Enhanced Transport of Shape and Rigidity-Tuned α-Lactalbumin Nanotubes across Intestinal Mucus and Cellular Barriers

Abstract

Mucus is a viscoelastic biological hydrogel that protects the epithelial surface from penetration by most nanoparticles, which limits the efficiency of oral drug delivery. Pursuing highly efficient, biocompatible, and biodegradable oral drug vehicles is of central importance to the development of promising nanomedicine. Here, we prepared five peptosomes (PSs) with various sizes, shapes, and rigidities based on self-assembly of amphiphilic α-lactalbumin (α-lac) peptides from partial enzymolysis and cross-linking. The mucus permeation of α-lac PSs and release of curcumin (Cur) encapsulated in these PSs were evaluated. Compared with a long nanotube, big nanosphere, small nanosphere, and cross-linked short nanotube, we demonstrated that a short nanotube (SNT) exhibits excellent permeability in mucus, which enables it to arrive at epithelial cells quickly. Besides, SNT exhibits the highest cellular uptake and transmembrane permeability on Caco-2/HT29-MTX (E12) 3D coculture model. In vivo pharmacokinetic evaluation revealed that SNT formulation shows the highest curcumin bioavailability, which is 6.85-folds higher than free Cur. Most importantly, Cur loaded in SNT exhibits the optimum therapeutic efficacy for in vivo treatment of dextran sulfate sodium (DSS)-induced ulcerative colitis. In the end, the mechanism of the high permeability of SNTs through mucus was explained by coarse-grained molecular dynamics simulations, which indicated that short time scale jiggling and flying across pores of mucus network played key roles. These findings revealed the tubular α-lac PSs could be a promising oral drug delivery system targeted to mucosal for improving absorption and bioavailability of hydrophobic bioactive ingredients.

Interplay of Nanoparticle Properties during Endocytosis

“…Thus, NP shape and elasticity may be closely intertwined in affecting the endocytosis of NPs. Based on the self-assembly of amphiphilic α-lactalbumin (α-lac) peptides from partial enzymolysis and cross-linking, Bao et al prepared peptosomes (PSs) with various shapes and rigidities [70]. The combined experimental results and the molecular simulations demonstrated that short nanotube exhibits the highest cellular uptake and transmembrane permeability.…”

α-Lactalbumin, Amazing Calcium-Binding Protein

“…Practical application of α-LA nanotubes was demonstrated in the work of Bao et al [ 168 ]. They prepared five peptosomes of various sizes, shapes, and rigidities based on the self-assembly of α-LA peptides using partial enzymolysis and cross-linking.…”

Experimental and theoretical explorations of nanocarriers’ multistep delivery performance for rational design and anticancer prediction

“…To this end, we developed a set nanocarrier types with differing physical properties that were variously produced from hydrolyzed peptide fragments of α-lac. That is, building from previous understanding about how these α-lac peptide fragments can undergo a self-assembly process to produce nanostructures ( 26 , 27 ), we here systematically altered three separate production conditions to produce six different types of nanocarriers from the same starting material. The first condition that we altered was the controlled shape of the nanocarriers.…”