Penetratin derivative-based nanocomplexes for enhanced intestinal insulin delivery.

Sufficient mucosal permeability is the bottleneck problem in developing an efficient intestinal delivery system of insulin. Cell-penetrating peptide-based nanocomplexes for the enhanced mucosal permeation of insulin were developed in this study. Penetratin, a cell-penetrating peptide was site-specifically modified with a bis-β-cyclodextrin group. Insulin-loaded nanocomplexes were prepared by self-assembly using penetratin or its bis-β-cyclodextrin modified derivative (P-bis-CD). A stronger intermolecular interaction and higher complex stability were observed for P-bis-CD nanocomplexes than the penetratin nanocomplexes. P-bis-CD nanocomplexes were significantly more efficient for the permeation of insulin as compared to the penetratin nanocomplexes both in vitro and in situ. Interestingly, different cellular internalization mechanisms were observed for the two nanocomplexes. In diabetic rats, intestinal administration of P-bis-CD nanocomplexes resulted in a prominent hypoglycemic effect which lasted for 6 h with maximum inhibitory rate at 60%. The relative pharmacological availability and bioavailability of P-bis-CD nanocomplexes were 10.6% and 7.1%, which were 3.0-fold and 2.3-fold higher than that of penetratin nanocomplexes, respectively. In addition, no sign of toxicity was observed after 7 consecutive days of administration of P-bis-CD nanocomplexes with endotoxin. These results demonstrated that P-bis-CD was a promising epithelium permeation enhancer for insulin and suggested that the chemical modification of cell penetration peptides was a feasible strategy to enhance their potential.