International Journal of Nanomedicine (Mar 2018)
In vitro analysis of PARP inhibitor nanoformulations
Abstract
Paige Baldwin,1 Shifalika Tangutoori,1,2 Srinivas Sridhar1,2 1Nanomedicine Science and Technology Center, Northeastern University, Boston, MA, USA; 2Department of Radiation Oncology, Dana Farber Cancer Institute, Boston, MA, USA Abstract: 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. Keywords: PARP-l, olaparib, BMN-673, DNA repair protein, tumor accumulation
