title: A Multi-Mitochondrial Anticancer Agent that Selectively Kills Cancer Cells and Overcomes Drug Resistance.
abstract: Mitochondria are double-membrane-bound organelles involved mainly in supplying cellular energy, but also play roles in signaling, cell differentiation, and cell death. Mitochondria are implicated in carcinogenesis, and therefore dozens of lethal signal transduction pathways converge on these organelles. Accordingly, mitochondria provide an alternative target for cancer management. In this study, F16, a drug that targets mitochondria, and chlorambucil (CBL), which is indicated for the treatment of selected human neoplastic diseases, were covalently linked, resulting in the synthesis of a multi-mitochondrial anticancer agent, FCBL. FCBL can associate with human serum albumin (HSA) to form an HSA-FCBL nanodrug, which selectively recognizes cancer cells, but not normal cells. Systematic investigations show that FCBL partially accumulates in cancer cell mitochondria to depolarize mitochondrial membrane potential (MMP), increase reactive oxygen species (ROS), and attack mitochondrial DNA (mtDNA). With this synergistic effect on multiple mitochondrial components, the nanodrug can effectively kill cancer cells and overcome multiple drug resistance. Furthermore, based on its therapeutic window, HSA-FCBL exhibits clinically significant differential cytotoxicity between normal and malignant cells. Finally, while drug dosage and drug resistance typically limit first-line mono-chemotherapy, HSA-FCBL, with its ability to compromise mitochondrial membrane integrity and damage mtDNA, is expected to overcome those limitations to become an ideal candidate for the treatment of neoplastic disease.
authors.affiliation: Molecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering.|Collaborative Research Center of Molecular Engineering for Theranostics, Hunan University, Changsha, 410082, China.
authors.forename: Yong Bo
authors.initials: YB
authors.lastname: Peng
authors.affiliation: Molecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering.|Collaborative Research Center of Molecular Engineering for Theranostics, Hunan University, Changsha, 410082, China.
authors.forename: Zi Long
authors.initials: ZL
authors.lastname: Zhao
authors.affiliation: Molecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering.|Collaborative Research Center of Molecular Engineering for Theranostics, Hunan University, Changsha, 410082, China.|Department of Infectious Diseases, Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China.
authors.forename: Teng
authors.initials: T
authors.lastname: Liu
authors.affiliation: Changsha HuoZi Biological Science and Technology / Department of Urology, Third Xiangya Hospital, Central South University, Changsha, 410013, China.
authors.forename: Guo Jian
authors.initials: GJ
authors.lastname: Xie
authors.affiliation: Molecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering.|Collaborative Research Center of Molecular Engineering for Theranostics, Hunan University, Changsha, 410082, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Jin
authors.affiliation: Molecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering.|Collaborative Research Center of Molecular Engineering for Theranostics, Hunan University, Changsha, 410082, China.
authors.forename: Tang Gang
authors.initials: TG
authors.lastname: Deng
authors.affiliation: Molecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering.|Collaborative Research Center of Molecular Engineering for Theranostics, Hunan University, Changsha, 410082, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Infectious Diseases, Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China.
authors.forename: Xiong
authors.initials: X
authors.lastname: Li
authors.affiliation: Molecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering.|Collaborative Research Center of Molecular Engineering for Theranostics, Hunan University, Changsha, 410082, China.
authors.forename: Xiao Xiao
authors.initials: XX
authors.lastname: Hu
authors.affiliation: Molecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering.|Collaborative Research Center of Molecular Engineering for Theranostics, Hunan University, Changsha, 410082, China.
authors.forename: Xiao Bing
authors.initials: XB
authors.lastname: Zhang
authors.affiliation: Molecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering.|Collaborative Research Center of Molecular Engineering for Theranostics, Hunan University, Changsha, 410082, China.
authors.forename: Mao
authors.initials: M
authors.lastname: Ye
authors.affiliation: Molecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering.|Collaborative Research Center of Molecular Engineering for Theranostics, Hunan University, Changsha, 410082, China.|Department of Chemistry, Department of Physiology and Functional Genomics, Center for Research at Bio/Nano Interface, Shands Cancer Center, University of Florida Genetics Institute.|McKnight Brain Institute, University of Florida, Gainesville, FL, 32611-7200, USA.
authors.forename: Wei Hong
authors.initials: WH
authors.lastname: Tan
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000633:toxicity*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002699:Chlorambucil / Q000737:chemistry / Q000633:toxicity; D004249:DNA Damage / Q000187:drug effects; D004272:DNA, Mitochondrial / Q000737:chemistry / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004272:DNA, Mitochondrial; D002699:Chlorambucil
keywords: antitumor agents; chlorambucil; human serum albumin; mitochondria; nanodrugs