The delivery of therapeutics across the blood-brain barrier remains a considerable challenge in investigating central nervous system related processes. In this work, a liposome vehicle was surface-modified with an aptamer that binds to the transferrin receptor and was loaded with two different dopamine-binding aptamer payloads. This system was effectively used to promote the delivery of the aptamer cargo from the peripheral injection site into the brain. The effect of these delivered aptamers on behavior was investigated in vivo in a locomotor task. The first dopamine binding aptamer assessed was a DNA aptamer, the binding of which had been previously validated through the aptamer-based biosensor development reported by several independent research groups. The second aptamer investigated was the result of a novel in vitro selection experiment described herein. Our data suggest that systemic administration of the modified liposomes led to delivery of the dopamine aptamers into the brain. Fluorescence microscopy revealed differential distribution of fluorescence based on the presence or absence of the transferrin receptor aptamer on the surface of fluorescently modified liposomes. In a behavioral experiment using cocaine administration to induce elevated concentrations of neural dopamine, systemic pretreatment with the dopamine aptamer-loaded liposomes reduced cocaine-induced hyperlocomotion. Multiple controls including a transferrin-negative liposome control and transferrin-positive liposomes loaded with either a nonbinding, base-substituted dopamine aptamer or a random oligonucleotide were investigated. None of these controls altered cocaine-induced hyperlocomotion. Chronic systemic administration of the modified liposomes produced no deleterious neurobehavioral or neural degenerative effects. Importantly, this work is one example of an application for this versatile multiaptamer payload/targeting system. Its general application is limited only by the availability of aptamers for specific neural targets.

中文翻译：

---

体内使用基于多DNA适体的有效负载/靶向系统来研究中枢神经系统中的多巴胺失调。

在研究中枢神经系统相关过程中，跨血脑屏障的治疗药物的交付仍然是一个相当大的挑战。在这项工作中，脂质体载体用与运铁蛋白受体结合的适体进行了表面修饰，并装载了两种不同的多巴胺结合适体有效载荷。该系统有效地用于促进适体货物从周围注射部位向大脑的递送。在运动任务中体内研究了这些递送的适体对行为的影响。评估的第一个多巴胺结合适体是DNA适体，其结合先前已通过多个独立研究小组报告的基于适体的生物传感器开发得到验证。研究的第二个适体是本文所述的新型体外选择实验的结果。我们的数据表明，修饰脂质体的全身给药导致多巴胺适体进入大脑。荧光显微镜显示荧光的差异分布是基于荧光修饰脂质体表面上转铁蛋白受体适体的存在与否。在使用可卡因给药引起神经多巴胺浓度升高的行为实验中，用多巴胺适体负载脂质体进行全身预处理可卡因引起的运动过度减少。多种对照，包括运铁蛋白阴性脂质体对照和载有未结合的运铁蛋白阳性脂质体，研究了碱基取代的多巴胺适体或随机寡核苷酸。这些对照都没有改变可卡因诱导的运动过度。长期全身性施用修饰脂质体不会产生有害的神经行为或神经退行性作用。重要的是，这项工作是这种多功能多适体有效载荷/目标系统应用的一个例子。它的一般应用仅受特定神经靶标的适体的限制。