Silica-Coated Nanoparticles with a Core of Zinc, l-Arginine, and a Peptide Designed for Oral Delivery

Abstract

Nanoparticle constructs for oral peptide delivery at a minimum must protect and present the peptide at the small intestinal epithelium in order to achieve oral bioavailability. In a reproducible, scalable, surfactant-free process, a core was formed with insulin in ratios with two established excipients and stabilizers, zinc chloride and Larginine. Cross-linking was achieved with silica, which formed an outer shell. The process was reproducible across several batches, and physicochemical characterization of a single batch was confirmed in two independent laboratories. The silica-coated nanoparticles (SiNPs) entrapped insulin with high entrapment efficiency, preserved its structure, and released it at a pH value present in the small intestine. The SiNP delivered insulin to the circulation and reduced plasma glucose in a rat jejunal instillation model. The delivery mechanism required residual L-arginine in the particle to act as a permeation enhancer for SiNPreleased insulin in the jejunum. The synthetic process was varied in terms of ratios of zinc chloride and L-arginine in the core to entrap the glucagon-like peptide 1 analogue, exenatide, and bovine serum albumin. SiNP-delivered exenatide was also bioactive in mice to some extent following oral gavage. The process is the basis for a platform for oral peptide and protein delivery.

Synthesis and In Vivo Evaluation of Insulin-Loaded Whey Beads as an Oral Peptide Delivery System

“…The Cmax and % F were higher when C 10 was administered with the insulin-dWPI beads compared to the beads without C 10 , but values were significantly different at 20 min. The 100 mM concentration of C 10 that was present in the jejunal loops was also enough to independently reduce plasma glucose, as was also documented in ad-mixtures with insulin in rat intestinal instillations in other studies [ 37 , 51 ]. This response was rapid and occurred within 10–20 min [ 51 ].…”

“…The 100 mM concentration of C 10 that was present in the jejunal loops was also enough to independently reduce plasma glucose, as was also documented in ad-mixtures with insulin in rat intestinal instillations in other studies [ 37 , 51 ]. This response was rapid and occurred within 10–20 min [ 51 ]. This would suggest that the bead-released insulin was not able to take full advantage of the PE action of C 10 using the current study design.…”

“…administration via a delivery funnel. It has been observed in previous studies that oral insulin particulate formulations often need additional help from PEs to enable released peptide to cross the epithelium [ 34 , 51 ]. It was for this reason that an established PE, C 10 , was tested in combination with the insulin-loaded beads.…”

Cloaking Silica Nanoparticles with Functional Protein Coatings for Reduced Complement Activation and Cellular Uptake

“…In an in vivo setting, we anticipate that a protein precoating on the nanoparticle surface may play a critical role in dictating the organization of the biomolecular corona, whereby the engineered protein precoating would replace the biological hard corona. Consequently, the protein precoating would influence the assembly of additional plasma protein layers constituting the soft corona and thus enable control over cellular interactions and related immune responses. ,, In addition, past studies have shown that it is possible to preserve the biological functions of proteins in the precoated adlayer on nanoparticle surfaces even after subsequent formation of the soft corona. ,, While the nanoparticle design in our study was simple and consisted of bulk SiNPs, the design principles and methods employed are broadly extendable to various classes of SiNPs, including silica-coated nanoparticles. − Indeed, there are many types of silica-coated nanoparticles that are routinely used in intravenous administration settings, − and establishing effective strategies to mitigate potential immunotoxicities such as CARPA effects is paramount. Together, our findings show that SiNPs can induce complement activation along the alternative pathway and protein coatings can mitigate SiNP-triggered complement activation and related adverse effects such as macrophage uptake.…”

Advances in oral peptide drug nanoparticles for diabetes mellitus treatment

“…Oral administration is a simple and repeatable administration route [ 55 ]. Additionally, insulin secreted from pancreatic β-cells gets access to systematic circulation via the portal vein, and GLP-1 is directly secreted by intestinal L-cells [ 56 , 57 ]. Oral administration of insulin or GLP-1RA can imitate the dynamics of the endogenous insulin or GLP-1, and provides better glucose homeostasis.…”