Wound microenvironment-responsive peptide hydrogel with multifunctionalities for accelerating wound healing.

The fabrication of wound microenvironment-responsive peptide hydrogels with hemostatic ability, antibacterial activity, and wound healing potential remains a challenge. Herein, we constructed a multifunctional dressing by inducing the self-assembly of a peptide (Pep-1) and water-soluble new methylene blue (NMB) through electrostatic interaction. The self-assembly mechanism was demonstrated using a combination of transmission electron microscopy, circular dichroism spectrum, fluorescence spectrum, Zeta potential, and rheological analysis. The Pep-1/NMB hydrogel also exhibited a faster drug release rate in wound acidic environment. Furthermore, when Pep-1/NMB was exposed to a 635 nm laser, its antibacterial ratios increased sharply to 95.3%, indicating remarkably improved antibacterial effects. The findings from the blood coagulation and hemostasis assay indicated that Pep-1/NMB effectively enhanced the speed of blood clotting in vitro and efficiently controlled hemorrhage in a mouse liver hemorrhage model. Meanwhile, hemolytic and cytotoxicity evaluation revealed that the hydrogel had excellent hemocompatibility and cytocompatibility. Finally, the findings from the wound healing studies and H&E staining indicated that the Pep-1/NMB hydrogel had a significant impact on cell migration and wound repair. The results indicated that wound microenvironment-responsive Pep-1/NMB hydrogel had significant potential as a highly effective wound dressing platform, offering rapid hemostasis, antibacterial, and wound healing acceleration properties.

Rheological investigation of a versatile salecan/curdlan gel matrix.

Hydrogel, as a three-dimensional material with high water content, has unique physicochemical and variable mechanical properties. Natural polysaccharide-based composite hydrogels are very popular within medical industry as these viscoelastic materials are non-toxic, biodegradable, bioabsorbable, and biocompatible. This research investigates the engineering of novel composite hydrogels from natural polysaccharides salecan and curdlan without any structural modification and chemical crosslinking. The scanning electron microscopy, Fourier transform infrared spectroscopy and various rheological methods were employed to investigate the morphology, molecular interaction, and flow behavior of the samples respectively. The key rheological parameters were compared using the Power Law, Herschel-Bulkley and Arrhenius models. This is the first study reporting a novel composite hydrogel made from Salecan and Curdlan with ideal elasticity, enhanced thermostability, good injectability, self-recovery and other rheological properties that will pave the way for application in different fields.

Co-assembled supramolecular hydrogels of cell adhesive peptide and alginate for rapid hemostasis and efficacious wound healing.

Injectable hydrogels are promising materials for applications in non-compressive wound management. Yet difficulties remain for the fabrication of mechanically stable hydrogel materials with inherent functionalities in both hemostatic control and wound healing without additional supplements of growth factors. Herein, we reported the co-assembly of a cell adhesive peptide conjugate (Pept-1) and alginate (ALG), to confer supramolecular hydrogels with excellent mechanical properties and high efficacy in both hemostatic control and wound healing requiring no additional growth factors. The co-assembling process of Pept-1 and ALG, which was mediated by electrostatic interactions and metal chelation, afforded a composite hydrogel with denser nanofibrillar structures and better mechanical strength when comparing to the Pept-1 gel alone. As-prepared Pept-1/ALG hydrogels exhibited excellent injectability and thixotropic properties, making them ideal materials for wound dressing. The composite hydrogel induced fast hemostasis when spiked with whole blood in vitro, and reduced the amount of bleeding to ∼18% of the untreated control in a liver puncture mouse model. Meanwhile, it promoted adhesion and migration of fibroblast NIH3T3 cells in vitro, and accelerated the rate of wound healing in a full-thickness skin defect model of mice. In addition, the Pept-1/ALG hydrogel showed excellent biocompatibility with no obvious hemolytic activity. In future, the strategy of utilizing co-assembled nanostructures composed of biofunctional peptides and polysaccharides could be further exploited to construct a broad range of nanocomposite materials for a variety of biomedical applications.

Doxorubicin-reinforced supramolecular hydrogels of RGD-derived peptide conjugates for pH-responsive drug delivery.

Drug incorporation in hydrogels often brings undesirable effects on the stability or mechanical properties of the system. To address this problem, we report the design and synthesis of a RGD-derived peptide conjugate (1-RGDH) for its co-assembly with a commonly used chemotherapeutic drug, doxorubicin (DOX), that formed electrostatic interactions with the 1-RGDH peptide and reinforced the supramolecular network of nanofibers within the matrix of the hydrogel. The hybrid hydrogel demonstrated excellent viscoelastic and shear-thinning properties that greatly facilitated the development of injectable drug delivery systems. Furthermore, it demonstrated a unique pH responsive release of DOX under weakly acidic conditions, paving ways for the controlled release of drug cargos in a typical tumor microenvironment with mild acidity. Finally, the DOX-incorporated hydrogel exhibited a superior anti-tumor efficacy in non-small-cell lung cancer cells A549 compared to the aqueous solution of free DOX, with an integrin receptor-mediated endocytosis pathway revealed for the cellular uptake of DOX-incorporated nanofibers.

Co-assembled supramolecular hydrogels of doxorubicin and indomethacin-derived peptide conjugates for synergistic inhibition of cancer cell growth.

Conjugation of indomethacin with a self-assembling peptide moiety affords co-assembled supramolecular nanostructures of doxorubicin and peptide derivatives for tunable release of two drugs and synergistic effects against cancer cells, which illustrates a simple and effective approach to utilize co-assembled nanostructures for co-delivery of self-complementary drug pairs.

