Assessing the targeting and fate of cathepsin k antibody-modified nanoparticles in a rat abdominal aortic aneurysm model
Assessing the targeting and fate of cathepsin k antibody-modified nanoparticles in a rat abdominal aortic aneurysm model
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DOI：
10.1016/j.actbio.2020.05.037
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发表时间：
2020-08-01
影响因子：
9.7
通讯作者：
Ramamurthi, Anand
中科院分区：
文献类型：
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作者：
Camardo, Andrew;Carney, Sarah;Ramamurthi, Anand
腹主动脉瘤(AAA)是一种典型的蛋白水解性心血管疾病，是主动脉壁的局限性扩张。长期上调和过度表达的蛋白水解酶不可逆转地降解和破坏弹性基质，这为主动脉壁提供了拉伸和回缩特性。成人血管平滑肌细胞天生不能产生足够的弹性蛋白来形成新的弹性纤维来自然修复主动脉壁，AAA继续生长直到致命破裂。对于破裂风险较高的AAA保留手术干预措施，但目前还没有针对仍在增长的小AAA的治疗方法。我们以前已经开发了基质再生的聚乙二醇聚乳酸纳米粒(NPs)，具有促弹性和抗蛋白质降解的特性，与释放的治疗药物协同作用。然而，需要制定战略，有效地将这些核蛋白送到疾病现场，以利用这些好处。我们已经确定组织蛋白酶K是一种在AAA组织中过度表达的蛋白酶，是基于抗体的主动靶向的潜在底物。我们试图评估NPs与NP表面结合的抗组织蛋白酶K抗体(CAT K Ab-NPs)的安全性和生物相容性，然后在大鼠AAA模型中评估它们在靶向主动脉和非靶器官中的生物分布和滞留。在这项工作中，我们证明了CAT K Ab-NPs可以选择性地靶向大鼠腹主动脉动脉瘤模型。然而，在非靶器官中存在不必要的NP摄取和滞留，这可以在未来的工作中解决。尽管如此，组织蛋白酶K仍然是AAA模型中主动递送NPs的一个可行的靶点。意义陈述我们以前开发了弹性基质再生聚合物纳米粒(NPs)，但需要有效靶向疾病部位的策略。组织蛋白K是一种在腹主动脉瘤中过度表达的蛋白酶，其抗体已经连接到NP表面，作为靶向部分。在这项工作中，我们评估了NP在动脉瘤大鼠模型中的安全性和体内生物分布，并证明了阳性靶向和在主动脉壁内滞留长达2周。(C)2020年，由爱思唯尔有限公司代表Acta Materialia Inc.出版。
Abdominal aortic aneurysms (AAAs), a prototypic proteolytic cardiovascular disorder, are localized expansions of the aortal wall. Chronically upregulated and overexpressed proteases irreversibly degrade and disrupt the elastic matrix, which provides stretch and recoil properties to the aortal wall. Adult vascular smooth muscle cells are inherently unable to produce sufficient elastin to form new elastic fibers to naturally repair the aortal wall and the AAA continues to grow until fatal rupture. Surgical intervention is reserved for AAAs with a high risk of rupture, but there is currently no treatment for small, still growing AAAs. We have previously developed matrix regenerative PEG-PLGA nanoparticles (NPs) with pro-elastogenic and anti-proteolytic properties that act synergistically with a released therapeutic. However, strategies are required to effectively deliver these NPs to the disease site to avail of these benefits. We have identified cathepsin K, a protease overexpressed in AAA tissue, as a potential substrate for antibody based active targeting. We sought to assess the safety and biocompatibility of NPs with anti-cathepsin K antibodies conjugated to the NP surface (cat K Ab-NPs) and then assess their biodistribution and retention in both the targeted aorta and non-target organs in a rat AAA model. In this work, we show that cat K Ab-NPs can selectively target the aneurysmal aorta in a rat AAA model. However, there is unwanted NP uptake and retention in non-target organs that can be addressed in future work. Still, cathepsin K is a viable target for active delivery of NPs in an AAA model.Statement of SignificanceWe have previously developed elastic matrix regenerative polymer nanoparticles (NPs), but require strategies to efficiently target the disease site. Antibodies against cathepsin K, an overexpressed protease in abdominal aortic aneurysms, have been conjugated to the NP surface to act as a targeting moiety. In this work, we assessed NP safety and in vivo biodistribution in an aneurysmal rat model and demonstrated positive targeting and retention for up to 2 weeks within the aortal wall. (c) 2020 Published by Elsevier Ltd on behalf of Acta Materialia Inc.