周邊動脈疾病　(Peripheral Artery Disease, PAD)　是常見的全身系統性動脈粥樣硬化及狹窄的表現，好發於下肢動脈，而引起組織性的缺血以及血管內皮細胞的損傷，造成慢性發炎反應、動脈管徑中的凝血反應與最後形成動脈粥樣硬化的病理變化。現行主要治療方式為藥物治療、血管腔內治療及血管繞道手術，然而現行治療方式的目的主要是為了避免血管再次阻塞，但並未積極的治療受損的組織或促使缺血組織之血管新生。丹參酸B (salvianolic acid B, SAB)　為丹參中的一種水溶性活性成分，具有抗氧化和促血管新生的特性，可以透過清除自由基，協同其血管舒張的功能來減輕動脈的阻塞，並保護內皮細胞免於活性氧類　(reactive oxygen species, ROS)　引發的細胞凋亡，並在嚴重阻塞的動脈中協助血管的重建。葡聚糖　(Dextran, DEX)　被指出具有血流改善的心血管保護作用，已被應用在臨床上作為恢復末稍循環及速效營養補充劑多年。在本研究中製備具有氧化應答特性的苯棚酸酯葡聚糖共軛物 (PHB-DEX) 奈米粒子並將SAB包覆其中，含有SAB之奈米粒子能於氧化壓力的疾病環境下較精準的釋放藥物以達到更好的治療效果。
在本研究中以1,1'-羰基二咪唑　(1,1'-Carbonyldiimidazole, CDI)、 4-(羥甲基)苯硼酸頻哪醇酯　(4-(Hydroxymethyl)phenylboronic acid pinacol ester, PBAP) 及Dextran製備具有氧化應答特性的　PHB-DEX　，利用傅里葉轉換紅外光譜與熱重分析儀分析材料改質前後的特徵峰及熱裂解溫度變化，並進一步評估奈米粒子的形態、粒徑、粒徑分布及界達電位 (zeta potential)，而在過氧化氫 (hydrogen peroxide, H2O2) 作用下，也可觀察到所製備出的 PHB-DEX 奈米粒子產生顯著的水解，證明其氧化應答之特性。
在載藥濃度的選擇上，從細胞存活率的結果顯示， SAB對人類臍靜脈內皮細胞 (human umbilical vein endothelial cells, HUVECs) 的安全濃度約為200 μM，利用所合成　PHB-DEX　之自組裝的特性將SAB包覆於材料中，將載有SAB之奈米粒子分為低、中及高濃度分別與HUVECs進行共培養，發現低及中濃度的SAB奈米粒子具有促進HUVECs細胞增殖特性。在SAB奈米粒子的療效評估上，先以H2O2所誘發HUVECs的氧化壓力再投予含有SAB的奈米粒子，研究結果顯示SAB奈米粒子具有下調受到氧化損傷的 HUVECs 中 IL-6 的基因表現，並且能顯著的使細胞存活率回升。
本研究結果顯示，包覆SAB之PHB-DEX活性氧應答奈米粒子應具有調節過量ROS所誘發的內皮細胞損傷的能力，未來應用於周邊動脈疾病治療上應具有一定的潛力。

Peripheral Artery Disease (PAD) is a common systemic disease which feactures atherosclerosis and stenosis. It is more likely to occur in lower extremity arteries, causing tissue ischemia and vascular endothelial cell damage, resulting in chronic inflammation, coagulation and eventually giving rise to atherosclerosis. The current main treatment approaches are drug therapy, intravascular treatment and vascular bypass surgery. However, the main purpose of the current treatment methods is to avoid restenosis but not to actively treat damaged tissues or promote angiogenesis in ischemic tissues. Salvianolic acid B (SAB) is one of the water-soluble bioactive components in Salvia miltiorrhiza. Its antioxidant and angiogenic properties have the effects of relieving the blocked arteries by removing free radicals through synergizing the vasodilation function and protecting endothelial cells from reactive oxygen species (ROS)-induced apoptosis. In severely blocked arteries, SAB can assist the reconstruction of blood vessels. Dextran has been shown to have property of cardiovascular protection by improving blood flow. It has been used clinically for many years and can promote the recovery of blood flow cycle and be treated as fast-acting supplementary. In this reaserch, ROS-responsive-phenylboronic ester-modified dextran nanoparticle were prepared and loaded with SAB. The SAB-loaded nanoparticles can achieve better treatment effect by accurate drug release.
In this research, 1,1'-carbonyl diimidazole (CDI), 4-(hydroxymethyl) phenylboronic acid pinacol ester (PBAP) and dextran are applied to prepare oxidative responsive PHB-DEX. The characterization of PHB-DEX was confirmed by Fourier transform infrared spectroscopy and thermogravimetric analyzer. The morphology and particle size of nanoparticles, size distribution and zeta potential were evaluated. Under the stimulation of hydrogen peroxide (H2O2), PHB-DEX nanoparticles show the significant hydrolysis property, proving its oxidative response characteristics. In-vitro test of cell viability show that the safety concentration of SAB for human umbilical vein endothelial cells (HUVECs) is 200 μM. During self-assembly of PHB-DEX, SAB was loaded in the NPs to form SAB-NPs which were diluted to formulate low, medium and high concentrations of it. HUVECs were cultured with SAB-NPs and proliferated when treated with low and medium concentrations of SAB-NPs. The efficacy of SAB nanoparticles was evaluated by building up the H2O2-induced oxidative stress model on HUVECs and treated with SAB-NPs. The results show that SAB-NPs can downregulate the gene expression of IL-6 in HUVECs undergone H2O2-induced oxidative damage and significantly increase the cell viability. In summary, the SAB-loaded PHB-DEX NP can regulate excessive ROS-induced endothelial cell damage, and have potential for the treatment of PAD in the future.

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