PDF(Pubmed)
Abstract：
A major and irreversible complication of diabetes is diabetic peripheral neuropathy (DPN), which can lead to significant disability and decreased quality of life. Prior work demonstrates the peptide hormone Angiotensin II (Ang II) is released locally in neuropathy and drives inflammation and impaired endoneurial blood flow. Therefore, we proposed that by utilizing a local thermoresponsive hydrogel injection, we could deliver inhibitors of angiotensin-converting enzyme (ACE) to suppress Ang II production and reduce nerve dysfunction in DPN through local drug release. The ACE inhibitor captopril was encapsulated into a micelle, which was then embedded into a reversibly thermoresponsive pluronics-based hydrogel matrix. Drug-free and captopril-loaded hydrogels demonstrated excellent product stability and sterility. Rheology testing confirmed sol properties with low viscosity at ambient temperature and increased viscosity and gelation at 37 °C. Captopril-loaded hydrogels significantly inhibited Ang II production in comparison to drug-free hydrogels. DPN mice treated with captopril-loaded hydrogels displayed normalized mechanical sensitivity and reduced inflammation, without side-effects associated with systemic exposure. Our data demonstrate the feasibility of repurposing ACE inhibitors as locally delivered anti-inflammatories for the treatment of sensory deficits in DPN. To the best of our knowledge, this is the first example of a locally delivered ACE inhibitor for the treatment of DPN.
摘要：
糖尿病的主要和不可逆的并发症是糖尿病周围神经病变（DPN）。这可能导致严重的残疾和生活质量下降。先前的工作表明肽激素血管紧张素II（AngII）在神经病中局部释放，并引起炎症和神经内膜血流受损。因此,我们提出，通过利用局部热响应水凝胶注射，我们可以提供血管紧张素转换酶（ACE）的抑制剂，以抑制AngII的产生，并通过局部药物释放减少DPN的神经功能障碍。ACE抑制剂卡托普利被包裹在胶束中，然后将其嵌入可逆的热响应性基于pluronics的水凝胶基质中。无药物和卡托普利负载的水凝胶显示出优异的产品稳定性和无菌性。流变性测试证实了在环境温度下具有低粘度和在37°C下具有增加的粘度和凝胶化的溶胶性质。与不含药物的水凝胶相比，装载卡托普利的水凝胶显着抑制了AngII的产生。用卡托普利水凝胶处理的DPN小鼠表现出正常的机械敏感性和减少的炎症,没有与全身暴露相关的副作用。我们的数据证明了将ACE抑制剂重新用作局部递送的抗炎药以治疗DPN中的感觉缺陷的可行性。据我们所知,这是用于治疗DPN的局部递送ACE抑制剂的第一个例子.
