当前位置: X-MOL 学术ACS Nano › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Accelerated Blood Clearance of Antibodies by Nanosized Click Antidotes.
ACS Nano ( IF 15.8 ) Pub Date : 2018-12-05 , DOI: 10.1021/acsnano.8b07003
Weston J Smith , Guankui Wang , Hanmant Gaikwad , Vivian P Vu , Ernest Groman , David W A Bourne , Dmitri Simberg

Long blood half-life is one of the advantages of antibodies over small molecule drugs. At the same time, prolonged half-life is a problem for imaging applications or in the case of antibody-induced toxicities. There is a substantial need for antidotes that can quickly clear antibodies from systemic circulation and peripheral tissues. Engineered nanoparticles exhibit intrinsic affinity for clearance organs (mainly liver and spleen). trans-Cyclooctene (TCO) and methyltetrazine (MTZ) are versatile copper-free click chemistry components that are extensively being used for in vivo bioorthogonal couplings. To test the ability of nanoparticles to eliminate antibodies, we prepared a set of click-modified, clinically relevant antidotes based on several classes of drug carriers: phospholipid-PEG micelles, bovine serum albumin (BSA), and cross-linked dextran iron oxide (CLIO) nanoparticles. Mice were injected with IRDye 800CW-labeled, click-modified IgG followed by a click-modified antidote or PBS (control), and the levels of the IgG were monitored up to 72 h postinjection. Long-circulating lipid micelles produced a spike in IgG levels at 1 h, decreased IgG levels at 24 h, and did not decrease the area under the curve (AUC) and IgG accumulation in main organs. Long-circulating BSA decreased IgG levels at 1 and 24 h, decreased the AUC, but did not significantly decrease organ accumulation. Long-circulating CLIO nanoworms increased IgG levels at 1 h, decreased IgG levels at 24 h, did not decrease the AUC, and did not decrease the organ accumulation. On the other hand, short-circulating CLIO nanoparticles decreased IgG levels at 1 and 24 h, significantly decreasing the AUC and accumulation in the main organs. Multiple doses of CLIO and BSA were not able to completely eliminate the antibody from blood, despite the click reactivity of the residual IgG, likely due to exchange of IgG between blood and tissue compartments. Pharmacokinetic modeling suggests that short antidote half-life and fast click reaction rate should result in higher IgG depletion efficiency. Short-circulating click-modified nanocarriers are the most effective antidotes for elimination of antibodies from blood. This study sets a stage for future development of antidotes based on nanomedicine.

中文翻译:

纳米点击解毒剂可加速血液的抗体清除。

血液半衰期长是抗体相对于小分子药物的优势之一。同时,对于成像应用或在抗体诱导的毒性的情况下,延长的半衰期是一个问题。非常需要能够从全身循环和周围组织中清除抗体的解毒剂。工程纳米粒子对清除器官(主要是肝脏和脾脏)表现出内在的亲和力。反式环辛烯(TCO)和甲基四嗪(MTZ)是通用的无铜点击化学组分,已广泛用于体内生物正交偶联。为了测试纳米颗粒消除抗体的能力,我们基于几类药物载体制备了一组点击修饰的,与临床相关的解毒剂:磷脂-PEG胶束,牛血清白蛋白(BSA),和交联的葡聚糖氧化铁(CLIO)纳米粒子。给小鼠注射IRDye 800CW标记的单击修饰的IgG,然后单击修饰的解毒剂或PBS(对照),并在注射后72小时内监测IgG的水平。长循环脂质胶束在1 h时产生IgG水平的峰值,在24 h时降低IgG水平,并且没有减小曲线下面积(AUC)和主要器官中IgG的积累。长循环BSA在1和24小时降低了IgG水平,降低了AUC,但并未显着降低器官蓄积。长循环的CLIO纳米蠕虫在1 h时升高IgG水平,在24 h时降低IgG水平,没有降低AUC,也没有降低器官蓄积。另一方面,短周期的CLIO纳米颗粒可在1和24 h降低IgG水平,大大减少了AUC和主要器官的蓄积。尽管残留IgG的点击反应性很强,但由于血液和组织隔室之间IgG的交换,多次服用CLIO和BSA仍无法从血液中完全清除抗体。药代动力学模型表明解毒剂半衰期短和点击反应速率快应导致更高的IgG消耗效率。短循环点击修饰的纳米载体是消除血液中抗体的最有效解毒剂。这项研究为基于纳米药物的解毒剂的未来发展奠定了基础。可能是由于血液和组织隔室之间的IgG交换所致。药代动力学模型表明解毒剂半衰期短和点击反应速率快应导致更高的IgG消耗效率。短循环点击修饰的纳米载体是消除血液中抗体的最有效解毒剂。这项研究为基于纳米药物的解毒剂的未来发展奠定了基础。可能是由于血液和组织隔室之间IgG的交换。药代动力学模型表明解毒剂半衰期短和点击反应速率快应导致更高的IgG消耗效率。短循环点击修饰的纳米载体是消除血液中抗体的最有效解毒剂。这项研究为基于纳米药物的解毒剂的未来发展奠定了基础。
更新日期:2018-12-05
down
wechat
bug