Poly(l-cysteine) Peptide Amphiphile Derivatives Containing Disulfide Bonds: Synthesis, Self-Assembly-Induced β-Sheet Nanostructures, pH/Reduction Dual Response, and Drug Release

Abstract

Three disulfide bond-containing peptide amphiphiles (PA1−3) with different lengths of alkyl tails (PA1 for C 6 , PA2 for C 12 , and PA3 for C 18 ) were synthesized by ring-opening polymerization of α-amino acid N-carboxyanhydride followed by post-polymerization modification. The peptide segments were composed of 3-mercaptopropionic acid-modified poly(L-cysteine) [P(Cys-SS-CH 2 CH 2 COOH)]. We characterized the chemical structure and molecular parameters by 1 H NMR, 13 C NMR, gel permeation chromatography, Fourier transform infrared spectroscopy, and circular dichroism spectroscopy. It is found that alkyl-P(Cys-SS-CH 2 CH 2 COOH) mainly presents a β-sheet conformation at the solid state. However, the PAs present predominant random coils at pH 7.4 in aqueous solutions. The β-sheet conformation increased dramatically when the concentration of the PA exceeded its critical micelle concentration (ca. 0.3 mg/mL for PA3), indicating the formation of self-assembly-induced β-sheet nanostructures. Elongation of the alkyl chain length or a decrease of the pH of the PA solution can promote the formation of the β-sheet conformation. The three PAs can self-assemble into spherical micelles or nanofibrous hydrogels, which can be utilized as nanocarriers for systemic drug delivery or implants for localized drug delivery, respectively. Cisplatin (CDDP) was loaded as a model medicine to examine the drug delivery potential of PA3. We found that the CDDP-loaded PA3 micelles are stable at pH 7.4, have a spherical morphology with a hydrodynamic diameter of ca. 52 nm, and accomplish pH/reduction dual-responsive release of CDDP. In addition, alkyl-P(Cys-SS-CH 2 CH 2 COOH) can self-assemble into nanofibrous hydrogels at pH 5.0−6.0 or upon the addition of certain metal ions and show excellent dynamic reversibility. Moreover, the CDDP-loaded PA3 hydrogel exhibits a sustained release profile and a nearly linear release over 48 h. In vitro cytotoxicity of PA3 also indicates its nontoxicity. Thus, our findings suggest that alkyl-P(Cys-SS-CH 2 CH 2 COOH) has great potential for both systemic and localized delivery of therapeutics.

Naphthyl-Poly(S-((2-carboxyethyl)thio)-l-cysteine) Peptide Amphiphiles with Different Degrees of Polymerization: Synthesis, Self-Assembly, pH/Reduction-Triggered Drug Release, and Cytotoxicity

“…At present, PAs with aliphatic alkyl chains as the hydrophobic end are more popular. PAs with alkyl chains as hydrophobic groups have also been discussed previously by our group . In this work, we thought the interaction interfiber provided by the ionic force and the alkyl chain was weak or inefficient.…”

“…PAs with alkyl chains as hydrophobic groups have also been discussed previously by our group. 45 In this work, we thought the interaction interfiber provided by the ionic force and the alkyl chain was weak or inefficient. Aromatic−aromatic interactions play an irreplaceable role in the stability of natural proteins, providing more vital interaction forces than van der Waals forces of alkyl chains in a compact volume, can effectively predict the self-assembly of polypeptides, and can form hydrogels with high mechanical strength or stability.…”

Platinum-based drugs and hydrogel: a promising anti-tumor combination

“…It could self-assemble into hydrogel nanofibers when Ca 2+ or CDDP was added. CDDP release from these amphiphilic peptide hydrogels was sustained, and half of the CDDP was released near the lining (Dong et al., 2021 ).…”

One-pot preparation of polypeptide nanogels in aqueous solutionviaring-opening polymerization-induced nano-gelation

“…The incorporation of disulfide linkages can enhance the extracellular stability of nano-objects and present a controlled cellresponsive cargo release via rapid and selective cleavage in the presence of a reductive reagent in the cells. [46][47][48][49][50][51][52][53] By aqueous ROP of L-cystine N-carboxyanhydride (CYS-NCA) and γ-benzyl-Lglutamate N-carboxyanhydride (BLG-NCA) using α-amino-poly (ethylene oxide) (mPEG-NH 2 ) as a macroinitiator, two types of polymer nanogels, from PEG-b-PCYS and PEG-b-P(CYS-co-BLG), were readily prepared. The kinetics of ROP in NaHCO 3 aqueous solution was systematically investigated by FTIR and 1 H NMR.…”