Browsing by Subject "Polypeptides"

Now showing 1 - 6 of 6

Open Access
Antigenic GM3 lactone mimetic molecule integrated mannosylated glycopeptide nanofibers for the activation and maturation of dendritic cells
(American Chemical Society, 2017) Gunay, Gokhan; Ekiz, Melis Sardan; Ferhati, X.; Richichi, B.; Nativi, C.; Tekinay, Ayse B.; Güler, Mustafa O.
The ability of dendritic cells to coordinate innate and adaptive immune responses makes them essential targets for vaccination strategies. Presentation of specific antigens by dendritic cells is required for the activation of the immune system against many pathogens and tumors, and nanoscale materials can be functionalized for active targeting of dendritic cells. In this work, we integrated an immunogenic, carbohydrate melanoma-associated antigen-mimetic GM3-lactone molecule into mannosylated peptide amphiphile nanofibers to target dendritic cells through DC-SIGN receptor. Based on morphological and functional analyses, when dendritic cells were treated with peptide nanofiber carriers, they showed significant increase in antigen internalization and a corresponding increase in the surface expression of the activation and maturation markers CD86, CD83 and HLA-DR, in addition to exhibiting a general morphology consistent with dendritic cell maturation. These results indicate that mannosylated peptide amphiphile nanofiber carriers are promising candidates to target dendritic cells for antigen delivery. © 2017 American Chemical Society.
Open Access
Cellular internalization of therapeutic oligonucleotides by peptide amphiphile nanofibers and nanospheres
(American Chemical Society, 2016-04) Mumcuoglu, D.; S. Ekiz, M.; Gunay, G.; Tekinay, T.; Tekinay, A. B.; Güler, Mustafa O.
Oligonucleotides are promising drug candidates due to the exceptionally high specificity they exhibit toward their target DNA and RNA sequences. However, their poor pharmacokinetic and pharmacodynamic properties, in conjunction with problems associated with their internalization by cells, necessitates their delivery through specialized carrier systems for efficient therapy. Here, we investigate the effects of carrier morphology on the cellular internalization mechanisms of oligonucleotides by using self-assembled fibrous or spherical peptide nanostructures. Size and geometry were both found to be important parameters for the oligonucleotide internalization process; direct penetration was determined to be the major mechanism for the internalization of nanosphere carriers, whereas nanofibers were internalized by clathrin- and dynamin-dependent endocytosis pathways. We further showed that glucose conjugation to carrier nanosystems improved cellular internalization in cancer cells due to the enhanced glucose metabolism associated with oncogenesis, and the internalization of the glucose-conjugated peptide/oligonucleotide complexes was found to be dependent on glucose transporters present on the surface of the cell membrane.
Open Access
Effects of temperature, pH and counterions on the stability of peptide amphiphile nanofiber structures
(Royal Society of Chemistry, 2016) Ozkan A.D.; Tekinay, A. B.; Güler, Mustafa O.; Tekin, E. D.
Peptide amphiphiles are a class of self-assembling molecules that are widely used to form bioactive nanostructures for various applications in bionanomedicine. However, peptide molecules can exhibit distinct behaviors under different conditions, suggesting that environmental variables such as temperature, pH, electrolytes and the presence of biological factors may greatly affect the self-assembly process. In this work, we used united-atom molecular dynamics simulations to understand the effects of three counterions (Na+, Ca2+ at pH 7 and Cl- at pH 2) and temperature change on the stability of the lauryl-VVAGERGD peptide amphiphile self-assembly. This molecule contains a bioactive RGD peptide sequence and has been shown to support cellular adhesion and proliferation in vitro. A 19-layered peptide nanostructure, containing 12 peptide amphiphile molecules per layer, was previously shown to exhibit optimal stability and it was used as the model nanofiber system. Peptide backbone stability was studied under increasing temperatures (300-358 K) using the number of hydrogen bonds and root-mean-square deviations of nanofiber size. At higher temperatures, fiber disintegration was observed to be dependent on the type of counter-ion used for nanofiber formation. Interestingly, rapid heating to higher temperatures could sometimes reestablish the integrity of the nanofiber backbone, possibly by allowing the system to bypass an energy barrier and assuming a more thermodynamically stable configuration. As counterion identity was observed to exhibit remarkable effects on the thermal stability of peptide nanofibers, we suggest that these behaviors should be considered while developing new materials for potential applications.
