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Pharmaceutics
2022 Jan 06;141:. doi: 10.3390/pharmaceutics14010133.
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NGIWY-Amide: A Bioinspired Ultrashort Self-Assembled Peptide Gelator for Local Drug Delivery Applications.
Theodoroula NF
,
Karavasili C
,
Vlasiou MC
,
Primikyri A
,
Nicolaou C
,
Chatzikonstantinou AV
,
Chatzitaki AT
,
Petrou C
,
Bouropoulos N
,
Zacharis CK
,
Galatou E
,
Sarigiannis Y
,
Fatouros DG
,
Vizirianakis IS
.
Abstract
Fibrillar structures derived from plant or animal origin have long been a source of inspiration for the design of new biomaterials. The Asn-Gly-Ile-Trp-Tyr-NH2 (NGIWY-amide) pentapeptide, isolated from the sea cucumber Apostichopus japonicus, which spontaneously self-assembles in water to form hydrogel, pertains to this category. In this study, we evaluated this ultra-short cosmetic bioinspired peptide as vector for local drug delivery applications. Combining nuclear magnetic resonance, circular dichroism, infrared spectroscopy, X-ray diffraction, and rheological studies, the synthesized pentapeptide formed a stiff hydrogel with a high β-sheet content. Molecular dynamic simulations aligned well with scanning electron and atomic-force microscopy studies, revealing a highly filamentous structure with the fibers adopting a helical-twisted morphology. Model dye localization within the supramolecular hydrogel provided insights on the preferential distribution of hydrophobic and hydrophilic compounds in the hydrogel network. That was further depicted in the diffusion kinetics of drugs differing in their aqueous solubility and molecular weight, namely, doxorubicin hydrochloride, curcumin, and octreotide acetate, highlighting its versatility as a delivery vector of both hydrophobic and hydrophilic compounds of different molecular weight. Along with the observed cytocompatibility of the hydrogel, the NGIWY-amide pentapeptide may offer new approaches for cell growth, drug delivery, and 3D bioprinting tissue-engineering applications.
Figure 1. The structure of the pentapeptide NGIWY-amide.
Figure 2. (A) 1H NMR spectrum of NGIWY (1.3 mM) peptide in solution (500 MHz, PBS in D2O pH 7.4). (B) 1H NMR spectrum of NGIWY (1% w/v, 15.3 mM) (500 MHz, PBS in D2O pH 7.4) ~10 min after the initial preparation. (C) 1H NMR spectrum of NGIWY (1% w/v, 15.3 mM) (500 MHz, PBS in D2O pH 7.4) 24 h after the initial preparation.
Figure 3. (A) Selective region of 2D NOESY NMR spectrum of NGIWY peptide (1.3 mM) in solution (500 MHz, PBS in D2O pH 7.4). (B) Selective region of 2D NOESY NMR spectrum of NGIWY peptide (1% w/v, 15.3 mM) (500 MHz, PBS in D2O pH 7.4). New Tr-NOE cross-peaks are denoted with the red color.
Figure 4. (A) 1H NMR spectrum of NGIWY (500 MHz, PBS in D2O pH 7.4). (B) STD NMR spectrum of NGIWY (1% w/v, 15.3 mM) peptide (500 MHz, PBS in D2O pH 7.4). On-resonance selective irradiation occurred at â0.6 ppm. (C) 1H NMR spectrum of NGIWY (1% w/v, 15.3 mM) (500 MHz, PBS in D2O pH 7.4). (D) STD NMR spectrum of NGIWY peptide (1.3 mM) in solution (500 MHz, PBS in D2O pH 7.4). On-resonance selective irradiation occurred at 6.70 ppm. (E) STD NMR spectrum of NGIWY (1% w/v, 15.3 mM) (500 MHz, PBS in D2O pH 7.4). On-resonance selective irradiation occurred at 6.70 ppm.
Figure 5. Dihedral angle conformations of the NGIWY peptide and energy formation during the simulation process.
Figure 6. Information received by the DFT studies revealed a fully hydrophilic peptide and an electrostatic potential profile. The MD simulations showed the 5 most possible conformations of the pentapeptide.
Figure 7. Oscillatory (A) time-sweep and (B) frequency-sweep measurements of the pentapeptide hydrogel (2% w/v) at a constant frequency of 1 Hz and strain of 0.1% performed at 25 °C.
Figure 8. (A) UV adsorption and (B) fluorescence spectra of the pentapeptide hydrogel (0.02% w/v) in water. (C) FTIR and (D) XRD diffractogram of the pentapeptide hydrogel. (E) CD spectra of the pentapeptide at different concentrations in double-distilled water at 25 °C.
Figure 9. (A,B) AFM images and (C,D) TEM micrographs of the NGIWY-amide pentapeptide hydrogel prepared at 2% w/v in Milli-Q water.
Figure 10. In vitro release profiles of octreotide acetate, doxorubicin hydrochloride, and curcumin from the pentapeptide in PBS pH 7.4 (in the presence of Tween 80 0.1% for curcumin) at 37 °C (n = 3, ±S.D.).
Figure 11. Cytotoxicity evaluation of the NGIWY-amide hydrogel. (AâC) Effect of NGIWY on MRC5 cell survival as assessed by CCK-8 analysis after treating with various concentrations of the NGIWY-amide pentapeptide hydrogel for (A) 24 h, (B) 48 h, and (C) 72 h. (DâF) Effect of NGIWY on HSC3 cells survival as assessed by CCK-8 analysis after treating with various dosages of NGIWY for (D) 24 h, (E) 48 h, and (F) 72 h. The data were analyzed using a t-test. Statistical significance was set at p < 0.05 (*: p < 0.05; **: p < 0.005; ***: p < 0.001).
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