Application Of Sorafenib-loaded Poly(Ethylene Glycol)-Poly(?-caprolactone) Micelles For Hepatocellular Carcinoma Therapy

Hepatocellular carcinoma(HCC)is one of the most common malignant tumors and ranks the second in cancer-associated deaths worldwide.The incidence of HCC is high in China,which accounts for about 50% of global morbidity and mortality.However,most HCC patients are diagnosed at the advanced stage due to the long incubation period and rapid progression,thus losing the opportunities of radical surgery for the early stage.It is reported that the 5-year survival of HCC in China is only 10.1%.HCC has seriously affected the people's health and hindered the development of society.Sorafenib is a multikinase inhibitor that inhibits the activities of tyrosine kinases and serine/threonine kinases,thus suppressing tumor angiogenesis and cell proliferation.Sorafenib can prolong the survival time and tumor progression time of patients with advanced HCC,which is the only molecule-targeting drug as the standard treatment for advanced HCC approved by US Food and Drug Administration.However,the clinical application of sorafenib is limited due to its hydrophobicity,low bioavailability,and serious adverse reactions.In this study,sorafenib-loaded poly(ethylene glycol)-poly(?-caprolactone)(PEG-PCL)micelles(SF micelles)were fabricated using a dialysis method to improve its water-solubility and thus solve a series of problems in clinical application.We investigated the size,zeta potential,stability,drug loading(DL)and entrapment efficiency(EE),and in vitro release behavior of the prepared SF micelles.The experimental data indicated,our prepared SF micelles were regular spheres of 73.32 ± 0.12 nm with narrow distribution and slightly negative charge.The DL and EE of sorafenib were 15.43% and 92.56%,respectively,and the water-solubility of sorafenib had been significantly improved.In vitro drug release experiments showed that sorafenib could release from SF micelles slowly.Subsequently,HepG2 and BEL-7402 cells were used to study the cellular uptake,cytotoxicity and apoptosis of SF micelles.The experimental data indicated,PEG-PCL was noncytotoxicity with good biocompatibility and could significantly enhance the cellular uptake capacity.Apoptosis experiments showed that SF micelles could induce more cell apoptosis compared with free sorafenib at a sorafenib concentration of 5 ?M.Finally,HepG2-Luc tumor-bearing mice model was established to study in vivo biodistribution and tumor penetrability through fluorescence molecular imaging and photoacoustic imaging.The results exhibited that the nano-micelles could selectively accumulate and retain in tumors,and the permeability in tumor tissue could be as deep as 4.5 mm.In vivo anti-tumor experiments confirmed that SF micelles had a significant inhibitory effect on tumor growth and good biosafety.The results of H&E staining and TUNEL staining of tumor sections were further evidences that SF micelles could achieve better therapeutic effect and apoptosis induction.Therefore,SF micelles possess a wide prospect of clinical application.