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Abstract Synthetic opioids, especially fentanyl and its analogs, have created an epidemic of abuse and significantly increased overdose deaths in the United States. Current detection methods have drawbacks in their sensitivity, scalability, and portability that limit field‐based application to promote public health and safety. The need to detect trace amounts of fentanyl in complex mixtures with other drugs or interferents, and the continued emergence of new fentanyl analogs, further complicates detection. Accordingly, there is an urgent need to develop convenient, rapid, and reliable sensors for fentanyl detection. In this study, a sensor is prepared based on competitive displacement of a fluorescent dye from the cavity of a supramolecular macrocycle, with subsequent fluorescence quenching from graphene quantum dots. This approach can detect and quantify small quantities of fentanyl along with 58 fentanyl analogs, including highly potent variants like carfentanil that are of increasing concern. Detection of these agents is possible even at 0.01 mol% in the presence of common interferents. This simple, rapid, reliable, sensitive, and cost‐effective approach couples supramolecular capture with graphene quantum dot nanomaterial quenchers to create a tool with the potential to advance public health and safety in the context of field‐based detection of drugs in the fentanyl class. 

Glucose-responsive hydrogel systems are increasingly explored for insulin delivery, with dynamic-covalent crosslinking interactions between phenylboronic acids (PBA) and diols forming a key glucose-sensing mechanism. However, commonly used PBA and diol chemistries often have limited responsiveness to glucose under physiological concentrations. This is due, in part, to the binding of PBA to the commonly used diol chemistries having higher affinity than for PBA to glucose. The present study addresses this challenge by redesigning the diol chemistry in an effort to reduce its binding affinity to PBA, thereby enhancing the ability of glucose to compete with these redesigned PBA–diol crosslinks at its physiological concentration, thus improving responsiveness of the hydrogel network. Rheological analyses support enhanced sensitivity of these PBA–diol networks to glucose, while insulin release likewise improves from networks with reduced crosslink affinities. This work thus offers a new molecular design approach to improve glucose-responsive hydrogels for insulin delivery in diabetes management. 

A need to enhance the precision and specificity of therapeutic nanocarriers inspires the development of advanced nanomaterials capable of sensing and responding to disease-related cues. Self-assembled peptides offer a promising nanocarrier platform with versatile use to create precisely defined nanoscale materials. Disease-relevant cues can range from large biomolecules, such as enzymes, to ubiquitous small molecules with varying concentrations in healthy versus diseased states. Notably, pH changes (i.e., H+ concentration), redox species (e.g., H2O2), and glucose levels are significant spatial and/or temporal indicators of therapeutic needs. Self-assembled peptides respond to these cues by altering their solubility, modulating electrostatic interactions, or facilitating chemical transformations through dynamic or labile bonds. This review explores the design and construction of therapeutic nanocarriers using self-assembled peptides, focusing on how peptide sequence engineering and the inclusion of non-peptidic components can link the assembly state of these nanocarriers to the presence of disease-relevant small molecules. 

This study investigates the development of a supramolecular peptide amphiphile (PA) material functionalized with phenylboronic acid (PBA) for glucose-responsive glucagon delivery. The PA-PBA system self-assembles into nanofibrillar hydrogels in the presence of physiological glucose levels, resulting in stable hydrogels capable of releasing glucagon under hypoglycemic conditions. Glucose responsiveness is driven by reversible binding between PBA and glucose, which modulates the electrostatic interactions necessary for hydrogel formation and dissolution. Through comprehensive in vitro characterization, including circular dichroism, zeta potential measurements, and rheological assessments, the PA-PBA system is found to exhibit glucose-dependent assembly, enabling controlled glucagon release that is inversely related to glucose concentration. Glucagon release is accelerated under low glucose conditions, simulating a hypoglycemic state, with a reduced rate seen at higher glucose levels. Evaluation of the platform in vivo using a type 1 diabetic mouse model demonstrates efficacy in protecting against insulin-induced hypoglycemia by restoring blood glucose levels following an insulin overdose. The ability to tailor glucagon release in response to fluctuating glucose concentrations underscores the potential of this platform for improving glycemic control. These findings suggest that glucose-stabilized supramolecular peptide hydrogels hold significant promise for responsive drug delivery applications, offering an approach to manage glucose levels in diabetes and other metabolic disorders. 

