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Liposomal Co-Delivery of Omacetaxine Mepesuccinate and Doxorubicin for Synergistic Potentiation of Antitumor Activity

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Abstract

Purpose

Anticancer chemotherapy usually involves the administration of several anticancer drugs that differ in their action mechanisms. Here, we aimed to test whether the combination of omacetaxine mepesuccinate (OMT) and doxorubicin (DOX) could show synergism, and whether the liposomal co-delivery of these two drugs could enhance their antitumor effects in cervical carcinoma model.

Method

OMT-loaded liposomes (OL) were prepared by loading the drug in the lipid bilayers. OL were then electrostatically complexed with DOX, yielding double-loaded liposomes (DOL). DOX-loaded liposomes (DL) were formulated by electrostatic interaction with negatively charged empty liposomes (EL). The combination index (CI) values were calculated to evaluate the synergism of two drugs. In vitro antitumor effects against HeLa cells were measured using CCK-8, calcein staining, and crystal violet staining. In vivo antitumor effects of various liposomes were tested using HeLa cell-bearing mice.

Results

Combination of DOX and OMT had ratio-dependent synergistic activities, with very strong synergism observed at a molar ratio of 4:1 (DOX:OMT). The sizes of EL, DL, OL, and DOL did not significantly differ, but the zeta potentials of DL and DOL were slightly higher than those of OL and EL. In vitro, DOL showed higher antitumor activity than OL, DL or EL in cervical carcinoma HeLa cells. In vivo, unlike other liposomes, DOL reduced the tumor growths by 98.6% and 97.3% relative to the untreated control on day 15 and 25 after the cessation of treatment, respectively.

Conclusions

These results suggest that liposomal co-delivery of DOX and OMT could synergistically potentiate antitumor effects.

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Abbreviations

CI:

combination index

DL:

doxorubicin-loaded liposomes

DOL:

doxorubicin and omacetaxine mepesuccinate-loaded liposomes

DOX:

doxorubicin

EL:

empty liposomes

OL:

omacetaxine mepesuccinate-loaded liposomes

OMT:

omacetaxine mepesuccinate

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ACKNOWLEDGMENTS AND DISCLOSURES

Gayong Shim and Sangbin Lee contributed equally to this work. This work was supported by research grants from the Ministry of Science, ICT and Future Planning (No. 2013035166; 2013036131), from the Korean Health Technology R&D project, Ministry of Health and Welfare (No. A092010), and from Business for Cooperative R&D between Industry, Academy, and Research Institute funded Korea Small and Medium Business Administration (No. C0010962).

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Authors and Affiliations

  1. College of Pharmacy Research Institute of Pharmaceutical Sciences, Seoul National University, Daehak-dong, Gwanak-gu, Seoul, 151-742, Korea

    Gayong Shim, Junhyeok Choi, Soondong Lee & Yu-Kyoung Oh

  2. School of Life Sciences and Biotechnology, Korea University, Anan-dong Seungbuk-gu, Seoul, 136-713, Korea

    Sangbin Lee & Chan-Wha Kim

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  1. Gayong Shim
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  2. Sangbin Lee
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Correspondence to Chan-Wha Kim or Yu-Kyoung Oh.

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Shim, G., Lee, S., Choi, J. et al. Liposomal Co-Delivery of Omacetaxine Mepesuccinate and Doxorubicin for Synergistic Potentiation of Antitumor Activity. Pharm Res 31, 2178–2185 (2014). https://doi.org/10.1007/s11095-014-1317-3

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  • DOI: https://doi.org/10.1007/s11095-014-1317-3

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