Novel Nanocrystal Injection of Insoluble Drug Anlotinib and Its Antitumor Effects on Hepatocellular Carcinoma

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.

Nanomedicine‐boosting icaritin-based immunotherapy of advanced hepatocellular carcinoma

“…Intravenous injection can be applied to overcome the problems from oral administration and thus obtain satisfactory therapeutic efficacy with a lower dose. A representative study on the intravenous injection of the anti-HCC agent anlotinib was performed by Luo et al [ 58 ], which showed that a greatly reduced dose (1/10 of the oral dose) produced a significantly improved anti-HCC effect.…”

miR-140-3p enhances the sensitivity of LUAD cells to antitumor agents by targeting the ADAM10/Notch pathway

“…On this basis, the four selected cytotoxic chemotherapy drugs, gemcitabine, paclitaxel, etoposide or doxorubicin, all act on biological macromolecules such as DNA and microtubules, and kill malignant tumor cells by causing macromolecular damage [59][60][61][62]. Among the selected four molecularly-targeted drugs, gefitinib, erlotinib and osimertinib, all mainly act on the EGFR, while anlotinib is a multi-target protein kinase inhibitor that targets the VEGFR [63,64]. Gefitinib is considered the first-generation of small molecule protein kinase inhibitors acting on EGFR, while erlotinib and osimertinib are the second-and third-generation agents acting on small molecule protein kinase inhibitors [63,64]; all these drugs were used in this study and killed A549 cells in a dose-dependent manner.…”

“…Among the selected four molecularly-targeted drugs, gefitinib, erlotinib and osimertinib, all mainly act on the EGFR, while anlotinib is a multi-target protein kinase inhibitor that targets the VEGFR 63 , 64 . Gefitinib is considered the first-generation of small molecule protein kinase inhibitors acting on EGFR, while erlotinib and osimertinib are the second- and third-generation agents acting on small molecule protein kinase inhibitors 63 , 64 ; all these drugs were used in this study and killed A549 cells in a dose-dependent manner. These drugs mainly act on the EGFR and the difference in their activity is mainly determined by the higher mutational status of the EGFR 64 .…”

“…It is worth mentioning that traditional molecular targeted drugs, as represented by Gefitinib, all act on the EGFR, and related research and development strategies should continue to exploit this potential. Currently, new molecular targeted drugs, represented by anlotinib act on VEGFR-related targets 63 , 64 , have been approved for marketing for NSCLC treatment, which will provide additional therapeutic options for NSCLC patients.…”

Recent developments in the use of nanocrystals to improve bioavailability of APIs

“…However, prolonged oral administration of this drug not only results in a low bioavailability but also induces multi‐drug resistance (MDR) in cancer cells. Therefore, Luo et al employed poloxamer 188 and egg yolk lecithin as the charge stabilizer and space stabilizer, respectively, to fabricate anlotinib nanocrystals through a ball milling method (Luo et al, 2021). The optimal nanocrystals, characterized with a uniform average particle size of 200 nm and a zeta potential of −30 mV, were obtained through continuous grinding using a high shear emulsifying homogenizer for a duration of 90–120 min.…”