A Progressively Disassembled DNA Repair Inhibitors Nanosystem for the Treatment of BRCA Wild-Type Triple-Negative Breast Cancer

Abstract

Weimin Fang,1,2,* Jinghao Wang,3,* Xiaocong Ma,1,2 Ni Shao,1,2 Kunlin Ye,1,2 Dong Zhang,1,2 Changzheng Shi,1,2 Liangping Luo1,2 1Medical Imaging Center, the First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, People’s Republic of China; 2The Guangzhou Key Laboratory of Molecular and Functional Imaging for Clinical Translation, Jinan University, Guangzhou, Guangdong, People’s Republic of China; 3Department of Pharmacy, the First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Changzheng Shi, Medical Imaging Center, The Guangzhou Key Laboratory of Molecular and Functional Imaging for Clinical Translation, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, People’s Republic of China, Email [email protected] Liangping Luo, Medical Imaging Center, The Guangzhou Key Laboratory of Molecular and Functional Imaging for Clinical Translation, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, People’s Republic of China. Department of Radiology, The Fifth Affiliated Hospital of Jinan University, Guangzhou, Guangdong, People’s Republic of China, Email [email protected]: Olaparib, a poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor has demonstrated promising efficacy in patients with triple-negative breast cancer (TNBC) carrying breast cancer gene (BRCA) mutations. However, its impact on BRCA wild-type (BRCAwt) TNBC is limited. Hence, it is crucial to sensitize BRCAwt TNBC cells to olaparib for effective clinical practice. Novobiocin, a DNA polymerase theta (POLθ) inhibitor, exhibits sensitivity towards BRCA-mutated cancer cells that have acquired resistance to PARP inhibitors. Although both of these DNA repair inhibitors demonstrate therapeutic efficacy in BRCA-mutated cancers, their nanomedicine formulations’ antitumor effects on wild-type cancer remain unclear. Furthermore, ensuring effective drug accumulation and release at the cancer site is essential for the clinical application of olaparib.Materials and Methods: Herein, we designed a progressively disassembled nanosystem of DNA repair inhibitors as a novel strategy to enhance the effectiveness of olaparib in BRCAwt TNBC. The nanosystem enabled synergistic delivery of two DNA repair inhibitors olaparib and novobiocin, within an ultrathin silica framework interconnected by disulfide bonds.Results: The designed nanosystem demonstrated remarkable capabilities, including long-term molecular storage and specific drug release triggered by the tumor microenvironment. Furthermore, the nanosystem exhibited potent inhibitory effects on cell viability, enhanced accumulation of DNA damage, and promotion of apoptosis in BRCAwt TNBC cells. Additionally, the nanosystem effectively accumulated within BRCAwt TNBC, leading to significant growth inhibition and displaying vascular regulatory abilities as assessed by magnetic resonance imaging (MRI).Conclusion: Our results provided the inaugural evidence showcasing the potential of a progressively disassembled nanosystem of DNA repair inhibitors, as a promising strategy for the treatment of BRCA wild-type triple-negative breast cancer.Keywords: olaparib, novobiocin, tumor microenvironment, disulfide bonds, drug release, magnetic resonance

Keywords

• olaparib
• novobiocin
• tumor microenvironment
• disulfide bonds
• drug release
• magnetic resonance