Preclinical evaluations of Norcantharidin liposome and emulsion hybrid delivery system with improved encapsulation efficiency and enhanced antitumor activity

ABSTRACT

Background

Norcantharidin (NCTD) has a certain degree of hydrophilicity and poor lipophilicity, and has some side-effects, including short t_1/2, vascular irritation, cardiotoxicity, and nephrotoxicity, which bring difficulties for formulation research. In this study, we aim to develop a novel nanocarrier to improve encapsulation efficiency, increase sterilization stability, and enhance antitumor activity.

Methods

Phospholipid complexes methods were used for increasing the lipophilicity of norcantharidin (NCTD), then NCTD phospholipid complexes were not only loaded in the oil phase and oil-water interface surface, but also encapsulated in phospholipid bilayers to obtain NCTD liposome-emulsion hybrid (NLEH) delivery system. The in vitro cytotoxicity and apoptosis, in vivo tissue distribution, tumor penetration, heterotopic, and orthotopic antitumor studies were conducted to evaluate therapeutic effect.

Results

NLEH exhibited an improved encapsulation efficiency (89.3%) and a better sterilization stability, compared to NCTD liposomes and NCTD emulsions. NLEH can achieve a better antitumor activity by promoting absorption (1.93-fold), prolonging blood circulation (2.08-fold), enhancing tumor-targeting accumulation (1.19 times), improving tumor penetration, and increasing antitumor immunity.

Conclusions

The liposome-emulsion hybrid (LEH) delivery system was potential carrier for NCTD delivery, and LEH could open opportunities for delivery of poorly soluble anticancer drugs, especially drugs that are more hydrophilicity than lipophilicity.

KEYWORDS:

• Norcantharidin
• Liposomes
• Emulsions
• Hybrid delivery system
• Antitumor activity

Author contributions

Zixu Liu: Conceptualization, Data curation, Methodology, Investigation, Visualization, Writing – original draft. Linxuan Zhao: Investigation, Formal analysis, Writing – original draft. Xinyi Tan: Investigation, Formal analysis, Data curation. Zixuan Wu: Investigation, Data curation, Methodology. Ning Zhou: Methodology, Validation. Nan Dong: Methodology, Validation. Yu Zhang: Visualization, Supervision. Tian Yin: Validation, Supervision. Haibing He: Visualization, Validation. Jingxin Gou: Visualization, Writing – review & editing. Xing Tang: Conceptualization, Supervision, Project administration, Writing – review & editing. Song Gao: Conceptualization, Supervision, Writing – review & editing. All authors agree to be accountable for all aspects of the work and they approve the final version of the paper.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by National Mega-project for Innovative Drugs [No.2019ZX09721001], Liaoning Revitalization Talents Program [XLYC1908031], National Science and Technology Major Project of the Ministry of Science and Technology of China [No.2018ZX09735005], Special Translational Project for Medical Scientific and Technological Achievements of Liaoning Province, 345 Talent Project, Shengjing Hospital of China Medical University (No. M0397), Liaoning Livelihood Science and Technology Plan Joint Project (No.2021JH2/10300130).