Silymarin-Loaded, Lactobionic Acid-Conjugated Porous PLGA Nanoparticles Induce Apoptosis in Liver Cancer Cells

Abstract

HepG2 cells (HCC), characterized by epithelial-like morphology, high proliferation rates, and nontumorigenicity, require cost-effective and efficient treatment. Silymarin, a flavonoid extract of Silybum marianum, is effective in the treatment of HCC. Here, we have reported a comparative anticancer study of the well-characterized nanoformulations of lactobionic acid-adorned porous PLGAencapsulated silymarin (LA-PLGA-Sil) with only porous PLGA-encapsulated silymarin (PLGA-Sil) against HepG2 cells. Treatment of HepG2 cells with LA-PLGA-Sil produced a significant deterioration in cell viability at an essentially low dose as compared with PLGA-Sil, due to the adorned lactobionic acid moiety, which results in better targeting. p53, a tumor suppressor gene, essentially initiates apoptosis in cells procuring wild-type p53 (p53 +/+). In our report, treatment of HepG2 cells (p53 +/+) with LA-PLGA-Sil activated p53, which in turn inhibited the proliferation of cells by instigating cell-cycle arrest and apoptosis in a concentration-dependent manner and simultaneously stabilized the nuclear translocation of NFκB-p65. To explore the effect of LA-PLGA-Sil on the expression of microRNA, we observed that LA-PLGA-Sil markedly upregulated the miR-29b in human HCC cells. Reactivation of the p53 gene by miR-29b targeted Bcl-2 and triggered the sequential activation of mediators such as proapoptotic Bax protein, release of cytochrome c, and the activation of caspase proteins (caspase-3 and caspase-9). Furthermore, the overexpression of NFκB-p65 in HepG2 cells reversed the repression, and this stabilization effect of LA-PLGA-Sil on the nuclear translocation of p65 led to the significant downregulation of miR-29b and successively decreased the p53 expression in LA-PLGA-Sil-treated cells, thereby providing a survival mechanism to HepG2. In entirety, our study demonstrated the extensive potential of LA-PLGA-Sil to instigate the cell death of HepG2 cells via apoptosis by targeting the miR-29b/p53 axis through the stabilization of NFκB. It also impaired the migratory activity of HepG2 cells and thereby furnished a comprehensive way to HCC therapeutic treatment.

Silymarin-Loaded Tin(IV) Nanoparticles Exhibit Enhanced Bioavailability and Antiproliferative Effects on Colorectal Cancer Cells

“…In this study, the SM–tin­(IV) complex effectively decreased cell viability and increased the apoptosis rate in the SW480 colon cancer cell line. This finding corroborates the idea of Upadhyay et al., who reported that treatment with nanocomposites silymarin leads to suppression of proliferation and induction of apoptosis in the HepG2 cell line . These findings further support the SM nanocomposite approach’s effectiveness in stimulating cancer cell death.…”

“…This finding corroborates the idea of Upadhyay et al, who reported that treatment with nanocomposites silymarin leads to suppression of proliferation and induction of apoptosis in the HepG2 cell line. 25 These findings further support the SM nanocomposite approach's effectiveness in stimulating cancer cell death.…”

“…In the in vitro investigations into the cytotoxicity effects of nanoparticles, the size and shape of the applied nanoparticles or microstructures appear to be essential properties . Interestingly, our SM–tin­(IV) complex was produced at a nanoscale level and had a nanorod shape with a large surface area.…”

Recent advances in lipid-engineered multifunctional nanophytomedicines for cancer targeting

“…Conjugation of PLGA nanoparticles with receptors (like antibody, epidermal factors, peptides), PEGylation, binding with ligands (like 1,2-distearoylglycerol-3-phospho-ethanolamine) helps in providing more specificity for targeting to cancer cells [99]. PLGA loadedsilymarin nanoparticles inhibited cancer proliferation by induction of apoptosis [100]. Furthermore, grape seed extract loaded in PLGA nanoparticles provided enhancement in apoptotic index in comparison to free extract [101].…”

An In-Vitro Evaluation of the Characteristics of Zein-Based Films for the Release of Lactobionic Acid and the Effects of Oleic Acid

“…These potent antioxidant properties are of interest in skincare, where LBA is used to facilitate wound healing, inhibit the production of both hydroxyl radicals and matrix metalloproteinases that contribute to skin aging, and promote the biosynthesis of glycosaminoglycans and collagen. In the drug delivery sector, numerous recent studies have reported on nanocarriers modified with LBA for the controlled release of anticancer drugs [ 9 , 10 , 11 , 12 , 13 ]. Examples include poly (lactide-co-glycolide; PLGA) nanoparticles with LBA surface functionalization via the amino groups of chitosan for the delivery of the drug etoposide to retinoblastoma cells [ 14 ]; porous PLGA nanoparticles conjugated with LBA for the controlled release of silymarin (a flavonoid extract of Silybum marianum) to inhibit the proliferation of human liver cancer cells and treat hepatocellular carcinoma [ 15 ]; PLGA nanoparticles coated with chitosan modified with polyethylene glycol (PEG) and LBA, for the targeted release of arsenic trioxide to the liver tumor [ 13 ].…”