Minic Zeljka, Zhang Yanhua, Mao Guangzhao, Goshgarian Harry G
Wayne State University School of Medicine, Department of Anatomy and Cell Biology, Detroit, Michigan 48201, and.
Wayne State University College of Engineering, Department of Chemical Engineering and Materials Science, Detroit, Michigan 48202.
J Neurosci. 2016 Mar 23;36(12):3441-52. doi: 10.1523/JNEUROSCI.2577-15.2016.
Respiratory complications in patients with spinal cord injury (SCI) are common and have a negative impact on the quality of patients' lives. Systemic administration of drugs that improve respiratory function often cause deleterious side effects. The present study examines the applicability of a novel nanotechnology-based drug delivery system, which induces recovery of diaphragm function after SCI in the adult rat model. We developed a protein-coupled nanoconjugate to selectively deliver by transsynaptic transport small therapeutic amounts of an A1 adenosine receptor antagonist to the respiratory centers. A single administration of the nanoconjugate restored 75% of the respiratory drive at 0.1% of the systemic therapeutic drug dose. The reduction of the systemic dose may obviate the side effects. The recovery lasted for 4 weeks (the longest period studied). These findings have translational implications for patients with respiratory dysfunction after SCI.
The leading causes of death in humans following SCI are respiratory complications secondary to paralysis of respiratory muscles. Systemic administration of methylxantines improves respiratory function but also leads to the development of deleterious side effects due to actions of the drug on nonrespiratory sites. The importance of the present study lies in the novel drug delivery approach that uses nanotechnology to selectively deliver recovery-inducing drugs to the respiratory centers exclusively. This strategy allows for a reduction in the therapeutic drug dose, which may reduce harmful side effects and markedly improve the quality of life for SCI patients.
脊髓损伤（SCI）患者的呼吸并发症很常见，对患者生活质量有负面影响。全身给药改善呼吸功能的药物往往会产生有害副作用。本研究考察了一种新型基于纳米技术的药物递送系统的适用性，该系统可在成年大鼠SCI模型中诱导膈肌功能恢复。我们开发了一种蛋白质偶联纳米缀合物，通过跨突触运输将少量治疗剂量的A1腺苷受体拮抗剂选择性地递送至呼吸中枢。单次给药纳米缀合物后，在全身治疗药物剂量的0.1%时恢复了75%的呼吸驱动。全身剂量的降低可能避免副作用。恢复持续了4周（研究的最长时间）。这些发现对SCI后呼吸功能障碍患者具有转化意义。
人类SCI后的主要死亡原因是呼吸肌麻痹继发的呼吸并发症。全身给予甲基黄嘌呤可改善呼吸功能，但由于药物对非呼吸部位的作用也会导致有害副作用的发生。本研究的重要性在于采用纳米技术将诱导恢复的药物仅选择性地递送至呼吸中枢的新型药物递送方法。这种策略可降低治疗药物剂量，这可能减少有害副作用并显著改善SCI患者的生活质量。
