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. 2021 Aug 11:16:5317-5331.
doi: 10.2147/IJN.S315310. eCollection 2021.

High-Loading Self-Assembling Peptide Nanoparticles as a Lipid-Free Carrier for Hydrophobic General Anesthetics

Jing Liu  1   2 , Fei Peng  1   2 , Yi Kang  1   2 , Deying Gong  1   2 , Jing Fan  1   2 , Wensheng Zhang  1   2 , Feng Qiu  1   2
Affiliations

High-Loading Self-Assembling Peptide Nanoparticles as a Lipid-Free Carrier for Hydrophobic General Anesthetics

Jing Liu et al. Int J Nanomedicine. .

Abstract

Purpose: Typical hydrophobic amino acids (HAAs) are important motifs for self-assembling peptides (SAPs), but they lead to low water-solubility or compact packing of peptides, limiting their capacity for encapsulating hydrophobic drugs. As an alternative, we designed a peptide GQY based on atypical HAAs, which could encapsulate hydrophobic drugs more efficiently. Although hydrophobic general anesthetics (GAs) have been formulated as lipid emulsions, their lipid-free formulations have been pursued because of some side effects inherent to lipids. Using GAs as targets, potential application of GQY as a carrier for hydrophobic drugs was evaluated.

Methods: Thioflavin-T (ThT) binding test, dynamic light scattering (DLS) and transmission electron microscopy (TEM) were used to examine the self-assembling ability of GQY. Pyrene and 8-Anilino-1-naphthalenesulfonic acid (ANS) were used to confirm formation of hydrophobic domain in GQY nanoparticles. Using pyrene as a model, GQY's capacity to encapsulate hydrophobic drugs was evaluated. GAs including propofol, etomidate and ET26 were encapsulated by GQY. Loss of righting reflex (LORR) test was conducted to assess the anesthetic efficacy of these lipid-free formulations. Paw-licking test was used to evaluate pain-on-injection of propofol-GQY (PROP-GQY) formulation. Hemolytic and cytotoxicity assay were used to evaluate biocompatibility of GQY.

Results: Stable nanoparticles containing plenty of hydrophobic cavities could be formed by GQY, which could encapsulate hydrophobic drugs at very high concentration and form stable suspensions. Propofol, etomidate and ET26 formulated by GQY showed anesthetic efficacy comparable to their currently available formulations. Unlike clinic lipid emulsion, PROP-GQY formulation did not cause pain-on-injection in rats. Neither obvious cytotoxicity nor hemolytic activity of GQY was observed.

Conclusion: GQY could encapsulate GAs to obtain stable and effective formulations. As a lipid-free carrier, GQY exhibited considerable biocompatibility and other side benefits such as reducing pain-on-injection. More SAPs based on atypical HAAs could be designed as promising carriers for hydrophobic drugs.

Keywords: general anesthetics; hydrophobic drugs; lipid-free formulations; nanoparticles; self-assembling peptides.

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Conflict of interest statement

The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Self-assembling and drug-loading model of GQY. (A) Chemical structure of GQY. (B) Chemical structure of pyrene and GAs including propofol, etomidate and ET26. (C) Schematic illustration of drug loading by GQY. Hydrophobic groups in the side chain of glutamine and tyrosine are shown in purple.
Figure 2
Figure 2
Formation of stable nanoparticles by GQY. (A–C) TEM images of GQY nanoparticles formed in H2O with pH 4.0 (A), in H2O with pH 7.4 (B) and in GI (C). Insertions show photographs of corresponding GQY solutions. (D) Representative particle size distribution of GQY in H2O with pH 4.0 and 7.4, and GQY in GI. (E) Representative Zeta potential plot of GQY in H2O with pH 4.0 and 7.4, and GQY in GI. (F) ThT-binding fluorescence spectra of GQY in H2O at different temperatures.
Figure 3
Figure 3
Formation of hydrophobic domain. (A) Fluorescence spectra of pyrene monomer in 5 mM GQY solution or H2O. (B) ANS-binding fluorescence spectra of 5 mM GQY or H2O.
Figure 4
Figure 4
Pyrene-GQY nanoparticles and stability. (A) Photograph of pyrene-GQY suspension with 5 mM pyrene dispersed in 2.5 mM GQY solution. (B) TEM images of pyrene-GQY nanoparticles collected at different time from 0–30 days. (C) Size distribution and zeta potential of pyrene-GQY nanoparticles within 30 days. (D) Fluorescence spectra of pyrene-GQY within 30 days.
Figure 5
Figure 5
Formation of drug-GQY nanoparticles. (A–C) TEM images of nanoparticles in PROP-GQY (A), ET-GQY (B) and ET26-GQY (C) formulations. Insertions show photographs of corresponding formulation. (D) Particle size and zeta potential of different formulations.
Figure 6
Figure 6
Serum corticosterone level. (A) Flow chart of blood collection for serum corticosterone determination, a–f: time for blood collection, which was counterpart of the x axis labels in Figure 6B. (B) The serum corticosterone level after ACTH stimulation and intravenous injection of 2 ED50 GQY, ET-GQY or ET26-GQY (n = 9). #P < 0.05, ET-GQY versus GQY. *P < 0.05, ET-GQY versus ET26-GQY. “1st DXM 2h” defined the timepoint that was 2 hours after 1st DXM was given, “ACTH 15min/30min/60min/90min” are the timepoints that were 15, 30, 60 or 90 minutes after ACTH was administered.
Figure 7
Figure 7
Biocompatibility of GQY. (A) Cytotoxicity of GQY in NRK-49F cells. (B) Cytotoxicity of GQY in L929 cells. (C) Hemolytic activity of GQY.
See this image and copyright information in PMC

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