Targeted Drug Delivery for Spinal Cord Injury Using Retrograde Transport of a Nanoconjugate

本项目“逆行转运靶向给药治疗脊髓损伤 将开发纳米疗法，用于将药物靶向输送到吻部 腹侧呼吸群(RVRG)神经元和膈运动神经元治疗慢性阻塞性肺疾病 脊髓损伤后的呼吸问题。项目团队由化学工程师组成， 脊髓损伤研究人员，生物统计学家，药理学和风险投资专家 发展。该团队已经展示了互补和集成的专业知识，以实现我们的 项目的方方面面。呼吸道问题，包括肺炎、败血症和肺部疾病 栓子是人类脊髓损伤后死亡的主要原因。腺苷受体 8-环戊基-1，3-二磷黄嘌呤(DPCPX)等拮抗剂可诱导呼吸 通过激活潜伏的呼吸运动通路恢复瘫痪的横隔肌 交叉的膈神经通路。然而，这些药物的严重副作用阻止了他们的 临床应用。我们在之前的工作中已经证明，有可能减少甚至是 通过选择性地将药物输送到呼吸神经元来消除副作用 纳米技术。纳米疗法有望改善体内药物稳定性和药代动力学 以及生物分布和有效性，所有这些都有可能减少毒性和副作用。我们的 由靶向/转运蛋白麦胚凝集素组成的纳米治疗设计 辣根过氧化物酶(WGA-HRP)，化学标记金纳米颗粒 (AUNP)，它又通过可生物降解的键与药物化学偶联 DPCPX。WGA-HRP被注射入膈神经轴突终末后被摄取 C2脊髓半横断大鼠的横隔肌，并逆行运输到 膈运动神经元。重要的是，它进一步通过突触在生理上运输 活性突触与rVRG中的神经元发生突触，不向任何其他神经元中心运输。通过 将选择性转运体和诱导恢复的药物与纳米载体相结合，我们可以 控制药物在控制隔膜的两个尾状神经元群中的释放 功能。我们的靶向给药可以使瘫痪的半横肌恢复 在大鼠身上使用全身剂量的一小部分。IGNITE赠款将支持早期翻译 努力证明纳米结合物将具有足够的生物活性(即70% 呼吸功能在4周内恢复)，同时使用当地药物的一小部分 剂量(即0.1%)，以保证进一步的治疗开发。

This IGNITE Project “Targeted Drug Delivery for Spinal Cord Injury Using Retrograde Transport of a Nanoconjugate” will develop nanotherapeutics for targeted delivery of drugs to the rostral ventral respiratory group (rVRG) neurons and phrenic motoneurons for the treatment of respiratory problems after spinal cord injury. The project team consists of chemical engineers, spinal cord injury researchers, a biostatistician, and an expert in pharmacology and venture development. The team has demonstrated complementary and integrated expertise to carry our all aspects of the project. Respiratory problems including pneumonia, septicemia, and pulmonary emboli are the leading causes of death in humans after spinal cord injury. Adenosine receptor antagonist drugs such as 8-cyclopentyl-1,3-diprophyxanthine (DPCPX) can induce respiratory recovery of the paralyzed hemidiaphragm by activating a latent respiratory motor pathway - the crossed phrenic pathway. However, the severe side effects of these drugs have prevented their clinical use. We have demonstrated in our previous work that it may be possible to reduce or even eliminate the side effects by delivering the drugs selectively to the respiratory neurons using nanotechnology. Nanotherapeutics promise to improve in vivo drug stability, pharmacokinetics and biodistribution, and efficacy, all of which can potentially reduce toxicity and side effects. Our nanotherapeutic design consists of a targeting/transporting protein, wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP), chemically conjugated to a gold nanoparticle (AuNP), which in turn is chemically conjugated, through a biodegradable bond, to the drug DPCPX. WGA-HRP is taken up by the terminals of phrenic axons when injected into the diaphragm muscle of C2 spinal cord hemisectioned rats, and it is retrogradely transported to the phrenic motoneurons. Importantly, it is further transported transsynaptically across physiologically active synapses to neurons in the rVRG, and does not transport to any other neuron centers. By coupling the selective transporter and the drug that induces recovery with a nano-carrier, we can control the release of the drug in the two caudal neuronal populations that control diaphragm function. Our targeted drug administration can induce recovery of the paralyzed hemidiaphragm in rats by using a fraction of the systemic dosage. The IGNITE grant will support early translational efforts to demonstrate that the nanoconjugate will have sufficient biological activity (i.e., 70% respiratory function recovery at 4 weeks) while administered at a small fraction of the native drug dosage (i.e., 0.1%) to warrant further therapeutic development.