Abstract
Multifunctional nanocarriers harbouring specific targeting moieties and with pH-responsive properties offer great potential for targeted cancer therapy. Several synthetic drug carriers have been studied extensively as drug delivery systems but not much information is available on the application of virus-like nanoparticles (VLNPs) as multifunctional nanocarriers. Here, we describe the development of pH-responsive VLNPs, based on truncated hepatitis B virus core antigen (tHBcAg), displaying folic acid (FA) for controlled drug delivery. FA was conjugated to a pentadecapeptide containing nanoglue bound on tHBcAg nanoparticles to increase the specificity and efficacy of the drug delivery system. The tHBcAg nanoparticles loaded with doxorubicin (DOX) and polyacrylic acid (PAA) demonstrated a sustained drug release profile in vitro under tumour tissue conditions in a controlled manner and improved the uptake of DOX in colorectal cancer cells, leading to enhanced antitumour effects. This study demonstrated that DOX-PAA can be packaged into VLNPs without any modification of the DOX molecules, preserving the pharmacological activity of the loaded DOX. The nanoglue can easily be used to display a tumour-targeting molecule on the exterior surface of VLNPs and can bypass the laborious and time-consuming genetic engineering approaches.
Highlights
Hepatitis B core antigen (HBcAg) self-assembles into viruslike nanoparticles (VLNPs), which have been shown to be some of the most powerful protein engineering tools employed to display immunogens and cell-targeting peptides, as well as for the packaging of genetic materials[10]
Transmission electron micrographs showed that cross-linking of the nanoglue followed by conjugation of folic acid (FA) did not have an adverse effect on the spherical structure of the truncated hepatitis B virus core antigen (tHBcAg) nanoparticles (Fig. 2c)
To verify that FA molecules were conjugated to Lys residues at the N-terminus of the pentadecapeptide, Lys-7 and Lys-96 of tHBcAg were first conjugated with NHS-fluorescein
Summary
Hepatitis B core antigen (HBcAg) self-assembles into VLNPs, which have been shown to be some of the most powerful protein engineering tools employed to display immunogens and cell-targeting peptides, as well as for the packaging of genetic materials[10]. A liver-specific ligand (preS1) fused at the N-terminus of the tHBcAg was demonstrated to deliver fluorescein molecules into HepG2 cells[14] These discoveries have paved the way for exploiting tHBcAg nanoparticle as targeted drug delivery systems. FA molecules were conjugated to the free Lys residues at the N-terminal end of the pentadecapeptide bound on tHBcAg nanoparticles In this manner, the FA molecules extend flexibly away from the nanoparticle, and their exposure to target FRs on the surface of cancer cells is maximized. PH-responsive tHBcAg nanoparticles displaying FA molecules were demonstrated to improve the uptake of DOX by colorectal cancer cells, and the drug was released in a controlled manner
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