PMID- 38518871 OWN - NLM STAT- MEDLINE DCOM- 20240415 LR - 20240415 IS - 1873-3476 (Electronic) IS - 0378-5173 (Linking) VI - 655 DP - 2024 Apr 25 TI - Co-delivery of Paclitaxel/Atovaquone/Quercetin to regulate energy metabolism to reverse multidrug resistance in ovarian cancer by PLGA-PEG nanoparticles. PG - 124028 LID - S0378-5173(24)00262-X [pii] LID - 10.1016/j.ijpharm.2024.124028 [doi] AB - Ovarian cancer is a malignant tumor that seriously endangers the lives of women, with chemotherapy being the primary clinical treatment. However, chemotherapy encounters the problem of generating multidrug resistance (MDR), mainly due to drug efflux induced by P-glycoprotein (P-gp), which decreases intracellular accumulation of chemotherapeutic drugs. The drugs efflux mediated by P-gp requires adenosine triphosphate (ATP) hydrolysis to provide energy. Therefore, modulating energy metabolism pathways and inhibiting ATP production may be a potential strategy to reverse MDR. Herein, we developed a PTX-ATO-QUE nanoparticle (PAQNPs) based on a PLGA-PEG nanoplatform capable of loading the mitochondrial oxidative phosphorylation (OXPHOS) inhibitor atovaquone (ATO), the glycolysis inhibitor quercetin (QUE), and the chemotherapeutic drug paclitaxel (PTX) to reverse MDR by inhibiting energy metabolism through multiple pathways. Mechanistically, PAQNPs could effectively inhibit the OXPHOS and glycolytic pathways of A2780/Taxol cells by suppressing the activities of mitochondrial complex III and hexokinase II (HK II), respectively, ultimately decreasing intracellular ATP levels in tumor cells. Energy depletion can effectively inhibit cell proliferation and reduce P-gp activity, increasing the chemotherapeutic drug PTX accumulation in the cells. Moreover, intracellular reactive oxygen species (ROS) is increased with PTX accumulation and leads to chemotherapy-resistant cell apoptosis. Furthermore, PAQNPs significantly inhibited tumor growth in the A2780/Taxol tumor-bearing NCG mice model. Immunohistochemical (IHC) analysis of tumor tissues revealed that P-gp expression was suppressed, demonstrating that PAQNPs are effective in reversing MDR in tumors by inducing energy depletion. In addition, the safety study results, including blood biochemical indices, major organ weights, and H&E staining images, showed that PAQNPs have a favorable in vivo safety profile. In summary, the results suggest that the combined inhibition of the two energy pathways, OXPHOS and glycolysis, can enhance chemotherapy efficacy and reverse MDR in ovarian cancer. CI - Copyright (c) 2024 Elsevier B.V. All rights reserved. FAU - Lu, Qingyu AU - Lu Q AD - School of Pharmacy, Fujian University of Chinese Traditional Medicine, Fuzhou 350122, PR China; Department of Pharmacy, Fuzong Clinical Medical College of Fujian Medical University (900 Hospital of the Joint Logistics Team), Fuzhou 350025, PR China. FAU - Gao, Wenhao AU - Gao W AD - Department of Pharmacy, Fuzong Clinical Medical College of Fujian Medical University (900 Hospital of the Joint Logistics Team), Fuzhou 350025, PR China; School of Pharmacy, Fujian Medical University, Fuzhou 350122, PR China. FAU - Chen, Zhenzhen AU - Chen Z AD - Department of Pharmacy, Fuzong Clinical Medical College of Fujian Medical University (900 Hospital of the Joint Logistics Team), Fuzhou 350025, PR China. FAU - Liu, Zhihong AU - Liu Z AD - Department of Pharmacy, Fuzong Clinical Medical College of Fujian Medical University (900 Hospital of the Joint Logistics Team), Fuzhou 350025, PR China. FAU - Wang, Jie AU - Wang J AD - School of Nursing, Fujian University of Chinese Traditional Medicine, Fuzhou 350122, PR China. FAU - Zeng, Lingjun AU - Zeng L AD - Department of Pharmacy, Fuzong Clinical Medical College of Fujian Medical University (900 Hospital of the Joint Logistics Team), Fuzhou 350025, PR China. FAU - Hu, Xiaomu AU - Hu X AD - Department of Pharmacy, Fuzong Clinical Medical College of Fujian Medical University (900 Hospital of the Joint Logistics Team), Fuzhou 350025, PR China. FAU - Zheng, Enqin AU - Zheng E AD - School of Pharmacy, Fujian University of Chinese Traditional Medicine, Fuzhou 350122, PR China. FAU - Zhang, Qian AU - Zhang Q AD - School of Pharmacy, Fujian Medical University, Fuzhou 350122, PR China. Electronic address: 1009467948@qq.com. FAU - Song, Hongtao AU - Song H AD - School of Pharmacy, Fujian University of Chinese Traditional Medicine, Fuzhou 350122, PR China; Department of Pharmacy, Fuzong Clinical Medical College of Fujian Medical University (900 Hospital of the Joint Logistics Team), Fuzhou 350025, PR China. Electronic address: sohoto@vip.163.com. LA - eng PT - Journal Article DEP - 20240320 PL - Netherlands TA - Int J Pharm JT - International journal of pharmaceutics JID - 7804127 RN - P88XT4IS4D (Paclitaxel) RN - Y883P1Z2LT (Atovaquone) RN - 9IKM0I5T1E (Quercetin) RN - 0 (Antineoplastic Agents) RN - 0 (ATP Binding Cassette Transporter, Subfamily B) RN - 0 (ATP Binding Cassette Transporter, Subfamily B, Member 1) RN - 8L70Q75FXE (Adenosine Triphosphate) SB - IM MH - Humans MH - Female MH - Mice MH - Animals MH - Paclitaxel MH - *Ovarian Neoplasms/pathology MH - Atovaquone/pharmacology/therapeutic use MH - Quercetin/pharmacology/therapeutic use MH - Cell Line, Tumor MH - Drug Resistance, Neoplasm MH - *Antineoplastic Agents MH - Drug Resistance, Multiple MH - ATP Binding Cassette Transporter, Subfamily B/metabolism MH - ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism MH - Energy Metabolism MH - Adenosine Triphosphate/metabolism MH - *Nanoparticles OTO - NOTNLM OT - Energy depletion OT - Glycolysis OT - Multidrug resistance OT - Ovarian cancer OT - Oxidative phosphorylation COIS- Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Hongtao Song reports financial support was provided by Fujian Provincial Department of Science and Technology. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper]. EDAT- 2024/03/23 05:42 MHDA- 2024/04/15 06:43 CRDT- 2024/03/22 20:25 PHST- 2023/11/28 00:00 [received] PHST- 2024/03/06 00:00 [revised] PHST- 2024/03/19 00:00 [accepted] PHST- 2024/04/15 06:43 [medline] PHST- 2024/03/23 05:42 [pubmed] PHST- 2024/03/22 20:25 [entrez] AID - S0378-5173(24)00262-X [pii] AID - 10.1016/j.ijpharm.2024.124028 [doi] PST - ppublish SO - Int J Pharm. 2024 Apr 25;655:124028. doi: 10.1016/j.ijpharm.2024.124028. Epub 2024 Mar 20.