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

  • Kexin Na
  • Kai Liu
  • Jiang Yu
  • Xue Wang
  • Meng Li
  • Chutong Tian
  • Haixia He
  • Yuan He
  • Yongjun WangEmail author
Original Article


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.


Gambogic acid Retinoic acid Co-encapsulated liposomes Solvent-assisted active loading technology Synergistic therapy 



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




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


Gambogic acid


Retinoic acid


Funding information

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

Compliance with ethical standards

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).

Conflict of interest

The authors declare that they have no conflict of interest.


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Copyright information

© Controlled Release Society 2019

Authors and Affiliations

  • Kexin Na
    • 1
  • Kai Liu
    • 2
  • Jiang Yu
    • 1
  • Xue Wang
    • 3
  • Meng Li
    • 1
  • Chutong Tian
    • 1
  • Haixia He
    • 1
  • Yuan He
    • 2
  • Yongjun Wang
    • 1
    Email author
  1. 1.Wuya College of InnovationShenyang Pharmaceutical UniversityShenyangChina
  2. 2.Research InstituteJiangsu Hengrui Medicine Co., Ltd.Lianyungang CityPeople’s Republic of China
  3. 3.Department of Pharmaceutics, School of PharmacyShenyang Pharmaceutical UniversityShenyangChina

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