Host–guest interactions have been increasingly explored for use in the dynamic physical crosslinking of polymeric precursors to form hydrogel networks. However, the orientation of guest motifs is restricted upon macromolecule conjugation. The implications of such restriction on both the kinetics and thermodynamics of the resulting host–guest supramolecular crosslinks are poorly understood. Herein, guest crosslinking motifs from controlled regioisomers are demonstrated to yield distinct material properties. Moreover, the underlying phenomena point to further unexpected impact of modular guest topology manifest on the molecular scale in both the affinity and dynamics of supramolecular complex formation. 

Mechanical stimuli such as strain, force, and pressure are pervasive within and beyond the human body. Mechanoresponsive hydrogels have been engineered to undergo changes in their physicochemical or mechanical properties in response to such stimuli. Relevant responses can include strain-stiffening, self-healing, strain-dependent stress relaxation, and shear rate-dependent viscosity. These features are a direct result of dynamic bonds or non- covalent/physical interactions within such hydrogels. The contributions of various types of bonds and intermolecular interactions to these behaviors are important to more fully understand the resulting materials and engineer their mechanoresponsive features. Here, strain-stiffening in carboxymethylcellulose hydrogels crosslinked with pendant dynamic-covalent boronate esters using tannic acid is studied and modulated as a function of polymer concentration, temperature, and effective crosslink density. Furthermore, these materials are found to exhibit self-healing and strain- memory, as well as strain-dependent stress relaxation and shear rate-dependent changes in gel viscosity. These features are attributed to the dynamic nature of the boronate ester crosslinks, inter-chain hydrogen bonding and bundling, or a combination of these two intermolecular interactions. This work provides insight into the interplay of such interactions in the context of mechanoresponsive behaviors, particularly informing the design of hydrogels with tunable strain- stiffening. The multi-responsive and tunable nature of this hydrogel system therefore presents a promising platform for a variety of applications. 

Supramolecular peptide-drug conjugates (sPDCs) are prepared by covalent attachment of a drug moiety to a peptide motif programmed for one-dimensional self-assembly, with subsequent physical entanglement of these fibrillar structures enabling formation of nanofibrous hydrogels. This class of prodrug materials presents an attractive platform for mass-efficient and site-specific delivery of therapeutic agents using a discrete single-component molecular design. However, a continued challenge in sPDC development is elucidating relationships between supramolecular interactions in their drug and peptide domains and the resultant impact of these domains on assembly outcomes and material properties. Inclusion of a saturated alkyl segment alongside the prodrug in the hydrophobic domain of sPDCs could relieve some of the necessity for ordered, prodrug-produg interactions. Accordingly, nine sPDCs are prepared here to iterate the design variables of amino acid sequence and hydrophobic prodrug/alkyl block design. All molecules spontaneously formed hydrogels under physiological conditions, indicating a less hindered thermodynamic path to self-assembly relative to previous prodrug-only designs. However, material studies on the supramolecular arrangement, formation, and mechanical properties of the resultant sPDC hydrogels, as well as their drug release profiles, showed complex relationships between the hydrophobic and peptide domains in the formation and function of the resulting assemblies. Together, these results indicate that sPDC material properties are intrinsically linked to holistic molecular design, with coupled contributions from their prodrug and peptide domains in directing properties of the emergent materials. 

A transient mechanism to achieve gelation in host–guest supramolecular hydrogels is demonstrated by acidification and pH correctionviaindirect control from a biocatalytic enzyme network.