Efficacy of Combination Therapy with Linalool and Doxorubicin Encapsulated by Liposomes as a Two-in-One Hybrid Carrier System for Epithelial Ovarian Carcinoma

Int J Nanomedicine. 2020 Oct 29;15:8427-8436. doi: 10.2147/IJN.S272319. eCollection 2020.


Background: Epithelial ovarian cancer (EOC) is a fatal gynecologic malignancy that is usually treated with chemotherapy after surgery. However, patients who receive chemotherapy experience severe side effects because of the inherent toxicity and high dose of chemotherapeutics. To overcome these issues, we suggest a combination therapeutic strategy using liposomes encapsulating linalool nanoemulsions (LN-NEs) and doxorubicin (DOX), a chemotherapeutic drug, to increase their synergistic antitumor efficacy and reduce the incidence of side effects from chemotherapeutics for EOC.

Methods: The physical properties of LN-NE-DOX-liposomes were characterized by light scattering with a particle size analyzer. Cell viability was determined by MTT assay. Therapeutic efficacy was evaluated in a mouse HeyA8 EOC tumor model of ovarian carcinoma. Additionally, biochemical toxicity was analyzed for levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and blood urea nitrogen (BUN) using BALB/c nude mice.

Results: The size of the liposomes encapsulating LN-NEs and DOX (LN-NE-DOX-liposomes) was 267.0 ± 4.6 nm, with a loading efficiency of 55.1 ± 3.1% and 27.2 ± 0.9% for linalool and DOX, respectively. Cell viability after treatment with LN-NE-DOX-liposomes was significantly decreased compared to that of cells treated with DOX liposomes, and apoptosis was significantly increased. Additionally, LN-NE-DOX-liposomes significantly inhibited HeyA8 EOC tumor growth compared to that of the control (p < 0.01) and DOX-liposome-treated groups (p < 0.05), while decreasing cell proliferation (Ki67) and microvessel density (CD31), and promoting apoptosis (caspase-3) compared to the control (p < 0.05). Moreover, the liposomal formulations induced no significant differences in biochemical toxicity (AST, ALT, and BUN) compared to healthy control mice, indicating that the liposomal formulations showed no overt toxicity in mice.

Conclusion: This study demonstrates that the production of LN-NE-DOX-liposomes is a pivotal approach for EOC treatment, suggesting a novel combination therapeutic strategy.

Keywords: combination therapy; doxorubicin; linalool; liposome; ovarian carcinoma.

MeSH terms

  • Acyclic Monoterpenes / pharmacology
  • Acyclic Monoterpenes / therapeutic use*
  • Animals
  • Apoptosis / drug effects
  • Carcinoma, Ovarian Epithelial / drug therapy*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Combined Modality Therapy
  • Doxorubicin / analogs & derivatives*
  • Doxorubicin / therapeutic use
  • Drug Carriers / chemistry*
  • Emulsions / chemistry
  • Female
  • Humans
  • Liposomes / chemistry
  • Mice, Inbred BALB C
  • Mice, Nude
  • Nanoparticles / chemistry
  • Particle Size
  • Polyethylene Glycols / therapeutic use
  • Treatment Outcome


  • Acyclic Monoterpenes
  • Drug Carriers
  • Emulsions
  • Liposomes
  • liposomal doxorubicin
  • Polyethylene Glycols
  • Doxorubicin
  • linalool

Grant support

This work was supported by the National Research Foundation of Korea (NRF) funded by the Korean government (NRF-2016R1A5A2012284 and NRF-2019R1A2C1085144 to Y.-M.P. and H.D.H.).