The aim of the present study was to develop zeta potential-changing polyphosphate nanoparticles (pp-NPs) in order to overcome the diffusion barrier of the mucus gel layer and to provide an enhanced cellular uptake. pp-NPs were obtained by in situ gelation between cationic polyethylene imine and anionic polyphosphate. The resulting pp-NPs were characterized with regard to size and zeta potential. Phosphate release studies were carried out by incubation of pp-NPs with isolated as well as cell-associated intestinal alkaline phosphatase (IAP) and quantified by malachite green assay. Correspondingly, change in the zeta potential was measured, and pp-NPs were analyzed by scanning electron microscopy studies. Mucus permeation studies were performed with porcine intestinal mucus via the transwell insert method and rotating tube method. Furthermore, cell viability and cellular uptake were investigated on Caco-2 cells. The resulting pp-NPs displayed a mean size of 269.16 ± 1.12 nm and a zeta potential between −9 and −10 mV in the characterization studies. Within 4 h, a remarkable amount of phosphate was released from pp-NPs incubated with isolated IAP as well as cell-associated IAP and zeta potential raised up from −9.14 ± 0.45 to −1.75 ± 0.46 mV. Compared with dephosphorylated polyphosphate nanoparticles (de-pp-NPs), a significantly enhanced mucus permeation of pp-NPs was observed. Moreover, pp-NPs did not exhibit cytotoxicity. Cellular uptake increased 2.6-fold by conversion of pp-NPs to de-pp-NPs following enzymatic cleavage. Taking the comparatively simple preparation method and the high mucus-permeating properties of pp-NPs and high cellular uptake properties of de-pp-NPs into account, these nanocarriers might be promising novel tools for mucosal drug delivery.
The
purpose of the study was to develop a per-6-thiolated α-cyclodextrin
(α-CD) by substituting all primary hydroxyl groups of α-CD
with thiol groups and to assess its solubility-improving and permeation-enhancing
properties for a BCS Class IV drug in vitro as well as in vivo. The
primary hydroxyl groups of α-CD were replaced by iodine, followed
by substitution with −SH groups. The structure of per-6-thiolated
α-CD was approved by FT-IR and 1H NMR spectroscopy.
The per-6-thiolated was characterized for thiol content, −SH
stability, cytotoxicity, and solubility-improving properties by using
the model BCS Class IV drug furosemide (FUR). The mucoadhesive properties
of the thiolated oligomer were investigated via viscoelastic measurements
with porcine mucus, whereas permeation-enhancing features were evaluated
on the Caco-2 cell monolayer and rat gut mucosa. Furthermore, oral
bioavailability studies were performed in rats. The per-6-thiolated α-CD
oligomer displayed 4244 ± 402 μmol/g thiol groups. These
−SH groups were stable at pH ≤ 4, exhibiting a pK
a value of 8.1, but subject to oxidation at
higher pH. Per-6-thiolated α-CD was not cytotoxic to Caco-2
cells in 0.5% (m/v) concentration within 24 h. It improved the solubility
of FUR in the same manner as unmodified α-CD. The addition of
per-6-thiolated α-CD (0.5% m/v) increased the mucus viscosity
up to 5.8-fold at 37 °C within 4 h. Because of the incorporation
in per-6-thiolated α-CD, the apparent permeability coefficient
(P
app) of FUR was 6.87-fold improved on
the Caco-2 cell monolayer and 6.55-fold on the intestinal mucosa.
Moreover, in vivo studies showed a 4.9-fold improved oral bioavailability
of FUR due to the incorporation in per-6-thiolated α-CD. These
results indicate that per-6-thiolated α-CD would be a promising
auxiliary agent for the mucosal delivery of, in particular, BCS Class
IV drugs.
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