Nanaware-Kharade Nisha, Thakkar Shraddha, Gonzalez Guillermo A, Peterson Eric C
Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, 4301 West Markham St., # 611, Little Rock, Arkansas 72205, USA.
Department of Physiology and Biophysics, College of Medicine, University of Arkansas for Medical Sciences, 4301 West Markham St., # 750, Little Rock, Arkansas 72205, USA.
Sci Rep. 2015 Jul 10;5:12060. doi: 10.1038/srep12060.
To address the need for effective medications to aid in the treatment of methamphetamine (METH) abuse, we used a nanotechnology approach to customize the in vivo behavior of an anti-METH single chain antibody (scFv7F9Cys). Anti-METH scFv7F9Cys was conjugated to dendrimer nanoparticles via a polyethylene glycol (PEG) linker to generate high-order conjugates termed dendribodies. We found that the high affinity (KD = 6.2 nM) and specificity for METH was unchanged after nanoparticle conjugation. The dendribodies were administered in an i.v. bolus to male Sprague Dawley rats after starting a s.c. infusion of METH. The PCKN values for clearance and volume of distribution of scFv7F9Cys after conjugation to dendrimers decreased 45 and 1.6-fold respectively, and the terminal elimination half-life increased 20-fold. Organ distribution of scFv7F9Cys and dendribody in blood and urine agreed well with the PCKN data. Renal clearance appeared to be the major route of elimination for both experimental medications. We have thus successfully developed a novel multivalent METH-binding nanomedicine by conjugating multiple anti-METH scFvs to dendrimer nanoparticles, extending the scFv half-life from 1.3 (± 0.3) to 26 (± 2.6) hr. These data suggest that the dendribody design could be a feasible platform for generating multivalent antibodies with customizable PCKN profiles.
为满足有效药物辅助治疗甲基苯丙胺（METH）滥用的需求，我们采用纳米技术方法来定制抗METH单链抗体（scFv7F9Cys）的体内行为。通过聚乙二醇（PEG）连接子将抗METH scFv7F9Cys与树枝状聚合物纳米颗粒偶联，生成称为树枝状抗体的高阶偶联物。我们发现纳米颗粒偶联后，对METH的高亲和力（KD = 6.2 nM）和特异性保持不变。在开始皮下注射METH后，将树枝状抗体静脉推注给雄性Sprague Dawley大鼠。与树枝状聚合物偶联后，scFv7F9Cys的清除率和分布容积的PCKN值分别降低了45倍和1.6倍，终末消除半衰期增加了20倍。scFv7F9Cys和树枝状抗体在血液和尿液中的器官分布与PCKN数据高度吻合。肾清除似乎是两种实验药物的主要消除途径。因此，我们通过将多个抗METH scFv与树枝状聚合物纳米颗粒偶联，成功开发了一种新型的多价METH结合纳米药物，将scFv的半衰期从1.3（±0.3）小时延长至26（±2.6）小时。这些数据表明，树枝状抗体设计可能是生成具有可定制PCKN谱的多价抗体的可行平台。