In situ hydrogelation of bicalutamide-peptide conjugates at prostate tissue for smart drug release based on pH and enzymatic activity.

Tissue-specific self-assemblies of supramolecular hydrogels have attracted great interest in material design and biomedical applications, for in situ-formed hydrogels serve as an excellent local depot with tunable release of drug therapeutics. Here we report the design and syntheses of a novel class of histidine-containing hexapeptide derivatives (Nap-1 and ID-1) for in situ hydrogelation at the zinc ion-rich prostate tissue. Thanks to the efficient co-ordination between zinc and histidine, both Nap-1 and ID-1 displayed excellent self-assembly capability with a high sensitivity to zinc ions at ∼0.1 equivalency. To foster a prostate-specific drug delivery system (DDS), ID-1 was chosen for further conjugation with bicalutamide (BLT), a clinically used drug for prostate cancer. The as-synthesized ID-1-BLT retained the self-assembly capability with zinc ions, and conferred supramoelcular hydrogels at the prostate site. Interestingly, ID-1-BLT hydrogels demonstrated tunable drug release profiles in a typical tumor microenvironment, with acidic pH and esterase activity regulating the drug release in a dose dependent manner. Consequently, the hydrogel-based DDS demonstrated enhanced potency and selective cytotoxicity against prostate cancer cell DU145 over normal fibroblast cell NIH3T3, plausibly due to differential cellular uptake of drugs as well as the elevated esterase activities in cancer cells. Finally, the biocompatible hydrogel system demonstrated sustained delivery of drugs at the prostate gland of rats, with a superior in situ drug distribution profile compared to that of aqueous solution of BLT alone.

Supramolecular self-assembly of fluorescent peptide amphiphiles for accurate and reversible pH measurement.

We report the synthesis and self-assembly of fluorescent peptide amphiphiles (NBD-PA) composed of a fluorescent NBD probe and a peptide derivative VVAADD with a C12-alkyl-chain as the linker (NBD-C12-VVAADD). The self-assembly of NBD-PA formed beta-sheet structures at neutral pH in aqueous solution, contributed to an ∼10-fold increase in the fluorescence and quantum yield of NBD molecules, and conferred a supramolecular hydrogel with excellent viscoelastic properties, while gel-to-sol transition of NBD-PA occurred rapidly when the pH value was adjusted to strongly alkaline (e.g. pH 11). Through the pH-responsive self-assembly behavior, we further explored the relationship between fluorescence of NBD-PA and pH values. Interestingly, the fluorescence of the NBD-PA system exhibited an excellent sigmoidal function relationship (R2 = 0.9999) with the alkaline pH values, which enabled accurate pH measurement regardless of salt types and ionic strength of solvents. Furthermore, the fluorescence of NBD-PA was fully reversible upon cycles of pH shifts, with the chemical structure of NBD-PA well-maintained throughout the process. These features of NBD-PA would facilitate the design of in situ pH detection systems as well as pH-responsive actuators for various applications in future.

The conjugates of forky peptides and nonsteroidal anti-inflammatory drugs (NSAID) self-assemble into supramolecular hydrogels for prostate cancer-specific drug delivery.

Herein, we report supramolecular hydrogelators made of forky peptides and nonsteroidal anti-inflammatory drugs (NSAID). Two zinc ions (ZIs)-responsive short peptide dendrons (E3FID and E3FNP) modified by NSAID (indometacinand naproxen) were designed and synthesized successfully. These novel small molecule hydrogelators can self-assemble in water to form stable supramolecular nanofibers/hydrogels. The formation of these supramolecular hydrogels can be triggered by zinc ions, which are highly concentrated in prostate tissue. The anticancer drug docetaxel (DTX) was employed as chemotherapeutic and loaded into the hydrogels to construct a novel drug delivery system for prostate cancer therapy. This approach is anticipated realizing the sustained release of antitumour drugs into the prostate and cancer associated pain relief, simultaneously. The E3FID hydrogel and E3FNP hydrogel have excellent biocompatibility and viscoelastic properties as a promising drug delivery materials. The result of drugs release in vitro indicated that DTX was released slowly following a non-Fickian diffusion mechanism. In addition, the results of the in vitro cytotoxicity assay demonstrated that these DTX-loaded hydrogels exhibited dose-dependent cytotoxicity to both DU-145 cells and PC-3 cells, in particular, the drug-loaded hydrogel of E3FID had better anticancer efficacy. As a drug delivery strategy, the system realizes better anticancer efficacy, excellent sustained-release and relief of cancer pain, simultaneously, the most important being that the DDS facilitates local delivery of drug to the prostate.

Overcoming multidrug resistance by a combination of chemotherapy and photothermal therapy mediated by carbon nanohorns.

Multidrug resistance (MDR) is a major obstacle to cancer chemotherapy due to the overexpression of P-glycoprotein (P-gp). Herein, etoposide (ETO) was loaded onto oxidized carbon nanohorns (oxCNHs), which were modified by polyethylene glycol (PEG) and further functionalized with the targeting ligand P-gp monoclonal antibody (PA) in an attempt to overcome MDR. The obtained drug delivery system (ETO@oxCNHs/PEG-PA) showed high drug loading efficiency, enhanced drug release under laser irradiation, improved cellular uptake and increased therapeutic effect both in vitro and in vivo. In addition, NIR laser irradiation had a synergistic effect on overcoming MDR. The MDR-overcoming mechanism could be the efficient cellular uptake, enhanced drug release and reduced drug efflux by P-gp. These results demonstrated that ETO@oxCNHs/PEG-PA could be a promising drug delivery system for cancer MDR reversion.