This was followed by a 30 min restoration of blood flow through the vessel. The arterial segments were excised and analyzed for drug levels. From the drug loading the NP and the drug levels in the artery, the quantity of nanoparticles retained was calculated and expressed as microgram per 10 mg dry arteries. In general, repeated short infusions of nanoparticle suspension (15 s x 4) were two-fold more effective in terms of higher arterial U-86 levels than a single prolonged infusion (60 s). A single 15 s infusion was not significantly different than a 60 s compared to non-modified NPs (39.2 +/- 2.5 and 49.1 +/- 2.4 vs. 21.5 +/- 0.6 micrograms/10 mg mean +/- s.e., respectively). A comparably enhanced NP uptake was noted with a combined heparin/DMAB modification. Increasing the concentration of NP in infusate from 5 to 30 mg ml-1 significantly increased arterial NP uptake level (from 22.5 +/- 3.5 to 83.7 +/- 1.4 micrograms/10 mg). Thus, the results support the view that modified nanoparticles along with optimized infusion conditions could enhance arterial wall drug concentrations of agents to treat restenosis.
研究了直径范围为70至160纳米的球形可生物降解纳米颗粒（NP）在再狭窄局部腔内治疗中的潜在用途，再狭窄是血管成形术后动脉再次阻塞的疾病过程。含有水不溶性抗增殖剂U-86983（U-86，Pharmacia and Upjohn，卡拉马祖，密歇根州）的纳米颗粒由油包水乳液使用可生物降解聚合物如聚（乳酸-共-乙醇酸）（PLGA）以及颗粒形成后使用的特定添加剂制成，以使用肝素、十二烷基二甲基溴化铵（DMAB）或纤维蛋白原或其组合来增强在动脉中的滞留。雄性杂种犬的股动脉和颈动脉在原位分离，然后进行球囊血管成形术。然后将预定浓度的纳米颗粒悬浮液注入动脉不同时间。随后恢复血管血流30分钟。切除动脉段并分析药物水平。根据纳米颗粒的载药量和动脉中的药物水平，计算保留的纳米颗粒数量并表示为每10毫克干动脉中的微克数。一般来说，重复短时间注入纳米颗粒悬浮液（15秒×4次）在提高动脉U-86水平方面比单次长时间注入（60秒）有效两倍。与未修饰的纳米颗粒相比，单次15秒注入与60秒注入没有显著差异（分别为39.2±2.5和49.1±2.4微克/10毫克平均值±标准误，而未修饰的纳米颗粒为21.5±0.6微克/10毫克）。在肝素/DMAB联合修饰下观察到纳米颗粒摄取有相当程度的增强。将注入液中纳米颗粒的浓度从5毫克/毫升增加到30毫克/毫升显著提高了动脉纳米颗粒摄取水平（从22.5±3.5微克/10毫克提高到83.7±1.4微克/10毫克）。因此，结果支持这样的观点，即修饰的纳米颗粒以及优化的注入条件可以提高治疗再狭窄药物在动脉壁中的浓度。
