Controlling the self-assembly pathways can be an effective means to create complex multifunctional structures based on a single gelator design. To this direction, an ion mediated approach to control ...and direct supramolecular structure of the low molecular weight peptide hydrogelator would be an excellent methodology for bottom-up nanofabrication of these advanced functional materials. Our work primarily aims to understand the role of different metal ions as well as anions in modulating the self-assembly of the peptide amphiphiles. Our approach relies on rational incorporation of histidine in the peptide amphiphile, which can impart an ion responsive behavior to the hydrogels. Interestingly, the self-assembly pathway of histidine based dipeptide amphiphile was found to be largely influenced by various metal salts. A gel to sol transition occurred at physiological pH in the presence of Cu2+, Ni2+ and Co2+ ions, owing to their strong interactions with the histidine, thus shifting the gelation to pH 3.0. However, in the case of Fe2+ and Mn2+, the weak interactions of histidine–metal ion can still hold the gel at physiological pH but gel strength was significantly decreased. Our studies provide a clear insight into this ion-responsive behavior across a wide pH range, which is mainly governed by the stability of a peptide–metal ion complex as per Irving–Williams series. Moreover, anions also influenced the mechanical strength as well as morphology of the nanostructures owing to their differential interaction with water as depicted in the Hofmeister series of anions. This bioinspired approach will provide an elegant strategy for accessing diverse structures, which are “out of equilibrium” and otherwise only accessible through differential molecular design. We envisage that our systematic studies on histidine–metal ion interaction can be an extremely useful methodology, which will pave a way to design and develop the stimuli responsive biomaterials.
Development of biomaterials, which are inherently antibacterial having broad-spectrum activity against both Gram-positive and Gram-negative bacteria with considerable biocompatibility, is of ...tremendous importance in biomedicinal chemistry. Microbial infections are still of great concern, often originated from indwelling medical devices typically in hospitalized patients. To this end, hydrogelating soft materials particularly from low-molecular-weight (LMW) gelators have generated significant interest in preparing and modifying biomedicinal implants. Herein, we have developed L-tryptophan based cationic amphiphilic hydrogelators with varying degree of hydrophobicity that exhibited remarkable bactericidal activity against wide range of Gram-positive (MIC = 0.1-75 μg/mL) and Gram-negative bacteria (MIC = 0.5-5 μg/mL). Antimicrobial efficacy of the amphiphiles was greatly influenced by their alkyl chain length. This bactericidal effect of cationic hydrogelators is quite comparable or in some cases markedly better than that of clinically available antibiotics. Most excitingly, they selectively attack the bacterial pathogens while remain biocompatible to the mammalian cells. Thus, we have developed LMW biocompatible, inherently antibacterial hydrogels having potential applications in biomedicines. Biotechnol. Bioeng. 2008;100: 756-764.
Triple negative breast cancer (TNBC) is a heterogeneous group of tumors which lack estrogen receptor, progesterone receptor, and HER2 expression. Targeted therapies have limited success in treating ...TNBC, thus a strategy enabling effective targeted combinations is an unmet need. To tackle these challenges and discover individualized targeted combination therapies for TNBC, we integrated phosphoproteomic analysis of altered signaling networks with patient-specific signaling signature (PaSSS) analysis using an information-theoretic, thermodynamic-based approach. Using this method on a large number of TNBC patient-derived tumors (PDX), we were able to thoroughly characterize each PDX by computing a patient-specific set of unbalanced signaling processes and assigning a personalized therapy based on them. We discovered that each tumor has an average of two separate processes, and that, consistent with prior research, EGFR is a major core target in at least one of them in half of the tumors analyzed. However, anti-EGFR monotherapies were predicted to be ineffective, thus we developed personalized combination treatments based on PaSSS. These were predicted to induce anti-EGFR responses or to be used to develop an alternative therapy if EGFR was not present.In-vivo experimental validation of the predicted therapy showed that PaSSS predictions were more accurate than other therapies. Thus, we suggest that a detailed identification of molecular imbalances is necessary to tailor therapy for each TNBC. In summary, we propose a new strategy to design personalized therapy for TNBC using pY proteomics and PaSSS analysis. This method can be applied to different cancer types to improve response to the biomarker-based treatment.
Supramolecular gels, which demonstrate tunable functionalities, have attracted much interest in a range of areas, including healthcare, environmental protection and energy-related technologies. ...Preparing these materials in a reliable manner is challenging, with an increased level of kinetic defects observed at higher self-assembly rates. Here, by combining biocatalysis and molecular self-assembly, we have shown the ability to more quickly access higher-ordered structures. By simply increasing enzyme concentration, supramolecular order expressed at molecular, nano- and micro-levels is dramatically enhanced, and, importantly, the gelator concentrations remain identical. Amphiphile molecules were prepared by attaching an aromatic moiety to a dipeptide backbone capped with a methyl ester. Their self-assembly was induced by an enzyme that hydrolysed the ester. Different enzyme concentrations altered the catalytic activity and size of the enzyme clusters, affecting their mobility. This allowed structurally diverse materials that represent local minima in the free energy landscape to be accessed based on a single gelator structure.
