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A solvent-assisted active loading technology to prepare gambogic acid and all-trans retinoic acid co-encapsulated liposomes for synergistic anticancer therapy

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Abstract

Liposomal drug delivery has become an established technology platform to deliver dual drugs to produce synergistic effects and reduce the adverse effects of traditional chemotherapy. Gambogic acid (GA) and retinoic acid (RA) are both effective anticancer components, but their low water-solubility (gambogic acid < 0.0050 mg/mL, retinoic acid 0.0048 < mg/mL) makes it difficult to load both drugs into the liposomes actively using the conventional method. We have successfully used solvent-assisted active loading technology (SALT) to load the insoluble drugs into the internal water phase via water-miscible organic solvent. Gambogic acid and retinoic acid co-encapsulated liposomes (weight ratio of GA to RA = 1:2, GRL) exhibited the strongest synergistic effect; combination index (CI) was 0.614 in 4T1 cells. Our studies demonstrated that GRL had uniform droplet size of about 130 nm, high stability, and controlled release behavior. GRL outperformed gambogic acid and retinoic acid solution (GRS) in pharmacokinetic profiles for a longer half-life and increased AUC. Comparing to GRS, GL, and RL, GRL showed increased cytotoxicity and apoptosis in 4T1 cells and showed the strongest anti-tumor ability in the in vivo anti-tumor efficacy. Overall, the SALT was a promising method to active loading poorly soluble drugs into liposomes, and the results showed GRL possessed a great potential for use in synergistic anticancer therapy.

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Abbreviations

DSPC:

1, 2-distearoyl-sn-glycero-3-phosphocholine

CHO:

Cholesterol

DSPE-PEG2000 :

2-distearoyl-snglycero-3-phosphoethanolamine-N-[methyl (polyethylene glycol)-2000

GA:

Gambogic acid

RA:

Retinoic acid

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Funding

This work was financially supported by the Career Development Program for Yong and Middle-aged Teachers in Shenyang Pharmaceutical University.

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Author notes

  1. Kexin Na and Kai Liu contributed equally to this work.

Authors and Affiliations

  1. Wuya College of Innovation, Shenyang Pharmaceutical University, Wenhua Road, Shenyang, 110016, China

    Kexin Na, Jiang Yu, Meng Li, Chutong Tian, Haixia He & Yongjun Wang

  2. Research Institute, Jiangsu Hengrui Medicine Co., Ltd., No. 7 Kunlunshan Road, Lianyungang City, Jiangsu Province, People’s Republic of China

    Kai Liu & Yuan He

  3. Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road, Shenyang, 110016, China

    Xue Wang

Authors
  1. Kexin Na
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  2. Kai Liu
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  3. Jiang Yu
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  4. Xue Wang
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  5. Meng Li
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  8. Yuan He
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  9. Yongjun Wang
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Corresponding author

Correspondence to Yongjun Wang.

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All procedures performed in studies involving animals were in accordance with the national regulations and were approved by Institutional Animal Ethical Care Committee of Shenyang Pharmaceutical University (SYPU-IACUC-C2018-4-2-203, approval date: 2 April 2018).

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The authors declare that they have no conflict of interest.

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Na, K., Liu, K., Yu, J. et al. A solvent-assisted active loading technology to prepare gambogic acid and all-trans retinoic acid co-encapsulated liposomes for synergistic anticancer therapy. Drug Deliv. and Transl. Res. 10, 146–158 (2020). https://doi.org/10.1007/s13346-019-00669-4

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