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

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 (Na(2)GA) was prepared by mechanical ball milling (Na(2)GA/SN-38-BM). Moreover, an untreated mixture of Na(2)GA and SN-38 (Na(2)GA/SN-38-UM), a pure drug SN-38, was prepared for comparison with Na(2)GA/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 Na(2)GA 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 Na(2)GA/SN-38-UM, Na(2)GA/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 Na(2)GA/SN-38-BM was about four times that of SN-38 suspension. CONCLUSION: Na(2)GA/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.