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-grafted-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.