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Published on: August 22, 2016
In vitro analysis of PARP inhibitor nanoformulations
Paige Baldwin1, Shifalika Tangutoori1,2, Srinivas Sridhar1,2
1Nanomedicine Science and Technology Center, Northeastern University, 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.
Insights
Injectable nanoparticle formulations of PARP inhibitors (PARPi) olaparib and BMN-673 were developed. BMN-673 demonstrated greater potency than olaparib, suggesting potential for combination therapies in resistant tumors.
Area of Science:
- Oncology
- Pharmacology
- Biotechnology
Background:
- Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) target DNA repair pathways.
- Olaparib, an oral PARPi, has limited tumor accumulation due to poor bioavailability.
- Novel drug delivery systems are needed to enhance PARPi efficacy.
Purpose of the Study:
- To develop injectable nanoparticle formulations of olaparib and BMN-673.
- To compare the potency of olaparib and BMN-673.
- To assess the potential of these nanoformulations in cancer therapy.
Main Methods:
- Development of injectable nanoparticle formulations for olaparib and BMN-673.
- In vitro efficacy testing of nanoformulated PARPi.
- Comparative analysis of BMN-673 and olaparib potency.
Main Results:
- Successful development of injectable nanoformulations for both olaparib and BMN-673.
- BMN-673 exhibited significantly higher potency as a PARPi compared to olaparib.
- Nanoformulated PARPi demonstrated efficacy in inhibiting cancer cell colony formation.
Conclusions:
- Injectable nanoformulations offer a promising delivery route for PARPi, improving bioavailability and tumor accumulation.
- BMN-673 represents a more potent PARPi than olaparib.
- These findings support the potential of nanoformulated PARPi, particularly BMN-673, as monotherapy or in combination treatments for various cancers, including resistant types.
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