Department of Pharmaceutical Sciences, College of Pharmacy, The University of Michigan, 428, Church Street, Ann Arbor, Michigan 48109-1065, USA.
J Control Release. 2010 May 21;144(1):82-90. doi: 10.1016/j.jconrel.2010.01.026. Epub 2010 Jan 28.
Hypoxia is a strong modulator of angiogenesis, accelerating adipose tissue expansion, suggesting that hypoxia inducible factor 1alpha (HIF1alpha) can be a novel target for anti-obesity. We conjugated antisense-HIF1alpha-oligonucleotide (ASO) with low molecular weight protamine (LMWP), a cell-penetrating peptide, to enhance its ability to block hypoxic-angiogenesis, thereby eliciting an anti-obesity effect. Nano-sized ASO-LMWP (AS-L) conjugates enhanced cellular uptake of ASO without yielding a cytotoxic effect and protected the ASO against enzymatic attack and chemical reduction. AS-L showed enhanced intra-cellular localization compared to naked ASO and the complex of ASO with lipofectamine during hypoxic-differentiation. Consequently AS-L induced significant down-regulation of leptin and VEGF gene expressions, thereby reducing fat accumulation in the cell. This proof-of-concept study shows that AS-L produces an inhibitory effect on adipogenesis and angiogenesis during differentiation, indicating LMWP mediated ASO delivery can potentially be a safe and promising treatment for obesity.
缺氧是血管生成的强调节剂，加速脂肪组织的扩张，这表明缺氧诱导因子 1α（HIF1α）可以成为一种新的抗肥胖靶标。我们将反义 HIF1α-寡核苷酸（ASO）与小分子鱼精蛋白（LMWP），一种穿透细胞膜的肽，连接起来，以增强其阻断缺氧血管生成的能力，从而产生抗肥胖作用。纳米大小的 ASO-LMWP（AS-L）缀合物增强了 ASO 的细胞摄取，而不会产生细胞毒性作用，并保护 ASO 免受酶攻击和化学还原。与缺氧分化期间的裸露 ASO 和 ASO 与脂质体的复合物相比，AS-L 显示出增强的细胞内定位。因此，AS-L 诱导瘦素和 VEGF 基因表达的显著下调，从而减少细胞内脂肪堆积。这项概念验证研究表明，AS-L 在分化过程中对脂肪生成和血管生成产生抑制作用，表明 LMWP 介导的 ASO 传递可能是一种安全且有前途的肥胖治疗方法。
