Our previous studies demonstrated that L-octaarginine grafted onto hyaluronic acid via a tetraglycine spacer significantly enhanced intranasal absorption of protein drugs with a molecular weight (Mw) of 22 kDa or less. The present study focused on its potential as an absorption enhancer for antibody drugs with a larger Mw and the enhancement mechanism. When ranibizumab (48 kDa) alone was intranasally administered in mice, its absolute bioavailability was 0.67% on average. The mean bioavailability elevated to 6.2% under coadministration with tetraglycine-L-octaarginine-linked hyaluronic acid. A similar result was observed under substitution of ranibizumab with certolizumab pegol (91 kDa), although bioavailability itself decreased with the Mw increase, irrespective of coadministration with the hyaluronic acid derivative. Rat experiments also revealed that coadministration with the polysaccharide derivative resulted in significant enhancement of intranasal absorption of trastuzumab (148 kDa). In vitro studies using gene-knocked down cells indicated that syndecan-4-induced macropinocytosis played a crucial role on acceleration of antibody uptake into epithelial cells on the nasal mucosa, irrespective of their Mw. It appeared that neither clathrin heavy chain nor caveolin-1 involved in cellular uptake of antibodies. Tetraglycine-L-octaarginine-linked hyaluronic acid was concluded to be a promising delivery tool that possessed universal absorption-enhancing abilities independent to Mw of biologics.
Keywords: Antibody; Cell-penetrating peptide-linked hyaluronic acid; Cell-penetrating peptides; Hyaluronic acid; Macropinocytosis; Mucosal absorption; Syndecan-4.
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