mp400493b_si_001.pdf (683.1 kB)
Penetratin Derivative-Based Nanocomplexes for Enhanced Intestinal Insulin Delivery
journal contribution
posted on 2014-01-06, 00:00 authored by Xi Zhu, Wei Shan, Peiwen Zhang, Yun Jin, Shan Guan, Tingting Fan, Yang Yang, Zhou Zhou, Yuan HuangSufficient
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.