Division of Rheumatology, Department of Medicine, Washington University School of Medicine, 660 S. Euclid Avenue, Box 8045, St. Louis, MO 63110, USA.
Biomaterials. 2012 Nov;33(33):8632-40. doi: 10.1016/j.biomaterials.2012.08.005. Epub 2012 Aug 24.
Nanoparticle-based therapeutics are emerging technologies that have the potential to greatly impact the treatment of many human diseases. However, drug instability and premature release from the nanoparticles during circulation currently preclude clinical translation. Herein, we use a lipase-labile (Sn 2) fumagillin prodrug platform coupled with a unique lipid surface-to-surface targeted delivery mechanism, termed contact-facilitated drug delivery, to counter the premature drug release and overcome the inherent photo-instability of fumagillin, an established anti-angiogenic agent. We show that α(v)β(3)-integrin targeted fumagillin prodrug nanoparticles, administered at 0.3 mg of fumagillin prodrug/kg of body weight suppress the clinical disease indices of KRN serum-mediated arthritis in a dose-dependent manner when compared to treatment with the control nanoparticles with no drug. This study demonstrates the effectiveness of this lipase-labile prodrug nanocarrier in a relevant preclinical model that approximates human rheumatoid arthritis. The lipase-labile prodrug paradigm offers a translatable approach that is broadly applicable to many targeted nanosystems and increases the translational potential of this platform for many diseases.
基于纳米粒子的治疗方法是新兴技术，有潜力极大地影响许多人类疾病的治疗。然而，在循环过程中，药物的不稳定性和从纳米粒子中的过早释放目前排除了临床转化。在此，我们使用脂酶不稳定（Sn 2 ）的苏拉明前药平台，结合独特的脂质表面到表面靶向递药机制，称为接触促进药物递药，来对抗过早的药物释放，并克服苏拉明的固有光不稳定性，苏拉明是一种已建立的抗血管生成剂。我们表明，当与没有药物的对照纳米粒子相比，以 0.3 毫克的苏拉明前药/千克体重给予靶向 α(v)β(3)-整合素的苏拉明前药纳米粒子，以剂量依赖性方式抑制 KRN 血清介导的关节炎的临床疾病指数。这项研究证明了这种脂酶不稳定前药纳米载体在接近人类类风湿关节炎的相关临床前模型中的有效性。脂酶不稳定的前药范式提供了一种可转化的方法，广泛适用于许多靶向纳米系统，并增加了该平台在许多疾病中的转化潜力。
