Thiolation and Cell‐Penetrating Peptide Surface Functionalization of Porous Silicon Nanoparticles for Oral Delivery of Insulin

Abstract

During the last decades, advanced oral delivery systems to enhance the intestinal absorption of widely applicable proteins and peptides, particularly insulin, have been developed. Here, chitosan-conjugated undecylenic acidmodifi ed thermally hydrocarbonized porous silicon nanoparticles (CSUn NPs) are used, which promote the mucoadhesion and cellular interactions, thus boosting the intestinal permeability of insulin. Then, to further potentiate the mucoadhesion and permeability enhancement of chitosan-modifi ed NPs, the surface of the NPs is further modifi ed with either L -cysteine (CYS-CSUn NPs) or a cell-penetrating peptide (CPP-CSUn NPs). CYS-CSUn and CPP-CSUn NPs show 17-and 12-fold increase in the apparent permeability of insulin across cellular intestinal cells, respectively, with signifi cant enhancement in the cellular interactions. The insulin uptake mechanism pathways in intestinal cells from the developed NPs are also unraveled, which demonstrates major involvement of active transport process and electrostatic interactions, along with adsorptive and clathrin-mediated endocytic pathways. Moreover, after oral administration in diabetic rats, CYS-CSUn NPs show 1.86-and 2.03-fold increase in the relative bioavailability of insulin, as compared to empty NPs and oral insulin solution, respectively. In conclusion, this study presents L -cysteine modifi ed CSUn NPs as a promising strategy with the ability to overcome the multiple barriers for oral delivery of insulin.

Smart Protein‐Based Formulation of Dendritic Mesoporous Silica Nanoparticles: Toward Oral Delivery of Insulin

“…Prior to the experiment, DMSNs and insulin were coupled with Rhodamine (Rhod) or FITC fluorescent probes (see SI for more details). As it can be observed in the Figure S7, Ins‐FITC was insufficiently taken up by the cells until at least 3 h. This supports the interpretation that insulin requires a performant shuttle to be transported through the intestinal epithelium and to help overcome oral bioavailability issues which were previously described in vivo . On the other hand, DMSNs penetrated efficiently the cytoplasm, as illustrated in Figure .…”

Dual-peptide functionalized acetalated dextran-based nanoparticles for sequential targeting of macrophages during myocardial infarction

“…74,75 Adsorptive-mediated uptake was inhibited by protamine sulphate. 76 All primary macrophages internalized the nanoparticles preferentially by macropynocytosis, as shown in Fig. 7.…”

Mucoadhesive nanostructured polyelectrolytes complexes modulate the intestinal permeability of methotrexate

“…Subsequently, cells were detached from the insert using 200 μL of trypsin and lysed with 1.5 mL of Triton-X overnight and then, centrifuged at 14,000 rpm for 20 min to the cells fragments separation. The supernatants were removed and filtrated to quantify the amount of MTX bounded or within the mucus layer or cell monolayer (Shrestha et al, 2016). All experiments were performed in triplicate, for each sample, and the MTX was quantified by UV-Vis spectrophotometer (Biotek Synergy 2, Winooski, VT, USA), at 303 nm.…”

“…5). These higher values of viability could be explained by the production and secretion of a mucus layer; which represents a physic barrier, protecting the cells (Antunes et al, 2013;Shrestha et al, 2016). In brief, besides evaluated the system safety, these studies were used to choose the nontoxic and measurable concentration to perform the in vitro permeability studies.…”