Nanoparticle targeting to the endothelium during normothermic machine perfusion of human kidneys.
Nanoparticle targeting to the endothelium during normothermic machine perfusion of human kidneys.
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DOI：
10.1126/scitranslmed.aam6764
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发表时间：
2017-11-29
影响因子：
17.1
通讯作者：
Pober JS
中科院分区：
文献类型：
--
作者：
Tietjen GT;Hosgood SA;DiRito J;Cui J;Deep D;Song E;Kraehling JR;Piotrowski-Daspit AS;Kirkiles-Smith NC;Al-Lamki R;Thiru S;Bradley JA;Saeb-Parsy K;Bradley JR;Nicholson ML;Saltzman WM;Pober JS
体外恒温机器灌注（NMP）是一种新的临床策略，用于评估和复苏可能被拒绝移植的器官，从而增加可用的活器官数量。短时间的NMP提供了一个机会窗口，可以将治疗药物直接输送到器官，特别是血管内皮细胞（ECs），这是与受体免疫系统的第一个接触点。内皮细胞是缺血再灌注损伤和预先形成的抗供体抗体损伤的主要靶点，减少围手术期内皮细胞损伤可能通过降低宿主同种免疫反应的强度而具有长期益处。使用NMP直接对移植物进行治疗，避免了与全身药物输送相关的许多限制。我们之前已经表明，聚合物纳米颗粒（NPs）可以作为长期药物释放的储存库，但确保在靶细胞类型（在这种情况下是移植物内皮细胞）中强大的NP积累仍然是纳米医学的一个基本挑战。我们发现抗cd31抗体的表面偶联增强了NPs对接受NMP的人肾脏移植ec的靶向性。使用双色定量显微镜方法，我们证明靶向可以提高EC在肾脉管系统离散区域的蓄积约5至10倍或更高。此外，我们的研究表明，NPs也可以非特异性地积聚在血管灌注不良的阻塞区域。这些定量的临床前人类研究证明了在体外NMP过程中靶向纳米药物的治疗潜力。
Ex vivo normothermic machine perfusion (NMP) is a new clinical strategy to assess and resuscitate organs likely to be declined for transplantation, thereby increasing the number of viable organs available. Short periods of NMP provide a window of opportunity to deliver therapeutics directly to the organ and, in particular, to the vascular endothelial cells (ECs) that constitute the first point of contact with the recipient’s immune system. ECs are the primary targets of both ischemia-reperfusion injury and damage from preformed antidonor antibodies, and reduction of perioperative EC injury could have long-term benefits by reducing the intensity of the host’s alloimmune response. Using NMP to administer therapeutics directly to the graft avoids many of the limitations associated with systemic drug delivery. We have previously shown that polymeric nanoparticles (NPs) can serve as depots for long-term drug release, but ensuring robust NP accumulation within a target cell type (graft ECs in this case) remains a fundamental challenge of nanomedicine. We show that surface conjugation of an anti-CD31 antibody enhances targeting of NPs to graft ECs of human kidneys undergoing NMP. Using a two-color quantitative microscopy approach, we demonstrate that targeting can enhance EC accumulation by about 5-to 10-fold or higher in discrete regions of the renal vasculature. In addition, our studies reveal that NPs can also non-specifically accumulate within obstructed regions of the vasculature that are poorly perfused. These quantitative preclinical human studies demonstrate the therapeutic potential for targeted nanomedicines delivered during ex vivo NMP.
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影响因子：
6.2
作者：
Hosgood, Sarah A.;Nicholson, Michael L.
通讯作者：
Nicholson, Michael L.
DOI：
10.1016/j.jconrel.2015.05.006
发表时间：
2015-07-28
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Han J;Shuvaev VV;Davies PF;Eckmann DM;Muro S;Muzykantov VR
通讯作者：
Muzykantov VR
影响因子：
14
作者：
Dziubla, Thomas D.;Shuvaev, Vladimir V.;Muzykantov, Vladimir R.
通讯作者：
Muzykantov, Vladimir R.
影响因子：
10.8
作者：
Garnacho, Carmen;Albelda, Steven M.;Muro, Silvia
通讯作者：
Muro, Silvia
影响因子：
16.1
作者：
Janib, Siti M.;Moses, Ara S.;MacKay, J. Andrew
通讯作者：
MacKay, J. Andrew