Lesion complexity determines arterial drug distribution after local drug delivery.
Lesion complexity determines arterial drug distribution after local drug delivery.
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DOI：
10.1016/j.jconrel.2009.11.007
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发表时间：
2010-03-19
影响因子：
10.8
通讯作者：
Edelman, Elazer R.
中科院分区：
文献类型：
--
作者：
Tzafriri, Abraham R.;Vukmirovic, Neda;Kolachalama, Vijaya B.;Astafieva, Irina;Edelman, Elazer R.
虽然支架被部署在病变的动脉中，但药物分布仅在完整的非病变血管中进行了量化。我们从动脉粥样硬化的人体尸检标本和饮食操纵和受控损伤所致损伤的兔的腹主动脉中，将稳态动脉药物分布与组织超微结构和成分相关联。紫杉醇、伊维洛莫司和西罗莫司在人的主动脉中沉积最多，与脂质含量成反比。与饮食无关，在轻度损伤的兔动脉中，净组织紫杉醇和埃博利莫斯的水平是无法区分的。然而，冷冻保存的动脉节段的连续切片显示出一种不同的跨壁沉积模式，这种沉积模式随着疾病的放大而扩大，并与其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量随着血管损伤和巨噬细胞的增多而增加，随着脂质含量的增加而减少。西罗莫司类似物及其特异性结合靶点FKBP-12对轻度损伤动脉中饮食的变化不那么敏感，推测反映了FKBP-12对损伤的更快瞬时反应。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，迫使人们考虑疾病可能如何影响这些和类似化合物局部释放的评估和疗效。
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 deposition in human aortae was 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 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 analogues 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 local release of these and like compounds.
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影响因子：
10.8
作者：
Balakrishnan, Brinda;Dooley, John;Kopia, Gregory;Edelman, Elazer R.
通讯作者：
Edelman, Elazer R.
影响因子：
37.8
作者：
Farb, A;Heller, PF;Virmani, R
通讯作者：
Virmani, R
影响因子：
20.1
作者：
PENN, MS;KOELLE, MR;CHISOLM, GM
通讯作者：
CHISOLM, GM
影响因子：
20.1
作者：
Aikawa, M;Rabkin, E;Libby, P
通讯作者：
Libby, P
影响因子：
37.8
作者：
Kastrati, A;Dibra, A;Schöming, A
通讯作者：
Schöming, A