Hepatocellular carcinoma (HCC) the most frequently diagnosed liver malignancy, is the third largest cause for cancer-related death in the world. Therefore, development of an effective HCC targeting drug delivery system is extremely important to improve the drug efficacy to hepatic cancer cells and reduce toxic side effects systematically. In this study, we have developed a dual drug delivery system depending on three aspects: First, lactoferrin (Lf) has strong binding affinity to multiple receptors including low-density lipoprotein receptor-related protein receptors (LRP-R) which are over expressed on hepatic cancer cells. Therefore, LF-DXT conjugate has been developed as HCC targeted micellar Nanocarrier which self-assembled with the hydrophobic drug dexamethasone (DXT). Second, developing a highly soluble prodrug of myricetin (MYR) by simple conjugation with safe biocompatible steviolbioside, which was physically entrapped within the LF-DXT micellar core. Third, DXT, reported to have therapeutic efficacy against liver cancer by intervention of abnormal glycolysis and anti-angiogenic effect, gave an excellent synergism with myricetin against HCC in cytotoxicity study on HepG-2 cell line, showing low combination index value (CI=0.321) compared to the free drugs. DXT was covalently bonded to Lf by a tumor cleavable ester bond via succinic anhydride linker, through carbodiimide coupling reaction using EDC.HCl/HOAt as coupling reagents, forming Lf-DXT nano micelles. While, the prodrug (St-MYR) was prepared through the coupling of steviolbioside with MYR using EDC.HCl/KOxyma as coupling reagents, in presence of DMAP. The dual drug-loaded nanoparticles demonstrated a sustained release of the prodrug. The particle size and PDI of the optimized formula was 257.6 nm and 0.399, respectively, with zeta potential of -31.0 mV. In addition, morphological analysis of the drug-loaded nanoparticles via transmission electron microscopy (TEM) exhibited spherical particles in the nano-size range (154-251 nm). High drug loading efficacy was obtained for both drugs; 8.25% (w/w) for DXT and 8.26% (w/w) for MYR. The dual-loaded micelles showed great hemocompatibility, as well as enhanced cytotoxicity and internalization into HepG-2 cells.

Targeted co-delivery of Stevia-myricetin prodrug and dexamethasone in lactoferrin nanomicelles to hepatocellular carcinoma

ACS Fall 2020 Virtual Meeting

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