Contrastive Studies of Cytarabine/Daunorubicin Dual-Loaded Liposomes Prepared by pH Gradient and Cu 2+ Gradient Method
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Research Article Contrastive Studies of Cytarabine/Daunorubicin Dual-Loaded Liposomes Prepared by pH Gradient and Cu2+ Gradient Method Jiaoyang Zhang,1 Lingli Zhou,1 Yu Zhang,1 Haibing He,1 Tian Yin,2 Jingxin Gou,1 Yanjiao Wang,1 and Xing Tang1,3
Received 28 August 2020; accepted 28 October 2020; published online 18 November 2020 Abstract. Conventional combination chemotherapy often leads to unsatisfactory clinical outcomes due to the different distribution characteristics in vivo and the superimposed systemic toxicity of the drug cocktail. Co-encapsulated nano preparations have been gradually developed in recent years. In this work, cytarabine (Ara-C)/daunorubicin (DNR) liposomes were prepared by the pH gradient (ADL-pH) and Cu2+ gradient (ADL-Cu) methods. Ara-C did not show significant release from either ADL-Cu or ADL-pH in vitro during 168 h, which related to its logPoct. Different drug-loading patterns showed different release characteristics of DNR due to the different existence forms, ADL-pH contains the citrate form, while in ADL-Cu, there is the Cu2+ complex. To evaluate the release behavior, daunorubicin liposome (DL) and daunorubicin-Cu2+ complex (DNR-Cu) were prepared. The addition of EDTA in the release medium significantly increased the release rate of DNR from DL-Cu, while lower pH accelerated DNR release from both DL-pH and DL-Cu. The PK confirmed that ADL-Cu and ADL-pH could prolong the drug circulation time, and ADL-Cu had a mean retention time 1.5 times that of ADL-pH. Furthermore, both liposomes allowed the two drugs to maintain a relatively constant plasma concentration ratio for a prolonged time. Cytotoxicity assays showed that Ara-C/DNR with a molar ratio of 5:1 and 3:1 exhibited an excellent synergistic effect, which was more obvious at 5:1. In vitro antitumor results revealed that ADL-Cu exhibited more cytotoxicity than ADL-pH. All factors tested in this work suggest the considerable potential of ADL-Cu and ADL-pH for anticancer treatment. KEY WORDS: dual-loaded liposome; drug copper ion complex; in vitro release kinetics; PK; cytotoxicity.
INTRODUCTION Over recent years, combination chemotherapy using two or more anticancer drugs with different mechanisms of action 1
Department of Pharmaceutics Science, Shenyang Pharmaceutical University, Shenyang, 110016, China. 2 Faculty of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang, 110016, China. 3 To whom correspondence should be addressed. (e–mail: [email protected]) Abbreviations: Ara-C, Cytarabine; DNR, Daunorubicin; ADL-pH, Cytarabine/daunorubicin liposome prepared by pH gradient method; ADL-Cu, Cytarabine/daunorubicin liposome prepared by Cu2+ gradient method; DL, Daunorubicin liposome; DNR-Cu, Daunorubicin-Cu2+ complex; AML, Acute myelogenous leukemia; DL-passive, Daunorubicin liposome prepared by passive drugloading method; DL-Cu, Daunorubicin liposome prepared by Cu2+ gradient method; DL-pH, Daunorubicin liposome prepared by pH gradient method; TEM, Transmission electron microscopy; PK, Pharmacokinetics; DMSO, Dimethy
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