Graphene oxide nanosheets conjugated PEG-Glu-Lys-Glu copolymer drug delivery system improves drug-loading rates and enables reduction-sensitive drug release and drug tracking.

In this study, the PEG-Glu-Lys-Glu copolymer drug delivery system (GO/PEG-Glu-Lys-Glu) is prepared using glutamate-lysine-glutamate (Glu-Lys-Glu) modified polyethylene glycol (PEG) and connected graphene oxide nanosheets (GO). The multiple carboxyl groups of Glu-Lys-Glu and π-π interactions of GO can increase drug loading rate, and the fluorescence characteristics of GO could monitor the distribution of drug-loading systems in cells and the uptake of cells without the need for external dyes. Paclitaxel (PTX) is loaded via reduction-responsive disulfide bonds as a model medicine to examine the drug delivery potential of GO/PEG-Glu-Lys-Glu. The results showed that the drug loading content of PEG-Glu-Lys-Glu and GO/PEG-Glu-Lys-Glu to PTX is 7.11% and 8.97%, and the loading efficiency is 71.05% and 89.68%, respectively. It's speculated that the π-π interaction between GO and PTX improved the drug-loading capacity and efficiency of GO/PEG-Glu-Lys-Glu. In vitro, in a simulated drug release test, at 48 h, the release of PTX was 85.51% at pH 5.0, 65.12% and 38.32% at pH 6.5 and 7.4, respectively. The cytotoxicity assay results showed that GO/PEG-Glu-Lys-Glu cell inhibition rate to MCF-7 cells was 7.36% at 72 h. The cell inhibition rate of GO/PEG-Glu-Lys-Glu/PTX system at 72 h was 92%, equivalent to free PTX. Therefore, the GO/PEG-Glu-Lys-Glu drug delivery system has the characteristics of good biocompatibility and sustainable release of PTX, which is expected to be applied in the field of tumor therapy.

Controllable release of self-assembled reduction-sensitive paclitaxel dimer prodrug and tetrandrine nanoparticles promotes synergistic therapy against multidrug-resistant cancer.

BACKGROUND: Multidrug resistance (MDR) is the main reason for chemotherapy failure. Nanocarriers combined delivery of anti-cancer drugs and MDR inhibitors is an effective strategy to avoid MDR and improve the anti-cancer activity of drugs. METHODS: Two paclitaxel (PTX) molecules are linked by disulfide bonds into PTX2. Then, the PTX2 and tetrandrine (TET) are coated together by mPEG-PLGA self-assembled NPs for combinational treatment. Microstructure, physiological stability, and cytotoxicity are characterized for the co-loaded NPs. RESULTS: The NPs exhibit excellent suitability and blood safety for intravenous injection, specifically responsive to pH 6-7, and promptly initiate chemical degradation. Ex vivo fluorescence microscopy image studies indicate that co-loaded NPs increase drug penetration into cancer cells compared with free drugs. MTT assay demonstrates that co-loaded NPs have higher cytotoxicity against HeLa and the flow cytometric analysis shows that co-loaded NPs trigger more apoptosis than the free drugs. Reactive oxygen species (ROS) assay indicates that the drug-loaded NPs generated higher levels of ROS to accelerate apoptosis in HeLa cells. CONCLUSIONS: TET can get desirable effects of inhibiting the MDR in advance by binding with the active site on P-gp, then the disulfide bond of PTX2 is broken by glutathione (GSH) in cancer cells and decomposed into PTX to inhibit cancer cell proliferation. GENERAL SIGNIFICANCE: Our studies indicate that the co-loaded NPs can potentially overcome the MDR of conventional chemotherapeutic agents.

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 1H 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 ß-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 ß-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.