One-step mechanochemical preparation and prominent antitumor activity of SN-38 self-micelle solid dispersion

Abstract

Purpose

The purpose of this study was to overcome the clinical defects of 7-ethyl-10-hydroxycamptothecin (SN-38) and explore its characteristics and antitumor effects.

Materials and methods

An amorphous solid dispersion of SN-38 with disodium glycyrrhizin (Na₂GA) was prepared by mechanical ball milling (Na₂GA/SN-38-BM). Moreover, an untreated mixture of Na₂GA and SN-38 (Na₂GA/SN-38-UM), a pure drug SN-38, was prepared for comparison with Na₂GA/SN-38-BM. The samples were characterized by powder X-ray diffraction (PXRD), scanning electron microscopy (SEM), dynamic light scattering, and transmission electron microscopy. Then, further in vitro and in vivo studies were performed including cell uptake, cytotoxicity, antitumor efficacy, tissue distribution, and histopathological evaluation (H&E staining).

Results

SN-38 loaded in Na₂GA was self-formed as nano-micelles in water. The particle size of nano-micelle was 69.41 nm and ζ-potential was −42.01 mV. XRD and SEM analyses showed that the ball milling transformed SN-38 crystals into amorphous form and that solubility increased by 189 times. Compared with SN-38 and Na₂GA/SN-38-UM, Na₂GA/SN-38-BM has a stronger cytotoxicity to tumor cells and exhibited a significant inhibition of tumor growth. Then, pharmacokinetic studies showed that the bioavailability of Na₂GA/SN-38-BM was about four times that of SN-38 suspension.

Conclusion

Na₂GA/SN-38-BM (69 nm, −42 mV) nanoparticles which had excellent phar-macokinetic and distribution properties can dramatically enhance the anticancer efficacy of SN-38 in vitro and in vivo, suggesting a promising formulation for efficient anticancer therapy.

Keywords:

• SN-38
• mechanical ball milling
• solid dispersion
• antitumor efficacy
• pharmacokinetics
• tissue distribution
• cell-micelle
• cytotoxic

Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (no. 21506192) and the Zhejiang Provincial Natural Science Foundation of China (no. LY16E030010).

Disclosure

The authors report no conflicts of interest in this work.