Department of Radiology , Memorial Sloan Kettering Cancer Center , New York , New York 10065 , United States.
Translational and Molecular Imaging Institute, Department of Radiology , Icahn School of Medicine at Mount Sinai , New York , New York 10029 , United States.
Bioconjug Chem. 2018 Nov 21;29(11):3776-3782. doi: 10.1021/acs.bioconjchem.8b00640. Epub 2018 Nov 7.
The preclinical potential of many diagnostic and therapeutic small molecules is limited by their rapid washout kinetics and consequently modest pharmacological performances. In several cases, these could be improved by loading the small molecules into nanoparticulates, improving blood half-life, in vivo uptake and overall pharmacodynamics. In this study, we report a nanoemulsion (NE) encapsulated form of PARPi-FL. As a proof of concept, we used PARPi-FL, which is a fluorescently labeled sensor for olaparib, a FDA-approved small molecule inhibitor of the nuclear enzyme poly(ADP-ribose)polymerase 1 (PARP1). Encapsulated PARPi-FL showed increased blood half-life, and delineated subcutaneous xenografts of small cell lung cancer (SCLC), a fast-progressing disease where efficient treatment options remain an unmet clinical need. Our study demonstrates an effective method for expanding the circulation time of a fluorescent PARP inhibitor, highlighting the pharmacokinetic benefits of nanoemulsions as nanocarriers and confirming the value of PARPi-FL as an imaging agent targeting PARP1 in small cell lung cancer.
许多诊断和治疗用小分子的临床前潜力受到其快速洗脱动力学的限制，因此其药理性能也较为温和。在某些情况下，通过将小分子加载到纳米颗粒中，可以改善其血液半衰期、体内摄取和整体药效动力学特性。在这项研究中，我们报告了一种 PARPi-FL 的纳米乳液（NE）封装形式。作为概念验证，我们使用了 PARPi-FL，它是一种荧光标记的奥拉帕利传感器，奥拉帕利是一种已获得 FDA 批准的核酶聚（ADP-核糖）聚合酶 1（PARP1）小分子抑制剂。封装的 PARPi-FL 显示出更长的血液半衰期，并描绘了小细胞肺癌（SCLC）的皮下异种移植物，SCLC 是一种快速进展的疾病，有效的治疗选择仍然是未满足的临床需求。我们的研究证明了一种有效延长荧光 PARP 抑制剂循环时间的方法，突出了纳米乳液作为纳米载体的药代动力学优势，并证实了 PARPi-FL 作为一种针对小细胞肺癌 PARP1 的成像剂的价值。
