Chida-Nagai Ayako, Masaki Naoki, Sato Hiroki, Kato Tatsuya, Takakuwa Emi, Matsuno Yoshihiro, Manabe Atsushi, Takeda Atsuhito
Department of Pediatrics, Hokkaido University Hospital, Sapporo, Japan.
Department of Pediatric Cardiology and Adult Congenital Cardiology, Tokyo Women's Medical University, Tokyo, Japan.
Front Pharmacol. 2025 Apr 30;16:1577570. doi: 10.3389/fphar.2025.1577570. eCollection 2025.
Pulmonary arterial hypertension (PAH) remains a challenge to tackle despite various available medications. Metformin, although promising, has major adverse effects; the use of an appropriate drug delivery method may improve its efficacy and safety. The aim of this study was to develop a novel treatment for PAH using metformin. We developed a novel approach of using low-dose metformin encapsulated in pulmonary artery-targeted nanocapsules to alleviate PAH while avoiding adverse effects.
Metformin-loaded lung-targeted nanocapsules (MET nanocapsules) were created using a specific lipid composition, including cationic lipids. Their uptake and effects on cell viability were assessed in human pulmonary arterial smooth muscle cells (hPASMCs) from healthy individuals and patients with PAH. Their therapeutic effects were assessed in a PAH rat model. The safety of MET nanocapsules was confirmed using rat serum biochemical tests.
We successfully prepared MET nanocapsules and demonstrated their effectiveness in inhibiting PASMC proliferation. In PAH model rats, MET nanocapsule treatment led to improved hemodynamics, right ventricular hypertrophy, and pulmonary arterial medial thickening. The nanocapsules effectively accumulated in the lungs of PAH model rats.
Intravenous administration of MET nanocapsules is a safe and innovative therapeutic approach for PAH. This method could improve PAH treatment outcomes while minimizing adverse effects, with potential applications in other types of pulmonary hypertension.
尽管有多种可用药物，但肺动脉高压（PAH）仍然是一个难以攻克的难题。二甲双胍虽然前景广阔，但有严重的不良反应；采用合适的药物递送方法可能会提高其疗效和安全性。本研究的目的是开发一种使用二甲双胍治疗PAH的新方法。我们开发了一种新方法，即使用包裹在肺动脉靶向纳米胶囊中的低剂量二甲双胍来缓解PAH，同时避免不良反应。
使用包括阳离子脂质在内的特定脂质组合物制备负载二甲双胍的肺靶向纳米胶囊（MET纳米胶囊）。在来自健康个体和PAH患者的人肺动脉平滑肌细胞（hPASMCs）中评估它们的摄取及其对细胞活力的影响。在PAH大鼠模型中评估它们的治疗效果。使用大鼠血清生化检测确认MET纳米胶囊的安全性。
我们成功制备了MET纳米胶囊，并证明了它们在抑制PASMC增殖方面的有效性。在PAH模型大鼠中，MET纳米胶囊治疗导致血流动力学改善、右心室肥厚和肺动脉中层增厚减轻。纳米胶囊有效地积聚在PAH模型大鼠的肺部。
静脉注射MET纳米胶囊是一种治疗PAH的安全且创新的治疗方法。这种方法可以改善PAH的治疗效果，同时将不良反应降至最低，在其他类型的肺动脉高压中具有潜在应用价值。
