title: Combination delivery of Adjudin and Doxorubicinviaintegrating drug conjugation and nanocarrier approaches for the treatment of drug-resistant cancer cells.
abstract: Combination therapy has been regarded as a potent strategy to overcome multidrug resistance (MDR). In this study, we adopt Adjudin (ADD), a mitochondria inhibitor, and Doxorubicin (DOX), a common chemo-drug, to treat drug-resistant cancer cells (MCF-7/ADR) in combination. Given the different physico-chemical properties of ADD and DOX, we develop a novel drug formulation (ADD-DOX (M)) by integrating drug conjugation and nanocarrier approaches to realize the co-delivery of the two drugs. We demonstrate the conjugation of ADD and DOXviaformation of an acid-sensitive hydrazone bond, and then the encapsulation of ADD-DOX conjugates by DSPE-PEG2000micelles with high drug encapsulation efficiency and well-controllable drug loading efficiency. The obtained ADD-DOX (M) micelles are found to be stable under physiological conditions, but can rapidly release drugs within acidic environments. Following cellular experiments confirm that ADD-DOX (M) vehicles can be internalized by MCF-7/ADR cancer cells through an endocytic pathway and exist within the moderate acidic endolysosomes, thus accelerating the hydrolysis of ADD-DOX and the release of free ADD and DOX. As a result, the ADD-DOX (M) formulation exhibits an excellent anti-MDR effect. In summary, we for the first time report the combinational use of ADD and DOX with an effective co-delivery strategy for the treatment of MDR cancer cells.
authors.affiliation: Tongji School of Pharmacy, National Engineering Research Center for Nanomedicine, Huazhong University of Science and Technology, Wuhan 430030, P.R. China. ; Tel: +86-027-83601832.
authors.forename: Xu
authors.initials: X
authors.lastname: Li
authors.affiliation: Tongji School of Pharmacy, National Engineering Research Center for Nanomedicine, Huazhong University of Science and Technology, Wuhan 430030, P.R. China. ; Tel: +86-027-83601832.
authors.forename: Cuixia
authors.initials: C
authors.lastname: Gao
authors.affiliation: Tongji School of Pharmacy, National Engineering Research Center for Nanomedicine, Huazhong University of Science and Technology, Wuhan 430030, P.R. China. ; Tel: +86-027-83601832.
authors.forename: Yupei
authors.initials: Y
authors.lastname: Wu
authors.affiliation: The Mary M. Wohlford Laboratory for Male Contraceptive Research, Center for Biomedical Research, Population Council, New York, NY 10065, USA.
authors.forename: C-Yan
authors.initials: CY
authors.lastname: Cheng
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, School of Biomedical Engineering & Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
authors.forename: Weiliang
authors.initials: W
authors.lastname: Xia
authors.affiliation: Tongji School of Pharmacy, National Engineering Research Center for Nanomedicine, Huazhong University of Science and Technology, Wuhan 430030, P.R. China. ; Tel: +86-027-83601832.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Zhang