pH-Responsive Co-Assembled Peptide Hydrogel to Inhibit Drug-Resistant Bacterial Infection and Promote Wound Healing.

Drug-resistant bacterial infection and biofilm formation are the key inhibitors of wound healing, and new strategies are urgently needed to address these issues. In this study, we designed a pH-responsive co-assembled peptide hydrogel to inhibit Methicillin-resistant Staphylococcus aureus (MRSA) infection and promote wound healing. We synthesized a cationic short peptide (Nap-FFKKK) and a co-assembled hydrogel with curcumin at pH ∼ 7.8. The loaded curcumin was continuously released in a weak acid environment (pH ∼ 5.5). The lysine-rich cationic peptide inhibited biofilm formation in MRSA via electrostatic interaction with the negatively charged bacterial cell surface and, thus, provided a reinforcing antibacterial effect with curcumin. In vitro antibacterial experiments showed that the co-assembled system considerably reduced the minimum inhibitory concentration of curcumin against MRSA by 10-fold and promoted wound healing in a mouse model of MRSA-infected wounds. This study provides a simple and promising strategy to treat drug-resistant bacterial infections in wounds.

Sorafenib-loaded nanostructured lipid carriers for topical ocular therapy of corneal neovascularization: development, in-vitro and in vivo study.

Sorafenib (SRB), a multikinase inhibitor, is effective in reducing experimental corneal neovascularization (CNV) after oral administration; however, its therapeutic use in ocular surface disorders is restricted due to poor solubility and limited bioavailability. This study aimed to develop and optimize SRB-loaded nanostructured lipid carriers (SRB-NLCs) for topical ocular delivery by a central composite design response surface methodology (CCD-RSM). It was spherical and uniform in morphology with an average particle size of 111.87 ± 0.93 nm and a narrow size distribution. The in vitro drug release from the released SRB-NLC formulation was well fitted to Korsmeyer Peppas release kinetics. The cell counting kit-8 (CCK-8) cell viability assay demonstrated that SRB-NLC was not obviously cytotoxic to human corneal epithelial cells (HCECs). An in vivo ocular irritation test showed that SRB-NLC was well tolerated by rabbit eyes. Ocular pharmacokinetics revealed 6.79-fold and 1.24-fold increase in the area under concentration-time curves (AUC0-12h) over 12 h in rabbit cornea and conjunctiva, respectively, treated with one dose of SRB-NLC compared with those treated with SRB suspension. Moreover, SRB-NLC (0.05% SRB) and dexamethasone (0.025%) similarly suppressed corneal neovascularization in mice. In conclusion, the optimized SRB-NLC formulation demonstrated excellent physicochemical properties and good tolerance, sustained release, and enhanced ocular bioavailability. It is safe and potentially effective for the treatment of corneal neovascularization.

Cytoprotective Effects of Water Soluble Dihydropyrimidinthione Derivative Against UV-B Induced Human Corneal Epithelial Cell Photodamage.

Excessive UV-B exposure is well known to be a risk factor for corneal phototoxicity including direct DNA damage and disturbances in the antioxidant balance. Here, we showed a successful synthesis of a water-soluble and biocompatible small molecule DHPM 1 with dihydropyrimidinthione skeleton, which could effectively protect human corneal epithelial (HCE-2) cells from UV-B damage. In separate experiments, DHPM 1 absorbed UV-B rays and exhibited scavenging activity against intracellular ROS induced by UV-B radiation, thereby reducing the levels of DNA fragmentation. Additionally, UV-B exposure increased the expression of cleaved caspase-3, as well as the ratio of Bax/Bcl-2 at protein levels, while pretreatment with DHPM 1 significantly reversed these changes. To the best of our knowledge, this is the first report of a study based on dihydropyrimidinthione derivatives to develop a promising eye drops, which may well find extensive applications in UV-B caused corneal damage.

A strong CD8+ T cell-stimulating supramolecular hydrogel.

The development of molecules with immune stimulatory properties is crucial for cancer immunotherapy. In this work, we combined two peptide-based molecules, tuftsin (TKPR) and Nap-GDFDFDY, to develop a novel self-assembling molecule Nap-GDFDFDYTKPR (Comp.3), which has strong CD8+ T cell stimulatory properties. Comp.3 could self-assemble into nanofibers and hydrogels, which significantly improved the stability of tuftsin against enzyme digestion. The nanofibers of Comp.3 enhanced the phagocytic activity of macrophages, promoted the maturation of DCs, and stimulated the expression of cytokines. In addition, it demonstrated an excellent anti-tumor efficacy in vivo by eliciting a strong CD8+ T immune response. Taken together, our observations revealed a powerful immune stimulating nanomaterial that is a promising compound for cancer immunotherapy.

Anticancer Supramolecular Hydrogel of D/L-Peptide with Enhanced Stability and Bioactivity.

Supramolecular nanofibers based on D-amino acid-containing peptide self-assembly have attracted increased interest recently because of their superior biostability. However, the construction of nanostructures containing D-amino acids is still insufficient at present, and their application in biomedical fields should be further explored. Herein, we demonstrated that the aggregation property of hydrophobic anticancer tyroservaltide (YSV) could be decreased by introducing D-amino acids. Using such strategy, we fabricated a novel anticancer hydrogelator based on the D/L-peptide of NapGDFDFDYGYSV (D-YSV). Through a heating-cooling process, NapGDFDFDYGYSV self-assembled into a stable hydrogel, while its control peptide of NapGFFYGYSV (L-YSV) self-assembled into an unstable suspension. The nanofiber of D-YSV exhibited an excellent resistance to proteinase digestion comparing with that of L-YSV, and a better anticancer efficiency in vitro due to its improved cellular uptake. Moreover, D-YSV possessed good biocompatibility and showed a prominent tumour inhibition capacity in vivo via tail vein injection. Our study demonstrates a powerful strategy to reduce the aggregation property and construct supramolecular hydrogels of bioactive hydrophobic L-peptides.

Gd(III)-induced Supramolecular Hydrogelation with Enhanced Magnetic Resonance Performance for Enzyme Detection.

Here we report a supramolecular hydrogel based on Gd(III)-peptide complexes with dramatically enhanced magnetic resonance (MR) performance. The hydrogelations were formed by adding Gd(III) ion to the nanofiber dispersion of self-assembling peptides naphthalene-Gly-Phe-Phe-Tyr-Gly-Arg-Gly-Asp (Nap-GFFYGRGD) or naphthalene-Gly-Phe-Phe-Tyr-Gly-Arg-Gly-Glu (Nap-GFFYGRGE). We further showed that, by adjusting the molar ratio between Gd(III) and the corresponding peptide, the mechanical property of resulting gels could be fine-tuned. The longitudinal relaxivity (r1) of the Nap-GFFYGRGE-Gd(III) was 58.9 mM-1 S-1, which to our knowledge is the highest value for such peptide-Gd(III) complexes so far. Such an enhancement of r1 value could be applied for enzyme detection in aqueous solutions and cell lysates.