A Nanotechnology-Based Platform for Extending the Pharmacokinetic and Binding Properties of Anti-methamphetamine Antibody Fragments.
A Nanotechnology-Based Platform for Extending the Pharmacokinetic and Binding Properties of Anti-methamphetamine Antibody Fragments.
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DOI：
10.1038/srep12060
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发表时间：
2015-07-10
影响因子：
4.6
通讯作者：
Peterson EC
中科院分区：
文献类型：
--
作者：
Nanaware-Kharade N;Thakkar S;Gonzalez GA 3rd;Peterson EC
为了解决对有效药物治疗甲基苯丙胺滥用的需求，我们使用纳米技术方法定制了一种抗甲基苯丙胺单链抗体（scFv7F9Cys）的体内行为。通过聚乙二醇（PEG）连接剂将抗甲基scFv7F9Cys偶联到树状纳米颗粒上，生成称为树状体的高阶偶联物。我们发现，纳米粒子偶联后对甲基安非他明的高亲和力（KD = 6.2 nM）和特异性没有改变。在开始s.c.注射冰毒后，雄性斯普拉格·道利大鼠静脉注射树突体。scFv7F9Cys与树状大分子结合后，其清除率和分布体积PCKN值分别降低了45倍和1.6倍，末端消除半衰期提高了20倍。scFv7F9Cys和树突体在血液和尿液中的器官分布与PCKN数据吻合良好。肾脏清除似乎是两种实验性药物的主要消除途径。因此，我们成功地开发了一种新型的多价甲基结合纳米药物，通过将多个抗甲基的scFvs偶联到树突状纳米颗粒上，将scFv的半衰期从1.3（±0.3）小时延长到26（±2.6）小时。这些数据表明，树突体设计可能是产生具有可定制PCKN谱的多价抗体的可行平台。
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.
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影响因子：
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