Multifunctional nanoparticles for doxycycline delivery towards localized elastic matrix stabilization and regenerative repair.
Multifunctional nanoparticles for doxycycline delivery towards localized elastic matrix stabilization and regenerative repair.
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DOI：
10.1016/j.actbio.2013.01.023
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发表时间：
2013-05
影响因子：
9.7
通讯作者：
Ramamurthi, Anand
中科院分区：
文献类型：
--
作者：
Sivaraman, Balakrishnan;Ramamurthi, Anand
关键词：
腹主动脉瘤（AAA）是主动脉壁的异常扩张，通常以基质金属蛋白酶（MMP）-2和-9的慢性上调为特征。这些MMPs降解主动脉壁内的弹性蛋白和弹性基质，导致腹主动脉随着病情进展而逐渐丧失弹性。多西环素（DOX）是一种以四环素为基础的抗生素，在临床研究和动物模型中显示出显著的延缓和减缓AAAs生长的前景。然而，已经发现，除了口服给药后的全身副作用之外，在µg/mL范围内的剂量下，它还可以抑制血管细胞的弹性基质沉积，这通常在循环中观察到。在本文中，我们描述了开发的阿霉素-聚（乳酸-羟基乙酸）（PLGA）纳米粒子的局部，控制和持续的阿霉素交付对AAA治疗。此外，我们证明了这些纳米颗粒与阳离子两亲物的表面功能化，不仅赋予它们潜在增强主动脉摄取的正电荷，而且还能够通过疏水相互作用增强弹性蛋白结合，以及上调弹性蛋白交联酶赖氨酰氧化酶（LOX）的活性。除了从纳米颗粒释放的DOX有效抑制MMP-2的产生和活性之外，我们还证明了纳米颗粒阳离子两亲物的表面官能化也可以通过（i）与MMP-2的活性位点中带负电荷的残基的静电相互作用，或（ii）由于DMAB分子中存在两个十二烷基链而对活性位点进行空间阻断。因此，除了在其他小组的研究中说明的增强的主动脉摄取和保留之外，我们已经证明PLGA纳米颗粒的阳离子官能化通过靶向结合弹性蛋白以及它们抑制弹性蛋白溶解的潜力来增强弹性生成结果。这些结果确立了其作为AAA治疗局部给药系统的多功能性。总的来说，该递送系统具有通过实现治疗剂的靶向、受控和长期释放来增强蛋白水解基质破坏/降解位点处的再生结果的潜力。
Abdominal aortic aneurysms (AAAs) are abnormal expansions of the aortic wall, typically characterized by chronic upregulation of matrix metalloproteases (MMPs) -2 and -9. These MMPs degrade elastin and elastic matrix within the aortic wall, leading to a progressive loss of elasticity of the abdominal aorta as the condition progresses. Doxycycline (DOX) is tetracycline-based antibiotic which has shown significant promise in delaying and slowing the growth of AAAs in clinical studies and in animal models. However, it has been found to inhibit elastic matrix deposition by vascular cells at dosages in the µg/mL range which is typically observed in the circulation, in addition to systemic side effects, following oral dosage. In this paper, we describe the development of DOX-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles for localized, controlled and sustained DOX delivery towards AAA therapy. Further, we demonstrate that surface-functionalization of these nanoparticles with cationic amphiphiles, not only impart them with a positive charge for potentially enhanced aortic uptake, but also enabled enhanced elastin binding via hydrophobic interactions, as well as upregulating activity of the elastin crosslinking enzyme lysyl oxidase (LOX). In addition to the DOX released from the nanoparticles being effective in inhibiting MMP-2 production and activity, we also demonstrate that surface-functionalization of the nanoparticles cationic amphiphiles may also play a role in MMP-2 inhibition via (i) electrostatic interactions with negatively-charged residues in the active-site of MMP-2, or (ii) steric blockade of the active site on account of the presence of two dodecyl chains in the DMAB molecule. Thus, in addition to enhanced aortic uptake and retention illustrated in studies by other groups, we have demonstrated that cationic functionalization of PLGA nanoparticles enhances elastogenic outcomes, by targeted binding to elastin, as well as their potential to inhibit elastolysis. These results establish their multifunctionality as a localized delivery system for AAA therapy. Overall, this delivery system has potential in enhancing regenerative outcomes at sites of proteolytic matrix disruption/degradation by enabling targeted, controlled, and long-term release of therapeutic agents.
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影响因子：
3.6
作者：
García, RA;Pantazatos, DP;Villarreal, FJ
通讯作者：
Villarreal, FJ
影响因子：
3.7
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作者：
DAVIES, AK;CUNDALL, RB;SLIFKIN, MA
通讯作者：
SLIFKIN, MA