Abstract
Non-invasive delivery of biotherapeutics, as an attractive alternative to injections, could potentially be achieved through the mucosal surfaces, utilizing nanoscale therapeutic carriers. However, nanoparticles do not readily cross the mucosal barriers, with the epithelium presenting a major barrier to their translocation. The transcytotic pathway of vitamin B12 has previously been shown to ‘ferry’ B12-decorated nanoparticles across intestinal epithelial (Caco-2) cells. However, such studies have not been reported for the airway epithelium. Furthermore, the presence in the airways of the cell machinery responsible for transepithelial trafficking of B12 is not widely reported. Using a combination of molecular biology and immunostaining techniques, our work demonstrates that the bronchial cell line, Calu-3, expresses the B12-intrinsic factor receptor, the transcobalamin II receptor and the transcobalamin II carrier protein. Importantly, the work showed that sub-200nm model nanoparticles chemically conjugated to B12 were internalised and transported across the Calu-3 cell layers, with B12 conjugation not only enhancing cell uptake and transepithelial transport, but also influencing intracellular trafficking. Our work therefore demonstrates that the B12 endocytotic apparatus is not only present in this airway model, but also transports ligand-conjugated nanoparticles across polarised epithelial cells, indicating potential for B12-mediated delivery of nanoscale carriers of biotherapeutics across the airways.
Highlights
Considering the recent emergence of biotherapeutics, developments in non-invasive delivery options for this class of medicines have been disappointing, with the parenteral method remaining the predominant administration route
The data confirm the expression of both cubilin (i) and TCII receptor (ii)
Immunostaining for TCII protein, a carrier protein involved in the binding and transport of B12 out of the enterocytes in vivo, indicates its presence in Calu-3 cells (Fig. 1b v), whilst fluorescence signal was largely absent in the relevant control experiment (Fig. 1b vi)
Summary
Considering the recent emergence of biotherapeutics, developments in non-invasive delivery options for this class of medicines have been disappointing, with the parenteral method remaining the predominant administration route. Mucosal absorption of biomolecules could potentially be improved by inducing reversible ‘opening’ of the epithelial tight junctions, creating a temporarily accessible corridor for the therapeutic to traverse the epithelial barrier [1,2,3]. This strategy may be limited to relatively small biomolecules (peptides or small proteins), whilst systemic delivery of larger biotherapeutics (e.g. antibodies or PEGylated antibody fragments) through this approach is shown to be inefficient [4]. Mucosal absorption of the therapeutic via transport through the epithelial cells (i.e. the transcellular route) would potentially overcome this problem
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