纳米载体奥美沙坦酯在实验性大鼠肺动脉高压的防治作用及机制研究

Pulmonary arterial hypertension (PAH) is an intractable disease of small pulmonary artery resulting in increased pulmonary vascular resistance and fatal right ventricular failure, in which multiple pathogenetic factors are involved. Recent evidences suggest the involvement of angiotensin II in the pathogenesis of PAH. However, the efficacy of angiotension II receptor antagonist (ARB) seems to be negligible in animals and patients.We recently succeeded to formulate local pulmonary drug delivery system (DDS) using bioabsorbable polymeric nanoparticles (NP) that is formulated from the poly (DL-lactide- co- glycolide) (PLGA).PLGA NP offers the advantages of safety, efficient intracellular delivery of drugs and retains in the cytoplasm or extracellular spaces after delivery, and releases encapsulated drug slowly with the hydrolysis of PLGA NP. We hypothesized that the beneficial effects of ARB can be maximized if ARB is directly inhaled to the lung using this nanoparticle (NP)-mediated DDS and tested this hypothesis in monocrotaline (MCT)-induced PAH model in rats. In this PAH model, single intratracheal treatment of fluorescence marker-incorporated NP (FITC-NP) resulted in sustained intracellular delivery into lung for up to 14 days post- application. We excepted that NP-mediated delivery of olmesartan medoxomil, but not other treatments( PBS control , empty-NP, olmesartan medoxomil alone), prevented the development of PAH. NP-mediated delivery of olmesartan medoxomil into lungs through respiratory tract prevented MCT-induced PAH, which may represent a less invasive option for therapeutic intervention in human PAH.

肺动脉高压是各种原因引起的肺小动脉的病变，引起肺血管抵抗的持续上升，最终可导致右心衰竭，甚至死亡。肺动脉高压的发病机制复杂，很多因素与之相关。有报道RAS系统也在肺动脉高压的病程中发挥重要作用，但是在动物模型和临床研究中，血管紧张素II受体拮抗剂ARB类药物的效果却不尽如人意。在此我们使用一种由乳酸和羟基乙酸高聚合物制成的生体可吸收的PLGA纳米粒子作为药物载体，并在大鼠肺动脉高压模型上建立了一种经气道对肺部局部的投药方式。PLGA纳米粒子可安全高效地进入细胞内部，并长时间存在于细胞内部，通过水解作用分解，缓慢释放出内部封入的药物。我们将纳米粒子载体的ARB类药物奥美沙坦酯，经气道对大鼠肺部局部投药，可以将其在局部的效果最大化，则有望对野百合碱诱导的大鼠肺动脉高压起到防治作用。我们相信将纳米粒子载体的奥美沙坦酯运用于临床，可以成为患者的一种更安全更有效的治疗手段，具有重要的科学意义。