Triple-negative breast cancer (TNBC) is an aggressive subgroup of breast cancers which is treated mainly with chemotherapy and radiotherapy. Epidermal growth factor receptor (EGFR) was considered to ...be frequently expressed in TNBC, and therefore was suggested as a therapeutic target. However, clinical trials of EGFR inhibitors have failed. In this study, we examine the relationship between the patient-specific TNBC network structures and possible mechanisms of resistance to anti-EGFR therapy. Using an information-theoretical analysis of 747 breast tumors from the TCGA dataset, we resolved individualized protein network structures, namely patient-specific signaling signatures (PaSSS) for each tumor. Each PaSSS was characterized by a set of 1–4 altered protein–protein subnetworks. Thirty-one percent of TNBC PaSSSs were found to harbor EGFR as a part of the network and were predicted to benefit from anti-EGFR therapy as long as it is combined with anti-estrogen receptor (ER) therapy. Using a series of single-cell experiments, followed by in vivo support, we show that drug combinations which are not tailored accurately to each PaSSS may generate evolutionary pressure in malignancies leading to an expansion of the previously undetected or untargeted subpopulations, such as ER+ populations. This corresponds to the PaSSS-based predictions suggesting to incorporate anti-ER drugs in certain anti-TNBC treatments. These findings highlight the need to tailor anti-TNBC targeted therapy to each PaSSS to prevent diverse evolutions of TNBC tumors and drug resistance development.
In this paper, we present the design and development of a novel miniaturized multimodal photonic sensor, which can be configured dually as a photodetector in the absorptive mode and as a ...pyro-detector in the photonic sensor mode. In this paper, we have fabricated a polyvinyl alcohol (PVA) photoactive layer-based MEMS structure and analysed the effect of effective inter-electrode separation on the photoactive area of the photoactive film using the four quadrant metal-semiconductor polymer-metal (MSM) design on the photoresponsivity of this device in terms of photoconductive and the pyroelectric responses. Our analysis reveals that the interdigitated electrode configuration is best suited for photoconductive response while the cross-electrode configuration with large effective interelectrode spacing is advantageous for pyroelectric measurement in the infrared region. Here, the unique design of this device offers the choice of electrode configurations that enables the utility of this device in various regions of the electromagnetic spectrum. In this regard, we demonstrate the optical detection of localized surface plasmon resonance of immobilized gold nanoparticle monolayer in the visible region, employing the absorptive mode and the detection of the spectroscopic signature of RDX and TNT molecules (134 μg/cm 2 ) in the midinfrared region using photonic sensor mode. This paper paves a way for designing a low-cost PVA-based miniaturized sensor architectures with huge potential for on-chip real-time detections in various fields of scientific and commercial applications.
We report on a pronounced specific‐ion effect on the intermolecular and chiral organization, supramolecular structure formation, and resulting materials properties for a series of low molecular ...weight peptide‐based hydrogelators, observed in the presence of simple inorganic salts. This effect was demonstrated using aromatic short peptide amphiphiles, based on fluorenylmethoxycarbonyl (Fmoc). Gel‐phase materials were formed due to molecular self‐assembly, driven by a combination of hydrogen bonding and π‐stacking interactions. Pronounced morphological changes were observed by atomic force microscopy (AFM) for Fmoc‐YL peptide, ranging from dense fibrous networks to spherical aggregates, depending on the type of anions present. The gels formed had variable mechanical properties, with G′ values between 0.8 kPa and 2.4 kPa as determined by rheometry. Spectroscopic analysis provided insights into the differential mode of self‐assembly, which was found to be dictated by the hydrophobic interactions of the fluorenyl component, with comparable H‐bonding patterns observed in each case. The efficiency of the anions in promoting the hydrophobic interactions and thereby self‐assembly was found to be consistent with the Hofmeister anion sequence. Similar effects were observed with other hydrophobic peptides, Fmoc‐VL and Fmoc‐LL. The effect was found to be less pronounced for a less hydrophobic peptide, Fmoc‐AA. To get more insights into the molecular mechanism, the effect of anions on sol–gel equilibrium was investigated, which indicates the observed changes result from the specific‐ion effects on gels structure, rather than on the sol–gel equilibrium. Thus, we demonstrate that, by simply changing the ionic environment, structurally diverse materials can be accessed providing an important design consideration in nanofabrication via molecular self‐assembly.
