School of Pharmacy and Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Ave., Pittsburgh, PA, 15282, USA.
Department of Symptom Research, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, 6565 MD Anderson Blvd., Houston, TX, 77030, USA.
Sci Rep. 2024 Aug 16;14(1):18978. doi: 10.1038/s41598-024-69437-w.
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.
糖尿病的一个主要且不可逆转的并发症是糖尿病周围神经病变(DPN),它可导致显著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(Ang II)在神经病变中局部释放,并驱动炎症和内神经血流受损。因此,我们提出通过利用局部热响应水凝胶注射,我们可以通过局部药物释放来递送血管紧张素转换酶(ACE)抑制剂,以抑制 Ang II 的产生并减轻 DPN 中的神经功能障碍。ACE 抑制剂卡托普利被包裹在胶束中,然后嵌入到可逆热响应性泊洛沙姆基水凝胶基质中。无药物和载有卡托普利的水凝胶表现出优异的产品稳定性和无菌性。流变学测试证实了在环境温度下具有低粘度的溶胶性质,并在 37°C 时增加了粘度和凝胶化。与无药物水凝胶相比,载有卡托普利的水凝胶显著抑制了 Ang II 的产生。用载有卡托普利的水凝胶治疗的 DPN 小鼠显示出机械敏感性正常化和炎症减少,而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来治疗 DPN 中的感觉缺陷的可行性。据我们所知,这是局部递送电刺激治疗 DPN 的第一个 ACE 抑制剂的例子。
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