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

利用纳米缀合物逆行运输靶向药物输送治疗脊髓损伤

• 批准号: 9809228
• 负责人: Guangzhao Mao
• 金额: $ 25.62万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9809228
• 关键词: Adverse drug effect; Animals; Axon; Axonal Transport; Biodistribution; Biological; Biological Availability; Blood - brain barrier anatomy; Brain; Breathing; Bypass; Carrier Proteins; Cause of Death; Cell Nucleus; Cervical; Cervical spinal cord injury; Chemical Engineering; Chemicals; Clinical; Clinical Trials; Collaborations; Coupled; Coupling; Data; Development; Disease; Dose; Drug Antagonism; Drug Delivery Systems; Drug Kinetics; Drug Stability; Drug Targeting; Drug or chemical Tissue Distribution; Embolism; Environmental air flow; Excretory function; FDA approved; Formulation; Frequencies; Gold; Grant; Horseradish Peroxidase; Human; Interruption; Investigation; Legal patent; Life; Link; Lung; Metabolism; Motor Neurons; Motor Pathways; Muscle; Muscle function; Nanoconjugate; Nanotechnology; Neurons; Organ; Paralysed; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Physiological; Pneumonia; Population Control; Proteins; Purinergic P1 Receptors; Quality Control; Rattus; Recovery; Recovery of Function; Research Personnel; Respiratory Center; Respiratory Diaphragm; Respiratory Muscles; Respiratory physiology; Route; Safety; Septicemia; Site; Spinal Cord; Spinal cord injury; Synapses; Tidal Volume; Toxic effect; Variant; Wheat Germ Agglutinins; Work; absorption; awake; biomaterial compatibility; chemical conjugate; clinical application; clinical translation; design; dosage; efficacy study; improved; in vivo; innovation; methylxanthine; motor recovery; nanoGold; nanocarrier; nanodevice; nanomaterials; nanomedicine; nanoparticle; nanoproducts; nanotherapeutic; off-patent; particle; prevent; protein transport; respiratory; response; retrograde transport; safety study; side effect; targeted delivery; therapeutic development

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.

这是IGNITE项目“逆行输送脊髓损伤靶向药物递送”