Conducting Polymer Nanoparticles with Intrinsic Aqueous Dispersibility for Conductive Hydrogels.

Conductive hydrogels are promising materials with mixed ionic-electronic conduction to interface living tissue (ionic signal transmission) with medical devices (electronic signal transmission). The hydrogel form factor also uniquely bridges the wet/soft biological environment with the dry/hard environment of electronics. The synthesis of hydrogels for bioelectronics requires scalable, biocompatible fillers with high electronic conductivity and compatibility with common aqueous hydrogel formulations/resins. Despite significant advances in the processing of carbon nanomaterials, fillers that satisfy all these requirements are lacking. Herein, intrinsically dispersible acid-crystalized PEDOT:PSS nanoparticles (ncrys-PEDOTX ) are reported which are processed through a facile and scalable nonsolvent induced phase separation method from commercial PEDOT:PSS without complex instrumentation. The particles feature conductivities of up to 410 S cm-1 , and when compared to other common conductive fillers, display remarkable dispersibility, enabling homogeneous incorporation at relatively high loadings within diverse aqueous biomaterial solutions without additives or surfactants. The aqueous dispersibility of the ncrys-PEDOTX particles also allows simple incorporation into resins designed for microstereolithography without sonication or surfactant optimization; complex biomedical structures with fine features (< 150 µm) are printed with up to 10% particle loading . The ncrys-PEDOTX particles overcome the challenges of traditional conductive fillers, providing a scalable, biocompatible, plug-and-play platform for soft organic bioelectronic materials.

An investigation of binding interactions of tumor-targeted peptide conjugated polyphenols with the kinase domain of ephrin B4 and B2 receptors.

Recent studies have shown that Ephrin receptors may be upregulated in several types of cancers including breast, ovarian and endometrial cancers, making them a target for drug design. In this work, we have utilized a target-hopping approach to design new natural product-peptide conjugates and examined their interactions with the kinase-binding domain of EphB4 and EphB2 receptors. The peptide sequences were generated through point mutations of the known EphB4 antagonist peptide TNYLFSPNGPIA. Their anticancer properties and secondary structures were analyzed computationally. Conjugates of most optimum of peptides were then designed by binding the N-terminal of the peptides with the free carboxyl group of the polyphenols sinapate, gallate and coumarate, which are known for their inherent anticancer properties. To investigate if these conjugates have a potential to bind to the kinase domain, we carried out docking studies and MMGBSA free energy calculations of the trajectories based on the molecular dynamics simulations, with both the apo and the ATP bound kinase domains of both receptors. In most cases binding interactions occurred within the catalytic loop region, while in some cases the conjugates were found to spread out across the N-lobe and the DFG motif region. The conjugates were further tested for prediction of pharmacokinetic properties using ADME studies. Our results indicated that the conjugates were lipophilic and MDCK permeable with no CYP interactions. These findings provide an insight into the molecular interactions of these peptides and conjugates with the kinase domain of the EphB4 and EphB2 receptor. As a proof of concept, we synthesized and carried out SPR analysis with two of the conjugates (gallate-TNYLFSPNGPIA and sinapate-TNYLFSPNGPIA). Results indicated that the conjugates showed higher binding with the EphB4 receptor and minimal binding to EphB2 receptor. Sinapate-TNYLFSPNGPIA showed inhibitory activity against EphB4. These studies reveal that some of the conjugates may be developed for further investigation into in vitro and in vivo studies and potential development as therapeutics.

Exploring the Interactions of Ionic Liquids with Bio-Organic Amphiphiles Using Computational Approaches.

Bio-organic amphiphiles have been shown to effectively impart unique physicochemical properties to ionic liquids resulting in the formation of versatile hybrid composites. In this work, we utilized computational methods to probe the formation and properties of hybrids prepared by mixing three newly designed bio-organic amphiphiles with 14 ionic liquids containing cholinium or glycine betaine cations and a variety of anions. The three amphiphiles were designed such that they contain unique biological moieties found in nature by conjugating (a) malic acid with the amino acid glutamine, (b) thiomalic acid with the antiviral, antibacterial pyrazole compound [3-(3,5-dimethyl-1H-pyrazol-1-yl)benzyl]amine, and (c) Fmoc-protected valine with diphenyl amine. Conductor-like screening model for real solvents (COSMO-RS) was used to obtain sigma profiles of the hybrid mixtures and to predict viscosities and mixing enthalpies of each composite. These results were used to determine optimal ionic liquid-bio-organic amphiphile mixtures. Molecular dynamics simulations of three optimal hybrids were then performed, and the interactions involved in the formation of the hybrids were analyzed. Our results indicated that cholinium-based ILs interacted most favorably with the amphiphiles through a variety of inter- and intramolecular interactions. This work serves to illustrate important factors that influence the interactions between bio-organic amphiphiles and bio-ILs and aids in the development of novel ionic liquid-based composites for a wide variety of potential biological applications.

