Cathepsin K-targeted sub-micron particles for regenerative repair of vascular elastic matrix.
Cathepsin K-targeted sub-micron particles for regenerative repair of vascular elastic matrix.
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DOI：
10.1016/j.actbio.2017.01.032
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发表时间：
2017-04-01
影响因子：
9.7
通讯作者：
Ramamurthi A
中科院分区：
文献类型：
--
作者：
Jennewine B;Fox J;Ramamurthi A
腹主动脉瘤（AAA）涉及主动脉壁的缓慢扩张和弱化，这是由于结构基质成分（如弹性纤维）被长期过度表达的基质金属蛋白酶（MMP）（主要是MMP-2和MMP-9）分解所致。AAA部位的平滑肌细胞（SMC）对破坏的弹性纤维的自动再生修复本质上很差，并且与慢性蛋白水解一起阻止了弹性蛋白稳态的恢复，这是使AAA生长停滞或回归健康状态所必需的。口服强力霉素（DOX）治疗可以抑制MMP以减缓AAA生长，但具有全身性副作用，并抑制AAA组织内的新弹性蛋白沉积，从而降低了恢复弹性蛋白稳态以防止AAA生长停滞/消退的前景。因此，我们开发了阳离子两亲物（DMAB）改性的亚微米颗粒（SMP），独特地表现出促弹性和抗蛋白水解的特性，从类似的封装药物的效果分开。这些SMP可以使得能够在AAA组织内持续低剂量DOX递送以增强弹性蛋白再生修复。为了提供SMP靶向的更大特异性，我们将DOX-SMP表面与针对组织蛋白酶K（在AAA组织内高度过表达的溶酶体蛋白酶）的抗体缀合。我们已经确定了有效的组织蛋白酶K Ab缀合到SMP上的条件，改善了SMP与培养物中的囊性SMC和离体损伤的血管壁的结合，缀合不影响DOX从SMP的释放，并且由于SMP而改善了促弹性蛋白生成和抗蛋白水解作用，这可能是由于它们通过结合增加了与细胞的接近度。我们的研究结果表明，组织蛋白酶K Ab缀合是我们的促再生SMP的有用的靶向方式。未来的研究将研究SMP的保留和生物分布后，通过静脉内或基于导管的腹膜内输注，在大鼠模型中诱导AAA的目标，然后他们的再生弹性基质修复AAA壁的疗效。
Abdominal Aortic Aneurysms (AAA) involve slow dilation and weakening of the aortic wall due to breakdown of structural matrix components, such as elastic fibers by chronically overexpressed matrix metalloproteinases (MMPs), primarily, MMPs-2 and −9. Auto-regenerative repair of disrupted elastic fibers by smooth muscle cells (SMCs) at the AAA site is intrinsically poor and together with chronic proteolysis prevents restoration of elastin homeostasis, necessary to enable AAA growth arrest or regression to a healthy state. Oral doxycycline (DOX) therapy can inhibit MMPs to slow AAA growth, but has systemwide side-effects and inhibits new elastin deposition within AAA tissue, diminishing prospects for restoring elastin homeostasis preventing the arrest/regression of AAA growth. We have thus developed cationic amphiphile (DMAB)-modified submicron particles (SMPs) that uniquely exhibit pro-elastogenic and anti-proteolytic properties, separate from similar effects of the encapsulated drug. These SMPs can enable sustained, low dose DOX delivery within AAA tissue to augment elastin regenerative repair. To provide greater specificity of SMP targeting, we have conjugated the DOX-SMP surface with an antibody against cathepsin K, a lysosomal protease that is highly overexpressed within AAA tissue. We have determined conditions for efficient cathepsin K Ab conjugation onto the SMPs, improved SMP binding to aneurysmal SMCs in culture and to injured vessel walls ex vivo, conjugation did not affect DOX release from the SMPs, and improved pro-elastogenic and anti-proteolytic effects due to the SMPs likely due to their increased proximity to cells via binding. Our study results suggest that cathepsin K Ab conjugation is a useful targeting modality for our pro-regenerative SMPs. Future studies will investigate SMP retention and biodistribution following targeting to induced AAAs in rat models through intravenous or catheter-based aortal infusion and thereafter their efficacy for regenerative elastic matrix repair in the AAA wall.
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