Joner Michael, Morimoto Katsumi, Kasukawa Hiroaki, Steigerwald Kristin, Merl Sabine, Nakazawa Gaku, John Michael C, Finn Aloke V, Acampado Eduardo, Kolodgie Frank D, Gold Herman K, Virmani Renu
Deutsches Herzzentrum Muenchen und Medizinische Klinik, Klinikum rechts der Isar, Muenchen, Germany.
Arterioscler Thromb Vasc Biol. 2008 Nov;28(11):1960-6. doi: 10.1161/ATVBAHA.108.170662. Epub 2008 Aug 7.
TRM-484 is a novel drug consisting of nanoparticles of prednisolone with high affinity to chondroitin sulfate proteoglycans (CSPGs). This may allow for neointimal suppression via directed targeting to areas of injury at systemic concentrations low enough to avoid adverse side effects known to occur with oral delivery of steroids.
Atherosclerotic New Zealand white Rabbits were implanted with bare metal stents and randomized to receive intravenous TRM-484 at doses of 1 mg/kg or 0.32 mg/kg starting at the day of stenting and continuing 3 times a week for the duration of the study. Control animals received empty liposomes (placebo) or saline infusion. Stented arterial segments were harvested at 42 days and processed for histomorphometry and immunohistochemistry. Tissue and plasma levels were determined along with confocal microscopic analysis to determine distribution of rhodamine-labeled TRM-484 at various time points. TRM-484 was exclusively observed at sites of stent-induced injury, with absence of drug in contralateral nonstented arteries. Tissue concentration of stented arteries exceeded that of contralateral nonstented arteries by 100-fold 24 hours after administration of 1 mg/kg TRM-484 and resulted in significant reduction of percent stenosis compared to saline and placebo treated rabbits (22.5+/-4.4 versus 31.0+/-8.4 and 29.5+/-8.1%, P<0.03).
TRM-484 at doses of 1 mg/kg resulted in significant suppression of in-stent neointimal growth in atherosclerotic rabbits. Site-specific targeting by this nanoparticle steroid in injured atherosclerotic areas might be a valuable and cost-effective approach for the prevention of in-stent restenosis.
TRM - 484是一种新型药物，由对硫酸软骨素蛋白聚糖（CSPGs）具有高亲和力的泼尼松龙纳米颗粒组成。这可能通过在全身浓度低至足以避免口服类固醇已知的不良副作用的情况下，定向靶向损伤区域来实现对新生内膜的抑制。
给动脉粥样硬化的新西兰白兔植入裸金属支架，并随机分组，从支架植入当天开始，以1mg/kg或0.32mg/kg的剂量静脉注射TRM - 484，每周持续给药3次，直至研究结束。对照动物接受空脂质体（安慰剂）或生理盐水输注。在42天时采集植入支架的动脉节段，进行组织形态计量学和免疫组织化学分析。测定组织和血浆水平，并进行共聚焦显微镜分析，以确定罗丹明标记的TRM - 484在各个时间点的分布。仅在支架诱导损伤的部位观察到TRM - 484，对侧未植入支架的动脉中没有药物。给予1mg/kg TRM - 484后24小时，植入支架动脉的组织浓度比对照侧未植入支架的动脉高100倍，与生理盐水和安慰剂处理的兔子相比，狭窄百分比显著降低（22.5±4.4对31.0±8.4和29.5±8.1%，P<0.03）。
1mg/kg剂量的TRM - 484可显著抑制动脉粥样硬化兔支架内新生内膜的生长。这种纳米颗粒类固醇在损伤的动脉粥样硬化区域的位点特异性靶向可能是预防支架内再狭窄的一种有价值且具有成本效益的方法。