Open Access
Hierarchical self-assembly of histidine-functionalized peptide amphiphiles into supramolecular chiral nanostructures
(American Chemical Society, 2017) Koc, M. H.; Ciftci, G. C.; Baday, S.; Castelletto, V.; Hamley, I. W.; Güler, Mustafa O.
Controlling the hierarchical organization of self-assembling peptide amphiphiles into supramolecular nanostructures opens up the possibility of developing biocompatible functional supramolecular materials for various applications. In this study, we show that the hierarchical self-assembly of histidine- (His-) functionalized PAs containing d- or l-amino acids can be controlled by both solution pH and molecular chirality of the building blocks. An increase in solution pH resulted in the structural transition of the His-functionalized chiral PA assemblies from nanosheets to completely closed nanotubes through an enhanced hydrogen-bonding capacity and π-π stacking of imidazole ring. The effects of the stereochemistry and amino acid sequence of the PA backbone on the supramolecular organization were also analyzed by CD, TEM, SAXS, and molecular dynamics simulations. In addition, an investigation of chiral mixtures revealed the differences between the hydrogen-bonding capacities and noncovalent interactions of PAs with d- and l-amino acids.
Open Access
Inhibition of VEGF mediated corneal neovascularization by anti-angiogenic peptide nanofibers
(Elsevier, 2016-11) Senturk, B.; Cubuk, M. O.; Ozmen, M. C.; Aydin B.; Güler, Mustafa O.; Tekinay, A. B.
Atypical angiogenesis is one of the major symptoms of severe eye diseases, including corneal neovascularization, and the complex nature of abnormal vascularization requires targeted methods with high biocompatibility. The targeting of VEGF is the most common approach for preventing angiogenesis, and the LPPR peptide sequence is known to strongly inhibit VEGF activity by binding to the VEGF receptor neuropilin-1. Here, the LPPR epitope is presented on a peptide amphiphile nanofiber system to benefit from multivalency and increase the anti-angiogenic function of the epitope. Peptide amphiphile nanofibers are especially useful for ocular delivery applications due to their ability to remain on the site of interest for extended periods of time, facilitating the long-term presentation of bioactive sequences. Consequently, the LPPR sequence was integrated into a self-assembled peptide amphiphile network to increase its efficiency in the prevention of neovascularization. Anti-angiogenic effects of the peptide nanofibers were investigated by using both in vitro and in vivo models. LPPR-PA nanofibers inhibited endothelial cell proliferation, tube formation, and migration to a greater extent than the soluble LPPR peptide in vitro. In addition, the LPPR-PA nanofiber system led to the prevention of vascular maturation and the regression of angiogenesis in a suture-induced corneal angiogenesis model. These results show that the anti-angiogenic activity exhibited by LPPR peptide nanofibers may be utilized as a promising approach for the treatment of corneal angiogenesis.
Open Access
Local delivery of doxorubicin through supramolecular peptide amphiphile nanofiber gels
(Royal Society of Chemistry, 2017) Cinar, G.; Ozdemir, A.; Hamsici, S.; Gunay, G.; Dana, A.; Tekinay, A. B.; Güler, Mustafa O.
Peptide amphiphiles (PAs) self-assemble into supramolecular nanofiber gels that provide a suitable environment for encapsulation of both hydrophobic and hydrophilic molecules. The PA gels have significant advantages for controlled delivery applications due to their high capacity to retain water, biocompatibility, and biodegradability. In this study, we demonstrate injectable supramolecular PA nanofiber gels for drug delivery applications. Doxorubicin (Dox), as a widely used chemotherapeutic drug for breast cancer treatment, was encapsulated within the PA gels prepared at different concentrations. Physical and chemical properties of the gels were characterized, and slow release of the Dox molecules through the supramolecular PA nanofiber gels was studied. In addition, the diffusion constants of the drug molecules within the PA nanofiber gels were estimated using fluorescence recovery after the photobleaching (FRAP) method. The PA nanofiber gels did not show any cytotoxicity and the encapsulation strategy enhanced the activity of drug molecules on cellular viability through prolonged release compared to direct administration under in vitro conditions. Moreover, the local in vivo injection of the Dox encapsulated PA nanofiber gels (Dox/PA) to the tumor site demonstrated the lowest tumor growth rate compared to the direct Dox injection and increased the apoptotic cells within the tumor tissue for local drug release through the PA nanofiber gels under in vivo conditions.