Hydrogels are a promising class of biomaterials for sustained drug release applications. The use of covalently cross‐linked hydrogels for drug delivery applications may be limited due to their manufacturing complexity and the high injection forces required for their administration. Stimulus‐responsive hydrogels, which are engineered to respond to stimuli such as pH, temperature, ionic strength, or chemical potential, may overcome these shortcomings and enable the development of injectable hydrogels. This study presents a strategy for forming hydrogels such that a sol–gel transition occurs in response to physiologically relevant glucose concentrations. A hyaluronic acid (HA) polymer backbone is modified with 3‐aminophenylboronic acid, which is able to reversibly bind glucose with a 2:1 stoichiometry. The boronic acid‐functionalized polymer is demonstrated to be glucose responsive, as indicated by its spontaneous hydrogelation and subsequent increase in stiffness as a function of glucose concentration. Furthermore, the transient nature of the boronic acid‐glucose cross‐linking enables the hydrogel to self‐heal after physical rupture. A proof‐of‐concept gelation in alkaline conditions is demonstrated, but the system may be adapted for gelation at physiological pH using modified boronic acids. These HA–boronic acid conjugates have potential utility as in situ‐forming hydrogels for sustained drug release applications.
Over the past few decades, the complexity of molecular entities being advanced for therapeutic purposes has continued to evolve. A main propellent fueling innovation is the perpetual mandate within the pharmaceutical industry to meet the needs of novel disease areas and/or delivery challenges. As new mechanisms of action are uncovered, and as our understanding of existing mechanisms grows, the properties that are required and/or leveraged to enable therapeutic development continue to expand. One rapidly evolving area of interest is that of chemically enhanced peptide and protein therapeutics. While a variety of conjugate molecules such as antibody–drug conjugates, peptide/protein–PEG conjugates, and protein conjugate vaccines are already well established, others, such as antibody–oligonucleotide conjugates and peptide/protein conjugates using non-PEG polymers, are newer to clinical development. This review will evaluate the current development landscape of protein-based chemical conjugates with special attention to considerations such as modulation of pharmacokinetics, safety/tolerability, and entry into difficult to access targets, as well as bioavailability. Furthermore, for the purpose of this review, the types of molecules discussed are divided into two categories: (1) therapeutics that are enhanced by protein or peptide bioconjugation, and (2) protein and peptide therapeutics that require chemical modifications. Overall, the breadth of novel peptide- or protein-based therapeutics moving through the pipeline each year supports a path forward for the pursuit of even more complex therapeutic strategies.
Purpose Diabetic macular edema (DME) is the leading cause of vision loss and blindness among working-age adults. Although current intravitreal anti-vascular endothelial growth factor (VEGF) therapies improve vision for many patients with DME, approximately half do not achieve the visual acuity required to drive. We therefore sought additional approaches to resolve edema and improve vision for these patients. Methods We explored direct agonists of Tie2, a receptor known to stabilize vasculature and prevent leakage. We identified a multivalent PEG–Fab conjugate, Tie2.1-hexamer, that oligomerizes Tie2 and drives receptor activation and characterized its activities in vitro and in vivo. Results Tie2.1-hexamer normalized and stabilized intercellular junctions of stressed endothelial cell monolayers in vitro, suppressed vascular leak in mice under conditions where anti-VEGF alone was ineffective, and demonstrated extended ocular exposure and robust pharmacodynamic responses in non-human primates. Conclusions Tie2.1-hexamer directly activates the Tie2 pathway, reduces vascular leak, and is persistent within the vitreal humor. Translational Relevance Our study presents a promising potential therapeutic for the treatment of DME.
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