Dual Stimuli-Responsive Nanoparticle-Incorporated Hydrogels as an Oral Insulin Carrier for Intestine-Targeted Delivery and Enhanced Paracellular Permeation.

For enhanced oral insulin delivery, a strategy of acid-resistant and enteric hydrogels encapsulating insulin-loaded nanoparticles was developed. The nanoparticles were prepared by the formation of an anionic insulin/heparin sodium (Ins/HS) aggregate, followed by coating of chitosan (CS) on the surface. The nanoparticles, tagged as CS/Ins/HS NPs, exhibited excellent mucosa affinity, effective protease inhibition, and marked paracellular permeation enhancement. Moreover, to improve the acid-stability of CS/Ins/HS NPs and impart the capacity of intestine-targeted delivery, a pH- and amylase-responsive hydrogel was synthesized via free radical copolymerization, using methacrylic acid as the monomer and acrylate--carboxymethyl starch as the cross-linker. The resulting hydrogel exhibited sharp pH-sensitivity in the gastrointestinal tract and rapid enteric behavior under intestinal amylase. The additional protection for insulin in artificial gastric fluid was confirmed by packaging CS/Ins/HS NPs into the hydrogel. The obtained nanoparticle-incorporated hydrogel was named as NPs@Gel-2. The release of insulin from NPs@Gel-2 was evidently accelerated in artificial intestinal fluid containing α-amylase. Furthermore, the hypoglycemic effects were evaluated with type-1 diabetic rats. Compared to subcutaneous injection of insulin solution, the relative pharmacological availability (rPA) for oral intake of NPs@Gel-2 (30 IU/kg) was determined to be 8.6%, along with rPA of 4.6% for oral administration of unpackaged CS/Ins/HS NPs (30 IU/kg). Finally, the two-week therapeutic outcomes in diabetic rats were displayed after twice-daily treatments by oral intake of NPs@Gel-2, showing the relief of diabetic symptoms and suppression of weight loss in the rats. Therefore, this dual stimuli-responsive nanoparticle-incorporated hydrogel system could be a promising platform for oral insulin delivery.