Abstract
Type 2 diabetes makes up approximately 85% of all diabetic cases and it is linked to approximately one-third of all hospitalisations. Newer therapies with long-acting biologics such as glucagon-like peptide-1 (GLP-1) analogues have been promising in managing the disease, but they cannot reverse the pathology of the disease. Additionally, their parenteral administration is often associated with high healthcare costs, risk of infections, and poor patient adherence associated with phobia of needles. Oral delivery of these compounds would significantly improve patient compliance; however, poor enzymatic stability and low permeability across the gastrointestinal tract makes this task challenging. In the present work, large pore dendritic silica nanoparticles (DSNPs) with a pore size of ~10 nm were prepared, functionalized, and optimized in order to achieve high peptide loading and improve intestinal permeation of exenatide, a GLP-1 analogue. Compared to the loading capacity of the most popular, Mobil Composition of Matter No. 41 (MCM-41) with small pores, DSNPs showed significantly high loading owing to their large and dendritic pore structure. Among the tested DSNPs, pristine and phosphonate-modified DSNPs (PDSNPs) displayed remarkable loading of 40 and 35% w/w, respectively. Furthermore, particles successfully coated with positively charged chitosan reduced the burst release of exenatide at both pH 1.2 and 6.8. Compared with free exenatide, both chitosan-coated and uncoated PDSNPs enhanced exenatide transport through the Caco-2 monolayer by 1.7 fold. Interestingly, when a triple co-culture model of intestinal permeation was used, chitosan-coated PDSNPs performed better compared to both PDSNPs and free exenatide, which corroborated our hypothesis behind using chitosan to interact with mucus and improve permeation. These results indicate the emerging role of large pore silica nanoparticles as promising platforms for oral delivery of biologics such as exenatide.
Highlights
Peptide-based therapeutics are specific and potent in action, and typically have better safety and tolerability profiles relative to small organic molecules [1]
The size measurement from Transmission electron microscopy (TEM) was slightly lower than that from DLS (226 nm) for dendritic silica nanoparticles (DSNPs), as the latter measures hydrodynamic diameter which is the size of a hypothetical hard sphere diffusing in the same manner as the particles, being measured in a suspension [33]
The pH of the loading solution seemed to play an important role in dictating the affinity of peptide with phosphonate-modified DSNPs (PDSNPs) confirming maximum exenatide loading achieved near its pI which was around pH 5
Summary
Peptide-based therapeutics are specific and potent in action, and typically have better safety and tolerability profiles relative to small organic molecules [1]. Oral delivery of peptides remains challenging due to the chemical and enzymatic hydrolysis and poor absorption, and poor drug likeness (peptide hydrophilicity and high molecular weight) [3,4]. Despite these hurdles, the pursuit to develop oral drug delivery systems for many proteins and peptides has been ongoing for many decades but without clinically approved oral formulation of peptides and proteins. The pursuit to develop oral drug delivery systems for many proteins and peptides has been ongoing for many decades but without clinically approved oral formulation of peptides and proteins Incretins such as GLP-1 are important regulators of metabolic homeostasis which are released by intestinal L cells in response to glucose and other ingested nutrients [5]. The system made use of significant amounts of surfactants to perform hydrophobic ion pairing and exenatide payload accounted for only 0.71% w/w [10,11]
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