To mimic native insulin activity, materials have been developed that encapsulate insulin, glucose oxidase, and catalase for glucose-responsive insulin delivery. A major challenge, however, has been achieving the desired kinetics of both rapid and extended release. Here, we tune insulin release profiles from polymeric nanoparticles by altering the degree of modification of acid-degradable, acetalated-dextran polymers. Nanoparticles synthesized from dextran with a high acyclic acetal content (94% of residues) show rapid release kinetics, while nanoparticles from dextran with a high cyclic acetal content (71% of residues) release insulin more slowly. Thus, coformulation of these two materials affords both rapid and extended glucose-responsive insulin delivery. In vivo analyses using both streptozotocin-induced type 1 diabetic and healthy mouse models indicate that this delivery system has the ability to respond to glucose on a therapeutically relevant time scale. Importantly, the concentration of human insulin in mouse serum is enhanced more than 3-fold with elevated glucose levels, providing direct evidence of glucose-responsiveness in animals. We further show that a single subcutaneous injection provides 16 h of glycemic control in diabetic mice. We believe the nanoparticle formulations developed here may provide a generalized strategy for the development of glucose-responsive insulin delivery systems.
A series of self-immolative boronic ester protected methyl salicylates and metal-binding groups with various linking strategies have been investigated for their use in the design of matrix metalloproteinase proinhibitors.
Histone deacetylase inhibitors (HDACi) target abnormal epigenetic states associated with a variety of pathologies, including cancer. Here, the development of a prodrug of the canonical broad-spectrum HDACi suberoylanilide hydroxamic acid (SAHA) is described. Although hydroxamic acids are utilized universally in the development of metalloenzyme inhibitors, they are considered to be poor pharmacophores with reduced activity in vivo. We developed a prodrug of SAHA by appending a promoiety, sensitive to thiols, to the hydroxamic acid warhead (termed SAHA-TAP). After incubation of SAHA-TAP with an HDAC, the thiol of a conserved HDAC cysteine residue becomes covalently tagged with the promoiety, initiating a cascade reaction that leads to the release of SAHA. Mass spectrometry and enzyme kinetics experiments validate that the cysteine residue is covalently appended with the TAP promoiety. SAHA-TAP demonstrates cytotoxicity activity against various cancer cell lines. This strategy represents an original prodrug design with a dual mode of action for HDAC inhibition.
Iontophoresis allows for localized drug ejections directly into brain regions of interest driven by the application of current. Our lab has previously adapted a method to quantitatively monitor iontophoretic ejections. Here those principles have been applied in vivo to modulate electrically evoked release of dopamine in anesthetized rats. A neutral, electroactive marker molecule that is ejected purely by electroosmotic flow (EOF) was used to monitor indirectly the ejection of electroinactive dopaminergic drugs (raclopride, quinpirole, and nomifensine). Electrode placements were marked with an iontophoretically ejected dye, pontamine sky blue. We show that EOF marker molecules, acetaminophen (AP) and 2-(4-nitrophenoxy) ethanol, have no effect on electrically evoked dopamine release in the striatum or the sensitivity of electrode. Additionally, we establish that a short, 30 second ejection of raclopride, quinpirole, or nomifensine with iontophoresis is sufficient to affect autoreceptor regulation and the re-uptake of dopamine. These effects vary in lifetime, indicating that this technique can be used to study receptor kinetics.
Prodrugs are effective tools in overcoming drawbacks typically associated with drug formulation and delivery. Those employing esterase-triggered functional groups are frequently utilized to mask polar carboxylic acids and phenols, increasing drug-like properties such as lipophilicity. Herein we detail a comprehensive assessment for strategies that effectively release hydroxyl and phenolic moieties in the presence of an esterase. Matrix metalloproteinases (MMPs) serve as our proof-of-concept target. Three distinct ester-responsive protecting groups are incorporated into MMP proinhibitors containing hydroxyl moieties. Analytical evaluation of the proinhibitors demonstrates that the use of a benzyl ether group appended to the esterase trigger leads to considerably faster kinetics of conversion and enhanced aqueous stability when compared to more conventional approaches where the trigger is directly attached to the inhibitor. Biological assays confirm that all protecting groups effectively cleave in the presence of esterase to generate the active inhibitor.
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