Novel Microcrystal Formulations of Sorafenib Facilitate a Long-Acting Antitumor Effect and Relieve Treatment Side Effects as Observed With Fundus Microcirculation Imaging

Abstract

The tyrosine kinase inhibitors (TKIs), including sorafenib, remain one first-line antitumor treatment strategy for advanced hepatocellular carcinoma (HCC). However, many problems exist with the current orally administered TKIs, creating a heavy medical burden and causing severe side effects. In this work, we prepared a novel microcrystalline formulation of sorafenib that not only achieved sustainable release and long action in HCC tumors but also relieved side effects, as demonstrated by fundus microcirculation imaging. The larger the size of the microcrystalline formulation of sorafenib particle, the slower the release rates of sorafenib from the tumor tissues. The microcrystalline formulation of sorafenib with the largest particle size was named as Sor-MS. One intratumor injection (once administration) of Sor-MS, but not Sor-Sol (the solution formulation of sorafenib as a control), could slow the release of sorafenib in HCC tumor tissues and in turn inhibited the in vivo proliferation of HCC or the expression of EMT/pro-survival–related factors in a long-acting manner. Moreover, compared with oral administration, one intratumor injection of Sor-MS not only facilitated a long-acting antitumor effect but also relieved side effects of sorafenib, avoiding damage to the capillary network of the eye fundus, as evidenced by fundus microcirculation imaging. Therefore, preparing sorafenib as a novel microcrystal formulation could facilitate a long-acting antitumor effect and relieve drug-related side effects.

Knockdown of FBI-1 Inhibits the Warburg Effect and Enhances the Sensitivity of Hepatocellular Carcinoma Cells to Molecular Targeted Agents via miR-3692/HIF-1α

“…Therefore, this study not only has scientific research value but also has great clinical value. The HCC cells may be resistant to molecular targeted drugs through a variety of mechanisms: (1) compensation between different signaling pathways ( 77 – 79 ); (2) epithelial–mesenchymal transition ( 80 – 82 ); (3) cancer stem cells ( 83 – 85 ); (4) PXR and other drug metabolism clearance mechanism ( 63 ); and (5) Notch pathway and other cell prosurvival and antiapoptotic mechanisms ( 38 , 86 – 88 ). This research not only expands our molecular mechanism of HCC cell resistance to molecular targeted drugs but also helps to provide new strategies for HCC treatment.…”

HCC and Molecular Targeting Therapies: Back to the Future

“…From this perspective, Wang et al prepared a novel microcrystalline formulation of sorafenib (Sor-MS) and evaluated its efficacy and toxicity in mouse models [124]. The release of sorafenib into HCC tissues by injection inhibited the in vivo proliferation of HCC and the expression of epithelial-mesenchymal transition (EMT)-related factors in a long-acting manner.…”

A Novel Microcrystalline BAY-876 Formulation Achieves Long-Acting Antitumor Activity Against Aerobic Glycolysis and Proliferation of Hepatocellular Carcinoma

“…The aerobic glycolysis of the tumor tissues were measured following the methods described by Yin et al (42). The body-weights or the liver-weights of Immunodeficiency rat were examined (24)(25)(26)(27).…”

“…First, most patients with HCC in China have intolerable cirrhosis, the patient's gastrointestinal function is insufficient/impaired, which results in such patients having poor absorption of oral drugs (22,23). Secondly, oral administration or intravenous infusion as the route of administration will cause the drug to be distributed systemically, which will not only interferes with the physical uptake of glucose of the human body, but also results in negligible dose of BAY-876 at the lesion site of HCC (24)(25)(26)(27). Therefore, the aim of this study was to establish a long-acting and sustained-release formulation of BAY-876 to achieve precise dose administration, and exert targeted anti-tumor activity at HCC lesions without affecting normal tissues and organs.…”