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.

Four peptide amphiphiles (PA1-4) with different degrees of polymerization (DP = 40, 15, 10, and 6) were synthesized by Fuchs-Farthing and ring-opening polymerization followed by post-polymerization modification, as fully characterized by H NMR, FT-IR, gel permeation chromatography, and circular dichroism (CD) spectroscopy. It was found that PAs could self-assemble to form regular spherical micelles in low-concentration (about 1 mg/mL) aqueous solution, which had different contents of secondary structures and mainly adopted random coil conformations. The water solubility of PAs increases with the increase of DP, the polypeptide chain stretches randomly in water, the β-sheets decrease, and the random coil conformations dominate. When the pH of PA solution decreases or increases, intramolecular hydrogen bonds break, and molecular chains stretch, leading to a decrease of α-helix, turn conformations, and an increase of β-sheets. Meanwhile, the particle size of micelles increases. At around 0.4 mg/mL, the hemolysis ability of PA2 is negligible at pH 7.4 and 6.5 and about 33% at pH 5.5. Cisplatin (CDDP) was linked to micelles by coordination bonds to explore their potential as drug carriers, exhibiting controlled pH and reduction in dual drug release effects. MTT assay showed that the HeLa cell viability was 78% when cultured in the 13.5 μg/mL PA2 blank micelles for 2 days, while the cell viability was 60% in the CDDP-loaded micelles. Furthermore, a high concentration of PA2 (about 100 mg/mL) could self-assemble into a fibrous hydrogel at pH 5.5, which self-healed 2 h after incision and self-degraded 71% within 14 days. The CDDP-loaded fiber hydrogel exhibited a sustained release effect similar to the CDDP-loaded micelles. The cytotoxicity of CDDP-loaded fibers at 48 h was detected to be the same as that of the same amount of CDDP, and the cell viability was 7%. Therefore, we provide a new strategy for the synthesis of amphiphilic peptides with potential applications in nano-drug carriers and cancer therapy.