Ions control hydrogelation: A dramatic specific‐ion effect on the intermolecular and chiral organization, supramolecular structure formation, and resulting materials properties was observed for a series of low molecular weight peptide‐based hydrogelators. Spectroscopic studies provided insights into the differential mode of self‐assembly with different ions, dictated by the hydrophobic interactions of the fluorenyl components (see figure).
The primary objective of the present study is to understand how the different nonionic surfactants modify the anisotropic interface of cationic water-in-oil (W/O) microemulsions and thus influences ...the catalytic efficiency of surface-active enzymes. Activity of Chromobacterium viscosum lipase (CV-lipase) was estimated in several mixed reverse micelles prepared from CTAB and four different nonionic surfactants, Brij-30, Brij-92, Tween-20, and Tween-80/water/isooctane/n-hexanol at different z (cosurfactant/surfactants) values, pH 6 (20 mM phosphate), 25 °C across a varying range of W 0 (water/surfactants) using p-nitrophenyl-n-octanoate as the substrate. Lipase activity in mixed reverse micelles improved maximum up to ∼200% with increasing content of non-ionic surfactants compared to that in CTAB probably due to the reduced positive charge density as well as plummeted n-hexanol (competitive inhibitor of lipase) content at the interfacial region of cationic W/O microemulsions. The highest activity of lipase was observed in CTAB (10 mM) + Brij-30 (40 mM)/isooctane/n-hexanol)/water system, k 2 = 913 ± 5 cm3 g-1 s-1. Interestingly, this observed activity is even higher than that obtained in sodium bis (2-ethyl-1-hexyl) sulfosuccinate (AOT)/n-heptane reverse micelles, the most popular W/O microemulsion in micellar enzymology. To ascertain the influence of non-ionic surfactants in improving the activity of surface-active enzymes is not limited to lipase only, we have also investigated the catalytic activity of Horseradish peroxidase (HRP) in different mixed W/O microemulsions. Here also following the similar trend as observed for lipase, HRP activity enhanced up to 2.5 fold with increasing concentration of nonionic surfactants. Finally, the enzyme activity was correlated with the change in the microenvironment of mixed reverse micelles by steady-state fluorescence study using 8-anilino-1-napthalenesulphonic acid (ANS) as probe.
Short bioactive peptide-based supramolecular hydrogels are emerging as interesting candidates for developing scaffolds for tissue engineering applications. However, proteins and peptides represent ...only a single class of molecules present in the native ECM, thus, recapitulating the complete ECM microenvironment
only peptide-based biomaterials is extremely challenging. In this direction, complex multicomponent-based biomaterials have started gaining importance for achieving the biofunctional complexity and structural hierarchy of the native ECM. Sugar-peptide complexes can be explored in this direction as they provide essential biological signaling required for cellular growth and survival
. In this direction, we explored the fabrication of an advanced scaffold by employing heparin and short bioactive peptide interactions at the molecular level. Interestingly, the addition of heparin into the peptide has significantly modulated the supramolecular organization, nanofibrous morphology and the mechanical properties of the scaffold. Additionally, the combined hydrogels demonstrated superior biocompatibility as compared to the peptide counterpart at certain ratios. These newly developed scaffolds were also observed to be stable under 3-D cell culture conditions and supported cellular adhesion and proliferation. Most importantly, the inflammatory response was also minimized in the case of combined hydrogels as compared to heparin. We expect that this approach of using simple non-covalent interactions between the ECM-inspired small molecules to fabricate biomaterials with improved mechanical and biological properties could advance the current knowledge on designing ECM mimetic biomaterials. Such an attempt would create a novel, adaptable and simplistic bottom-up strategy for the invention of new and more complex biomaterials of ECM origin with advanced functions.
For the development of applications and novel uses for peptide nanostructures, robust routes for their surface functionalization, that ideally do not interfere with their self‐assembly properties, ...are required. Many existing methods rely on covalent functionalization, where building blocks are appended with functional groups, either pre‐ or post‐assembly. A facile supramolecular approach is demonstrated for the formation of functionalized nanofibers by combining the advantages of biocatalytic self‐assembly and surfactant/gelator co‐assembly. This is achieved by enzymatically triggered reconfiguration of free flowing micellar aggregates of pre‐gelators and functional surfactants to form nanofibers that incorporate and display the surfactants’ functionality at the surface. Furthermore, by varying enzyme concentration, the gel stiffness and supramolecular organization of building blocks can be varied.
A facile supramolecular approach is demonstrated for the formation of functionalized nanofibers by combining the advantages of biocatalytic self‐assembly and surfactant/gelator co‐assembly. This is achieved by enzymatically triggered reconfiguration of free flowing micellar aggregates of pre‐gelators and functional surfactants to form nanofibers that incorporate and display the surfactants’ functionality at the surface.