Self-Assembling Peptide Nanofiber Hydrogels for Controlled Ocular Delivery of Timolol Maleate

Abstract

The self-assembling peptides Ac-(RADA) 4-CONH 2 and Ac-(IEIK) 3 I-CONH 2 which form hydrogels in physiological conditions were evaluated as carriers for ocular delivery of the βblocker timolol maleate. Electron microscopy studies revealed that hydrogels contain nanofibers, whereas rheological studies showed that the Ac-(IEIK) 3 I-CONH 2 self-assembles in a stiffer hydrogel compared with the Ac-(RADA) 4-CONH 2 peptide. The in vitro release and ex vivo permeation studies demonstrated controlled release and transport of the drug through the cornea, which depended on the self-assembling peptide sequence. In vivo studies in rabbits showed significant increase in the area under the concentration-time curve (AUC) after administration of the drug for the Ac-(RADA) 4-CONH 2 hydrogel compared to drug solution, whereas a sustained reduction of intraocular pressure for up to 24 h after instillation was achieved for both drug loaded hydrogels. Histological studies revealed good ocular tolerability upon application of the formulations, suggesting that self-assembling peptide hydrogels are promising systems for sustained ocular drug delivery.

Ocular Co-Delivery of Timolol and Brimonidine from a Self-Assembling Peptide Hydrogel for the Treatment of Glaucoma: In Vitro and Ex Vivo Evaluation

“…The in vitro release profiles of TM and BR from the peptide hydrogel were recorded in STF pH 7.4 at 37 °C. Both drugs demonstrated similar release profiles ( Figure 3 ) with a burst release of approximately 60% occurring within the first hour, achieving total release over a period of 8 h, in accordance to previous studies [ 11 , 21 ]. TM release from the peptide hydrogel was slightly slower, possibly due to the minor difference in its lipophilicity compared to BR (logP TM = 1.83; logP BR = 1.37), however this difference was not statistically significant.…”

“…The P app of TM in the peptide hydrogel and in solution were calculated to be 2.3 × 10 −6 ± 0.3 cm/s and 0.75 × 10 −6 ± 0.053 cm/s, respectively. Both values were found to be similar compared to the respective values reported in the literature for TM in the peptide hydrogel (1.91 × 10 −6 ± 0.11 cm/s) [ 11 ] and in solution form (0.9 × 10 −6 cm/s) [ 24 ]. The P app of BR in the peptide hydrogel was calculated to be 3.3 × 10 −6 ± 0.3 cm/s, which was almost five times higher than the P app value calculated for BR in solution (0.63 × 10 −6 ± 0.055 cm/s).…”

“…However, the static nature of the Franz cell assembly from which the normal functions of the eye, such as movement of the eyelids and nasolacrimal fluid drainage, are absent and may have resulted in an overestimation of the irritant action of the drug loaded peptide hydrogel. This hypothesis was further supported in a previous study, in which the in vivo histological findings showed no structural changes in the corneal integrity after treatment with the TM loaded formulations in contradiction with the mild irritation effects observed in the ex vivo histological findings [ 11 ].…”

“…During self-assembly, b-sheets are arranged in a highly oriented nanoscale structure consisting of β-sheet bilayers stacked together through hydrophobic interactions developed by lateral alanine chains. The peptide solution RADA16-I forms hydrogels of high-water content [up to 99.5% (w/w)], with a pore diameter between 5 and 200 nm, allowing entrapment and gradual release of small molecules [ 9 , 10 , 11 , 12 ] and macromolecules [ 13 , 14 , 15 ].…”

3D Macroscopic Architectures from Self‐Assembled MXene Hydrogels

“…The viscosity of the MXH decreased greatly as it was sheared, which is typical of an assembled hydrogel and similar to a self‐assembled graphene hydrogel . The storage and loss modulus of these materials are better those of conventional self‐assembled hydrogels and are comparable to those of various chemically crosslinked polymer hydrogels and some biological tissues, both in a small‐deformation oscillatory measurement and in a thermal stability test.…”