Self-Assembled Peptide-Based Biocomposites for Near-Infrared Light Triggered Drug Release to Tumor Cells.

Peptide-based nanomaterials are increasingly gaining popularity due to their specificity, biocompatibility, and biodegradability. In this work, a new multi-layered peptide-based biocomposite for targeting MCF-7 breast cancer cells is developed. The amphipathic Fluorenylmethyloxycarbonyl (Fmoc)-Leu-Ser peptide is synthesized, which is conjugated to a tumor-targeting peptide sequence Gly-Cys-Gly-Asn-Ser to form Fmoc-L-S-G-C-G-N-S (FLS) assemblies. To the FLS assemblies, gold nanorods are then attached to develop drug delivery vehicles (DDVs). The DDVs are entrapped with the anti-cancer drug fulvestrant. Entrapment efficiency is found to be 50.6%. Release studies indicate that irradiating the gold nanorod bound DDVs at NIR wavelength (785 nm) increases drug release by fourfold compared to assemblies that are not irradiated. These results also show higher cytotoxicity and lower cell invasion due to photo-triggered drug release. Furthermore, distinct actin cytoskeletal changes are observed. Such novel peptide-based gold nanorod bound DDVs demonstrate potential in dual targeting of MCF-7 breast cancer cells.

Development of Nanoscale Hybrids from Ionic Liquid-Peptide Amphiphile Assemblies as New Functional Materials.

Over the years, ionic liquids (ILs) have gained tremendous importance because of their unique properties and plethora of applications. In this work, we have developed a new nanoscale hybrid gel consisting of 1-ethyl-3-methylimidazolium dimethyl phosphate, [C2mim][dmp], and self-assembled peptide nanoassemblies. The peptide nanoassemblies were formed by self-assembly of a newly synthesized peptide bolaamphiphile bis(N-α-amido-threonine) 1,7 heptane dicarboxylate (ThrC7). Upon mild heating and sonication of the IL and ThrC7 nanoassemblies, ThrC7-IL nanocomposites were formed. We explored the formation of nanohybrids by varying the ratio of IL to ThrC7 assemblies. While at lower IL ratios, a gelatinous matrix was formed, at higher IL ratios, highly ordered multilayered structures were observed by atomic force microscopy (AFM) imaging. The interactions between the ThrC7 nanofibers and [C2mim][dmp] IL were probed by Fourier transform infrared spectroscopy, transmission electron microscopy, and AFM imaging. Differential scanning calorimetry and thermogravimetric analysis showed that the nanohybrids illustrated distinct thermal phase changes due to changes in hydrogen bonding interactions and unfolding of the nanoassemblies. The viscoelastic behavior of the nanohybrids indicated that the materials displayed higher storage modulus upon incorporation of the ThrC7 nanoassemblies when compared to the IL. Furthermore, the nanohybrids were found to adhere to and promote proliferation of human dermal fibroblasts, while cytotoxicity was observed toward MCF-7 breast cancer cells. Thus, for the first time, we have developed peptide-based nanohybrids with an imidazolium-based IL with unique structural properties that may open new avenues for exploring potential biological applications.

Varying fish scale derived hydroxyapatite bound hybrid peptide nanofiber scaffolds for potential applications in periodontal tissue regeneration.

New peptide based hybrid scaffolds were prepared by blending two different fish scale derived hydroxyapatite with functionalized peptide nanofibers for potential applications in periodontal tissue regeneration. The nanofibers were prepared by self-assembly of the newly designed peptide bolaamphiphile Bis (N-α-amido-glutamic acid) 1,7 heptane tetracarboxylate and functionalized with a segment of the tyrosine rich amylogenin peptide sequence MPLPPHPGHPGYINF followed by polygalacturnonic acid and hydroxyapatite derived from salmon or red-snapper fish scales. The binding interactions of the components of the scaffold was confirmed by FTIR spectroscopy as well as SEM imaging. Hybrids scaffolds with salmon scale derived HaP showed higher mechanical strength and Young's Modulus compared to snapper scale derived scaffolds. Our results indicated that while both the scaffolds supported cell proliferation and efficiently formed cell-scaffold matrices with gingival fibroblasts, we observed greater alignment of the cells in the case of scaffolds that contained snapper scale derived hydroxyapatite. Furthermore, higher differentiation ability into osteoblast like cells was seen in the case of the snapper scale derived HaP based scaffolds. Our studies indicate that the hybrid peptide nanofiber scaffold matrices, particularly those prepared using snapper scales may have significant utility in the development of biomaterials for periodontal tissue regeneration.