Abstract
The molecularly targeted agent anlotinib offers a novel therapeutic strategy against advanced hepatocellular carcinoma (HCC). With this study, we aimed to solve the technical problem of anlotinib being insoluble in injectable solutions; we also aimed to assess the antitumor activity of anlotinib on hepatocellular carcinoma cells. We prepared an anlotinib nanocrystal injection by wet grinding, and we optimized the prescription process using a transmission electron microscope (TEM) and a laser particle size analyzer (LPSA). The release of anlotinib from the injected nanocrystals was evaluated using LC-MS/MS in vitro, and the drug’s anti-tumor effects were assessed in a nude mice tumor model. The anlotinib nanocrystals had a uniform particle size distribution (the average nanoparticle size was ~200 nm). The preparation of anlotinib into nanocrystals did not change the original crystal structure. The intravenous injection of anlotinib nanocrystals achieved anti-tumor activity at very low doses compared to those required for oral administration of an anlotinib suspension: anlotinib nanocrystals at a dose of 50 μg/kg inhibited the subcutaneous growth of the HCC cell line MHCC97-H; whereas the dose of anlotinib suspension required for an equivalent effect was 1 mg/kg. Therefore, our novel anlotinib nanocrystal injection preparation provides an option for achieving a safe and effective molecularly targeted therapy against advanced HCC.
Highlights
Advanced hepatocellular carcinoma (HCC) is a serious physical and mental health threat in China [1,2,3,4]
The high-performance liquid chromatograph (HPLC), transmission electron microscope and other equipment are products of Hitachi (Japan); the liquid chromatography-mass spectrometer (ESI/TOF/API4000) was purchased from Applied Biosystems/MDS Analytical Technologies USA Products; the laser Zeta potential particle size analyzer (Zetasizer) is a product of Malvern (United Kingdom); the wet mill is a product of the Swiss WAB-Group (Basel Region, Switzerland); and, the T25 type dispersing and emulsifying homogenizer is a product of the German IKA company (Janke & Kunkel OHG, Germany)
These results indicate that our efforts to obtain anlotinib nanocrystals were successful
Summary
Advanced hepatocellular carcinoma (HCC) is a serious physical and mental health threat in China [1,2,3,4]. One of the main therapeutic strategies for advanced HCC is molecularly targeted therapy, that is, oral administration of molecularly targeted agents [5,6,7,8] These agents are small molecular tyrosine kinase inhibitors (TKIs) that directly prevent the proliferation, metastasis or, angiogenesis of tumors by inhibiting the activation of some receptor tyrosine protein kinases Anlotinib-Nanocrystal on HCC endothelial growth factor receptors [VEGFRs] or platelet-derived growth factor receptors [PDGFRs]) or kinases belonging to the MAPK (mitogen-activated protein kinase) pathway (for example, B-Raf) [9,10,11]. The first of these drugs approved for marketing was sorafenib [12,13,14].
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