Carie Adam, Sullivan Bradford, Ellis Tyler, Semple J Edward, Buley Taylor, Costich Tara Lee, Crouse Richard, Bakewell Suzanne, Sill Kevin
Intezyne Technologies, 3720 Spectrum Blvd. Ste. 104, Tampa, FL, USA.
J Drug Deliv. 2016;2016:8046739. doi: 10.1155/2016/8046739. Epub 2016 Dec 1.
Epothilones have demonstrated promising potential for oncology applications but suffer from a narrow therapeutic window. Epothilone D stabilizes microtubules leading to apoptosis, is active against multidrug-resistant cells, and is efficacious in animal tumor models despite lack of stability in rodent plasma. Clinical development was terminated in phase II due to dose limiting toxicities near the efficacious dose. Taken together, this made epothilone D attractive for encapsulation in a stabilized polymer micelle for improved safety and efficacy. We have designed a library of triblock copolymers to develop IT-147, a lead formulation of epothilone D that extends plasma circulation for accumulation in the tumor environment, and potentially decrease systemic exposure to reduce dose limiting toxicities. The drug loading efficiency for IT-147 exceeds 90%, is 75 nm in diameter, and demonstrates pH-dependent release of epothilone D without chemical conjugation or enzymatic activation. Administration of IT-147 at 20 mg/kg increases exposure of epothilone D to the plasma compartment over 6-fold compared to free drug. At the same dose, 20 mg/kg epothilone D from IT-147 is considered the no observed adverse effect level (NOAEL) but is the maximum tolerated dose for free drug. Consequently, IT-147 is positioned to be a safer, more effective means to deliver epothilone D.
埃坡霉素在肿瘤学应用方面已显示出有前景的潜力，但治疗窗口较窄。埃坡霉素D可稳定微管从而导致细胞凋亡，对多药耐药细胞有活性，并且在动物肿瘤模型中有效，尽管在啮齿动物血浆中缺乏稳定性。由于在有效剂量附近出现剂量限制性毒性，其临床开发在II期终止。综上所述，这使得埃坡霉素D对于封装在稳定的聚合物胶束中以提高安全性和有效性具有吸引力。我们设计了一个三嵌段共聚物库来开发IT-147，这是埃坡霉素D的一种先导制剂，可延长血浆循环时间以便在肿瘤环境中蓄积，并有可能减少全身暴露以降低剂量限制性毒性。IT-147的载药效率超过90%，直径为75纳米，并且在没有化学偶联或酶促激活的情况下表现出埃坡霉素D的pH依赖性释放。与游离药物相比，以20毫克/千克的剂量给药IT-147可使埃坡霉素D在血浆中的暴露增加6倍以上。在相同剂量下，来自IT-147的20毫克/千克埃坡霉素D被认为是未观察到不良反应水平（NOAEL），但却是游离药物的最大耐受剂量。因此，IT-147有望成为一种更安全、更有效的递送埃坡霉素D的手段。
