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Contrastive Studies of Cytarabine/Daunorubicin Dual-Loaded Liposomes Prepared by pH Gradient and Cu2+ Gradient Method

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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.

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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 drug-loading 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:

Dimethyl sulfoxide

CI:

Combination Index

MRT:

Mean residence time

ROS:

Reactive oxygen species

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Acknowledgments

Thanks to the help of my tutor Xing Tang and my sister Lingli Zhou, and Amanda Pearce is gratefully thanked for correcting English grammar of the manuscript.

Funding

This work was supported by the National Mega-project for Innovative Drugs (No. 2019ZX09721001).

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Authors and Affiliations

  1. Department of Pharmaceutics Science, Shenyang Pharmaceutical University, Shenyang, 110016, China

    Jiaoyang Zhang, Lingli Zhou, Yu Zhang, Haibing He, Jingxin Gou, Yanjiao Wang & Xing Tang

  2. Faculty of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang, 110016, China

    Tian Yin

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  1. Jiaoyang Zhang
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Correspondence to Xing Tang.

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All animal experiments were approved by the Ethics Committee of Shenyang Pharmaceutical University.

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All animal experiments are in line with guidelines for the care and use of laboratory animals.

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Zhang, J., Zhou, L., Zhang, Y. et al. Contrastive Studies of Cytarabine/Daunorubicin Dual-Loaded Liposomes Prepared by pH Gradient and Cu2+ Gradient Method. AAPS PharmSciTech 21, 325 (2020). https://doi.org/10.1208/s12249-020-01867-x

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