Enhanced anti-glioma activity of annonaceous acetogenins based on a novel liposomal co-delivery system with ginsenoside Rh2

Abstract

Annonaceous acetogenins (ACGs) have potent anti-tumor activity, and the problems of their low solubility, hemolysis, and in vivo delivery have been solved by encapsulation into nanoparticles. However, the high toxicity still limits their application in clinic. In this paper, the co-delivery strategy was tried to enhance the in vivo anti-tumor efficacy and reduce the toxic effects of ACGs. Ginsenoside Rh2, a naturally derived biologically active compound, which was reported to have synergistic effect with paclitaxel, was selected to co-deliver with ACGs. And due to its similarity with cholesterol in chemical structure, the co-loading liposomes, (ACGs + Rh2)-Lipo, were successfully constructed using Rh2 instead of cholesterol as the membrane material. The obtained (ACGs + Rh2)-Lipo and ACGs-Lipo had similar mean particle size (about 80 nm), similar encapsulation efficiency (EE, about 97%) and good stability. The MTS assay indicated that (ACGs + Rh2)-Lipo had stronger toxicity in vitro. In the in vivo study, in contrast to ACGs-Lipo, (ACGs + Rh2)-Lipo demonstrated an improved tumor targetability (3.3-fold in relative tumor targeting index) and significantly enhanced the antitumor efficacy (tumor inhibition rate, 72.9 ± 5.4% vs. 60.5 ± 5.4%, p < .05). The body weight change, liver index, and spleen index of tumor-bearing mice showed that Rh2 can attenuate the side effects of ACGs themselves. In conclusion, (ACGs + Rh2)-Lipo not only alleviated the toxicity of ACGs to the organism, but also enhanced their anti-tumor activity, which is expected to break through their bottleneck.

Keywords:

• Annonaceous acetogenins
• Rh2
• co-loaded liposomes
• anti-glioma
• systemic toxicity

Author contributions

All authors contributed to the article. Xiangtao Wang was responsible for conception, design, supervision, and guidance of experiments. Hui Ao performed the experiments, analyzed and interpretation the data, and drafted the manuscript. Huizhu Song and Jing Li prepared figures and revised the manuscript critically for intellectual content. All authors read and approved the final version of the manuscript.

Ethical approval

All animal experiments were conducted on the basis of the Guidelines for Ethical and Regulatory for Animal Experiments as defined by Institute of Medicinal Plant Development (IMPLAD), China. The ethics committee of IMPLAD granted ethical approval for this study. The approval number of the ethics committee was SLXD-20201218021. The animals were raised at 25 °C and a relative humidity of 70 ± 5% under 12 h light–dark cycle environment for 1 week before the experiments. In this study, the only trauma to the experimental mice was subcutaneous injection and tail vein injection, which was less painful, so no anesthesia was administered. In addition, in order to minimize the suffering of mice as much as possible, a clean and comfortable living environment was provided, ensuring sufficient food and water sources. At the end of the experiment, the mice were euthanized by 100% CO₂ anesthesia. The authors have adhered to the ARRIVE guidelines.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The data supporting this work are accessible upon reasonable request from the corresponding author.

Additional information

Funding

This work is financially supported by the Doctoral Talent Funding of the affiliated Wuxi People’s Hospital of Nanjing Medical University (No. BSRC202201), General Project of Wuxi Medical Center, Nanjing Medical University (No. WMCG202332), and the CAMS Innovation Fund for Medical Sciences (CIFMS) (No. 2021-I2M-1-071).