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Liposomal Doxorubicin: the Sphingomyelin/Cholesterol System Significantly Enhances the Antitumor Efficacy of Doxorubicin

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Abstract

Doxorubicin (DOX) has a cytotoxic effect on many tumor cells; however, its clinical application is limited owing to its strong side effects. Although Doxil® reduces the cardiotoxicity of free DOX, it has also introduced a new dose-limiting toxicity. In a previous study, a sialic acid-cholesterol conjugate (SA-CH) was synthesized and modified onto the surface of DOX-loaded liposomes to target tumor-associated macrophages (TAMs), further improving the efficacy of DOX-loaded liposomes over that of Doxil®. Meanwhile, the good retention characteristics and promising antitumor ability of sphingomyelin/cholesterol (SM/CH) system for water-soluble drugs have attracted wide attention. Therefore, we aimed to use SA-CH as the target and hydrogenated soybean phosphatidylcholine (HSPC) or egg sphingomyelin (ESM) as the membrane material to develop a more stable DOX-loaded liposome with stronger antitumor activity. The liposomes were evaluated for particle size, polydispersity index, zeta potential, entrapment efficiency, in vitro release, long-term storage, cytotoxicity, cellular uptake, pharmacokinetics, tumor targetability, and in vivo antitumor activity. In the liposomes prepared using HSPC/CH, sialic acid (SA) modification considerably increased the accumulation of DOX-loaded liposomes in the tumor, thus exerting a better antitumor effect. However, SA modification in DOX-ESL (SA-CH-modified DOX-loaded liposomes prepared by ESM/CH) destroyed the strong retention effect of the ESM/CH system on DOX, resulting in a reduced antitumor effect. Notably, DOX-ECL (DOX-loaded liposome prepared by ESM/CH) had the optimal storage stability, lowest toxicity, and optimal antitumor effect due to better drug retention properties. Thus, the ESM/CH liposome of DOX is a potential drug delivery system.

Graphical Abstract

Sketch of the effect of two DOX-loaded liposomes with hydrogenated soybean phospholipid (HSPC) and egg sphingomyelin (ESM) as lipid membrane material and surface-modified SA derivative on tumor growth inhibition.

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Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Abbreviations

DOX:

Doxorubicin

TAMs:

Tumor-associated macrophages

TME:

Tumor microenvironment

SA-CH:

Sialic acid-cholesterol conjugate

DOX-S:

DOX solution

DOX-HCL:

DOX-loaded liposome prepared by HSPC/CH

DOX-HSL:

SA-CH-modified DOX-loaded liposome prepared by HSPC/CH

DOX-ECL:

DOX-loaded liposome prepared by ESM/CH

DOX-ESL:

SA-CH-modified DOX-loaded liposome prepared by ESM/CH

DiR-HCL:

DiR-loaded liposome prepared by HSPC/CH

DiR-HSL:

SA-CH-modified DiR-loaded liposome prepared by HSPC/CH

DiR-ECL:

DiR-loaded liposome prepared by ESM/CH

DiR-ESL:

SA-CH-modified DiR-loaded liposome prepared by ESM/CH

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Acknowledgements

The authors are grateful for the laboratory facilities support provided by Shenyang Pharmaceutical University.

Funding

This study was supported by the Career Development Support Plan for Young and Middle-aged Teachers at Shenyang Pharmaceutical University (ZDN2021009) and the Natural National Science Foundation of China (Grant Numbers 81973271).

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Authors and Affiliations

  1. College of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning, 110016, People’s Republic of China

    Xianmin Meng, Hongxia Zhang, Lingyan Chen, Mingqi Wang, Kaituo Zhang, Xinrong Liu, Yihui Deng & Yanzhi Song

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  1. Xianmin Meng
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  2. Hongxia Zhang
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  3. Lingyan Chen
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  4. Mingqi Wang
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Contributions

Conceptualization: Hongxia Zhang, Yihui Deng, and Yanzhi Song; data curation: Xianmin Meng, Hongxia Zhang, Yihui Deng, and Yanzhi Song; acquisition: Hongxia Zhang, Lingyan Chen, Mingqi Wang, and Kaituo Zhang; writing and analysis: Xianmin Meng; supervision: Xinrong Liu. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Yihui Deng or Yanzhi Song.

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Meng, X., Zhang, H., Chen, L. et al. Liposomal Doxorubicin: the Sphingomyelin/Cholesterol System Significantly Enhances the Antitumor Efficacy of Doxorubicin. AAPS PharmSciTech 24, 64 (2023). https://doi.org/10.1208/s12249-022-02489-1

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