Division of Cardiology, Washington University School of Medicine, 4320 Forest Park Avenue, Saint Louis, MO 63108, USA.
Nanomedicine (Lond). 2012 Oct;7(10):1507-19. doi: 10.2217/nnm.12.27. Epub 2012 Jun 18.
The chemical instability of antiangiogenic fumagillin, combined with its poor retention during intravascular transit, requires an innovative solution for clinical translation. We hypothesized that an Sn-2 lipase-labile fumagillin prodrug, in combination with a contact-facilitated drug delivery mechanism, could be used to address these problems.
α(v)β(3)-targeted and nontargeted nanoparticles with and without fumagillin in the prodrug or native forms were evaluated in vitro and in vivo in the Matrigel™ (BD Biosciences, CA, USA) plug model of angiogenesis in mice.
In vitro experiments demonstrated that the new fumagillin prodrug decreased viability at least as efficacious as the parent compound, on an equimolar basis. In the Matrigel mouse angiogenesis model, α(v)β(3)-fumagillin prodrug decreased angiogenesis as measured by MRI (3T), while the neovasculature was unaffected with the control nanoparticles.
The present approach resolved the previously intractable problems of drug instability and premature release in transit to target sites.
抗血管生成药物 fumagillin 化学性质不稳定，且在血管内转运过程中保留性差，这为其临床转化带来了挑战。我们假设，一种 sn-2 脂肪酶不稳定的 fumagillin 前药，结合接触促进的药物递送机制，可以用来解决这些问题。
用和不用 fumagillin 的靶向和非靶向 α(v)β(3)-纳米颗粒，以原药或前药形式，在体外和体内进行了评估，分别在小鼠 MatrigelTM（BD Biosciences，CA，美国）血管生成 plugs 模型中进行了评估。
体外实验表明，新的 fumagillin 前药在等摩尔浓度下，其活性与母体化合物相当，降低细胞活力的效果至少一样好。在 Matrigel 小鼠血管生成模型中，3T MRI 测量表明，α(v)β(3)-fumagillin 前药减少了血管生成，而对照纳米颗粒对新生血管没有影响。
本研究解决了药物不稳定性和在向靶部位转运过程中过早释放这两个以前难以解决的问题。
