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Enhancing PARP inhibitor efficacy using reduction-responsive nanoparticles encapsulating NADP
Hao Chen1, Fan Tan1, Yukui Zhang1,2
1Key Laboratory of Molecular Medicine and Biological Diagnosis and Treatment (Ministry of Industry and Information Technology), School of Life Science, Beijing Institute of Technology, Beijing 100081, China. xiebingteng@bit.edu.cn.
Abstract:
Poly(ADP-ribose) polymerase inhibitors (PARPi) have shown success in cancer chemotherapy; however, not all tumors respond effectively to PARPi treatment, even in the presence of BRCA1/2 mutations or homologous recombination (HR) repair defects. NADP+ was recently identified as an endogenous inhibitor of ADP-ribosylation with the potential to sensitize cancer cells to PARPi, yet its lack of membrane permeability poses a significant challenge to its clinical application. In this study, we developed reduction-responsive nanoparticles (NPs) containing disulfide bonds, which can be cleaved in the reductive environment of tumor cells. These NPs encapsulate NADP+ and the commercially available PARP inhibitor olaparib. The uptake of these NPs significantly increases the intracellular concentration of NADP+, which negatively regulates DNA damage-induced PARylation and impairs DNA damage repair. The combined effects of elevated NADP+ levels and olaparib synergistically suppress tumor cell growth. Overall, our study offers a promising strategy for the clinical application of NADP+.
Insights
This study developed nanoparticles delivering NADP+ to sensitize tumors to PARP inhibitors like olaparib. This combination therapy effectively suppresses tumor cell growth by enhancing DNA repair inhibition.
Area of Science:
- Biochemistry
- Nanotechnology
- Oncology
Background:
- Poly(ADP-ribose) polymerase inhibitors (PARPi) are effective cancer treatments, but resistance limits their use.
- NADP+ inhibits ADP-ribosylation and can sensitize cancer cells to PARPi, but its poor cell membrane permeability is a challenge.
Purpose of the Study:
- To develop a nanoparticle delivery system for NADP+ to overcome its permeability issues.
- To investigate the synergistic effect of NADP+-loaded nanoparticles and olaparib on tumor cell growth.
Main Methods:
- Designed reduction-responsive nanoparticles (NPs) with disulfide bonds for intracellular NADP+ release.
- Encapsulated NADP+ and olaparib within these NPs.
- Evaluated NP uptake, intracellular NADP+ levels, and effects on DNA damage repair and tumor cell proliferation.
Main Results:
- NPs successfully delivered NADP+ into tumor cells, increasing intracellular concentrations.
- Elevated NADP+ inhibited DNA damage-induced PARylation and impaired DNA repair.
- Combined NADP+ and olaparib treatment synergistically suppressed tumor cell growth.
Conclusions:
- Reduction-responsive nanoparticles offer a viable strategy for delivering NADP+ to cancer cells.
- This NADP+-based nanoparticle system combined with olaparib shows significant potential for cancer therapy.
