Nanomedicine Science and Technology Center, Northeastern University, Boston, MA, USA.
Department of Radiation Oncology, Dana Farber Cancer Institute, Boston, MA, USA.
Int J Nanomedicine. 2018 Mar 15;13(T-NANO 2014 Abstracts):59-61. doi: 10.2147/IJN.S124992. eCollection 2018.
PARP-l is a DNA repair protein that plays a role in a number of repair pathways and also helps in transcriptional regulation; thus PARP inhibitors (PARPi), such as olaparib and BMN-673, act by inhibiting DNA damage repair. This leads to an accumulation of deleterious mutations leading to genetic instability as a result of a number of cell replications. Currently, olaparib is only available in an oral form and has poor bioavailability, consequently leading to poor accumulation in the tumor due to first-pass metabolism. Therefore, in the present study, an injectable nanoparticle formulation of olaparib was created that offers a delivery route in which the drug would be fully bioavailable in the vasculature, suggesting greater tumor accumulation. Our results illustrated that injectable nanoformulations of olaparib and BMN-673, a next generation PARPi, could be developed, and an efficacy test indicated that BMN-673 is a much more potent PARPi than olaparib. The success of these molecular inhibitors as a monotherapy in inhibiting colony formation suggests enhanced efficacy of these treatments in combination with other therapies, even in tumors which have developed resistance.
PARP-l 是一种 DNA 修复蛋白，在许多修复途径中发挥作用，同时也有助于转录调控；因此，PARP 抑制剂（PARPi），如奥拉帕利和 BMN-673，通过抑制 DNA 损伤修复起作用。这会导致有害突变的积累，导致由于多次细胞复制而导致遗传不稳定。目前，奥拉帕利仅以口服形式提供，生物利用度差，因此由于首过代谢，导致肿瘤中积累不良。因此，在本研究中，创建了奥拉帕利的可注射纳米颗粒制剂，提供了一种药物在脉管系统中完全具有生物利用度的给药途径，表明肿瘤积累增加。我们的结果表明，可以开发奥拉帕利和 BMN-673（下一代 PARPi）的可注射纳米制剂，并且功效测试表明，BMN-673 是比奥拉帕利更有效的 PARPi。这些分子抑制剂作为单一疗法抑制集落形成的成功表明，即使在已经产生耐药性的肿瘤中，这些治疗方法与其他疗法联合使用时，效果会更好。
