Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
J Control Release. 2010 Mar 19;142(3):332-8. doi: 10.1016/j.jconrel.2009.11.007. Epub 2009 Nov 17.
Though stents are deployed in diseased arteries drug distribution has only been quantified in intact, non-diseased vessels. We correlated steady-state arterial drug distribution with tissue ultrastructure and composition in abdominal aortae from atherosclerotic human autopsy specimens and rabbits with lesions induced by dietary manipulation and controlled injury. Paclitaxel, everolimus, and sirolimus depositions in the human aortae were maximal in the media and scaled inversely with lipid content. Net tissue paclitaxel and everolimus levels were indistinguishable in mildly injured rabbit arteries independent of diet. Yet, serial sectioning of cryopreserved arterial segments demonstrated a differential transmural deposition pattern that was amplified with disease and correlated with the expression of their intracellular targets, tubulin and FKBP-12. Tubulin distribution and paclitaxel binding increased with vascular injury and macrophage infiltration, and were reduced with lipid content. Sirolimus analogs and their specific binding target FKBP-12 were less sensitive to alterations of diet in mildly injured arteries, presumably reflecting a faster transient response of FKBP-12 to injury. The data demonstrate that disease-induced changes in the distribution of drug-binding proteins and interstitial lipid alter the distribution of these drugs, forcing one to consider how disease might affect the evaluation and efficacy of the local release of these and like compounds.
尽管支架已被用于病变动脉，但药物的分布仅在完整、无病变的血管中进行了量化。我们将稳态动脉药物分布与动脉粥样硬化人类尸检标本和通过饮食操作和控制损伤诱导病变的兔腹主动脉的组织超微结构和组成进行了相关性分析。紫杉醇、依维莫司和西罗莫司在人主动脉中的沉积在中膜中最大，并与脂质含量成反比。无论饮食如何，轻度损伤兔动脉中净组织紫杉醇和依维莫司水平无差异。然而，冷冻保存的动脉段的连续切片显示出不同的跨壁沉积模式，这种模式随着疾病的发展而放大，并与细胞内靶点微管蛋白和 FKBP-12 的表达相关。微管蛋白分布和紫杉醇结合随血管损伤和巨噬细胞浸润而增加，并随脂质含量减少而减少。西罗莫司类似物及其特异性结合靶标 FKBP-12 在轻度损伤的动脉中对饮食的变化不太敏感，这可能反映了 FKBP-12 对损伤的快速瞬时反应。这些数据表明，疾病引起的药物结合蛋白和间质脂质分布的变化改变了这些药物的分布，这使得人们不得不考虑疾病如何影响这些药物和类似化合物的局部释放的评估和疗效。
