3 research outputs found
Biomimetic Viruslike and Charge Reversible Nanoparticles to Sequentially Overcome Mucus and Epithelial Barriers for Oral Insulin Delivery
Nanoparticles
(NPs) for oral delivery of peptide/protein drugs are largely limited
due to the coexistence of intestinal mucus and epithelial barriers.
Sequentially overcoming these two barriers is intractable for a single
nanovehicle due to the requirements of different or even contradictory
surface properties of NPs. To solve this dilemma, a mucus-penetrating
virus-inspired biomimetic NP with charge reversal ability (P-R8-Pho
NPs) was developed by densely coating polyÂ(lactic-<i>co</i>-glycolic acid) NPs with cationic octa-arginine (R8) peptide and
specific anionic phosphoserine (Pho). The small size (81.81 nm) and
viruslike neutral charged surface (−2.39 mV) of the biomimetic
NPs achieved rapid mucus penetration, which was almost equal to that
of the conventional PEGylated mucus-penetrating nanoparticles. The
hydrolysis of surface-anchored anionic Pho was achieved by intestinal
alkaline phosphatase, which led to the turnover of ζ potential
to positive (+7.37 mV). This timely charge reversal behavior also
exposed cationic R8 peptide and induced efficient cell-penetrating
peptide (CPP)-mediated cellular uptake and transepithelial transport
on Caco-2/E12 cocultured cell model. What’s more, P-R8-Pho
NPs showed excellent stability in simulated gastrointestinal conditions
and enhanced absorption in intestine in vivo. Finally, oral administration
of insulin-loaded P-R8-Pho NPs enabled to induce a preferable hypoglycemic
effect and a 1.9-fold higher oral bioavailability was achieved compared
with single CPP-modified P-R8 NPs on diabetic rats. The combinative
application of biomimetic mucus-penetrating strategy and enzyme-responsive
charge reversal strategy in a single nanovehicle could sequentially
overcome mucus and epithelial barriers, thus showing great potential
for the oral peptide/protein delivery
Novel Solid Lipid Nanoparticle with Endosomal Escape Function for Oral Delivery of Insulin
Although
nanoparticles (NPs) have been demonstrated as promising
tools for improving oral absorption of biotherapeutics, most of them
still have very limited oral bioavailability. Lyso–endosomal
degradation in epithelial cells is one of the important but often-neglected
physiological barriers, limiting the transport of cargoes across the
intestinal epithelium. We herein reported a solid lipid nanoparticle
(SLN) platform with a unique feature of endosomal escape for oral
protein drug delivery. The SLNs consisted of a solid-lipid shell,
which contained an endosomal escape agent (GLFEAIEGFIENGWEGMIDGWYG,
HA2), and an aqueous core that is loaded with insulin (INS HA2-O-SLNs).
SLNs without and with the HA2 peptide in the aqueous core (INS SLNs
and INS HA2-W-SLNs, respectively) were used as the control groups.
Our study showed that INS HA2-O-SLNs effectively facilitated the escape
of the loaded insulin from the acidic endosomes, which preserved the
biological activity of insulin to a greater extent during the intracellular
transport. The spatial location of the HA2 peptide was demonstrated
to determine the endosomal escape efficiency. As demonstrated in the
intracellular trafficking of SLNs, INS HA2-O-SLNs displayed much less
distribution in late endosomes and lysosomes. Meanwhile, insulin in
INS HA2-O-SLNs exhibited the highest transepithelial permeation efficiency,
with 2.19 and 1.72 folds higher accumulated amount in the basolateral
side as compared to that in INS SLNs and INS HA2-W-SLNs. In addition,
insulin from INS HA2-O-SLNs exhibited the highest insulin permeation
in various regions of small intestines. INS HA2-O-SLNs generated an
excellent hypoglycemic response following oral administration in diabetic
rats. Thus, such functional SLNs demonstrated a great potency for
oral delivery of peptide/protein drugs
Enhanced Oral Delivery of Protein Drugs Using Zwitterion-Functionalized Nanoparticles to Overcome both the Diffusion and Absorption Barriers
Oral delivery of
protein drugs based on nanoparticulate delivery system requires permeation
of the nanoparticles through the mucus layer and subsequent absorption
via epithelial cells. However, overcoming these two barriers requires
very different or even contradictory surface properties of the nanocarriers,
which greatly limits the oral bioavailability of macromolecular drugs.
Here we report a simple zwitterions-based nanoparticle (NP) delivery
platform, which showed a great potency in simultaneously overcoming
both the mucus and epithelium barriers. The dense and hydrophilic
coating of zwitterions endows the NPs with excellent mucus penetrating
ability. Moreover, the zwitterions-based NPs also possessed excellent
affinity with epithelial cells, which significantly improved (4.5-fold)
the cellular uptake of DLPC NPs, compared to PEGylated NPs. Our results
also indicated that this affinity was due to the interaction between
zwitterions and the cell surface transporter PEPT1. Moreover, the
developed NPs loaded with insulin could induce a prominent hypoglycemic
response in diabetic rats following oral administration. These results
suggest that zwitterions-based NPs might provide a new perspective
for oral delivery of protein therapeutics