skip to main content


Title: Hydrogels for Gasotransmitter Delivery: Nitric Oxide, Carbon Monoxide, and Hydrogen Sulfide
Abstract

Gasotransmitters, gaseous signaling molecules including nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S), maintain myriad physiological processes. Low levels of gasotransmitters are often associated with specific problems or diseases, so NO, CO, and H2S hold potential in treating bacterial infections, chronic wounds, myocardial infarction, ischemia, and various other diseases. However, their clinical applications as therapeutic agents are limited due to their gaseous nature, short half‐life, and broad physiological roles. One route toward the greater application of gasotransmitters in medicine is through localized delivery. Hydrogels are attractive biomedical materials for the controlled release of embedded therapeutics as they are typically biocompatible, possess high water content, have tunable mechanical properties, and are injectable in certain cases. Hydrogel‐based gasotransmitter delivery systems began with NO, and hydrogels for CO and H2S have appeared more recently. In this review, the biological importance of gasotransmitters is highlighted, and the fabrication of hydrogel materials is discussed, distinguishing between methods used to physically encapsulate small molecule gasotransmitter donor compounds or chemically tether them to a hydrogel scaffold. The release behavior and potential therapeutic applications of gasotransmitter‐releasing hydrogels are also detailed. Finally, the authors envision the future of this field and describe challenges moving forward.

 
more » « less
NSF-PAR ID:
10441938
Author(s) / Creator(s):
 ;  ;  
Publisher / Repository:
Wiley Blackwell (John Wiley & Sons)
Date Published:
Journal Name:
Macromolecular Bioscience
Volume:
24
Issue:
1
ISSN:
1616-5187
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
More Like this
  1. Abstract

    Gaseous signaling molecules such as nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S) have recently been recognized as essential signal mediators that regulate diverse physiological and pathological processes in the human body. With the evolution of gaseous signaling molecule biology, their therapeutic applications have attracted growing attention. One of the challenges in translational research of gaseous signaling molecules is the lack of efficient and safe delivery systems. To tackle this issue, researchers developed a library of gas donors, which are low molecular weight compounds that can release gaseous signaling molecules upon decomposition under physiological conditions. Despite the significant efforts to control gaseous signaling molecule release from gas donors, the therapeutic potential of gaseous signaling molecules cannot be fully explored due to their unfavorable pharmacokinetics and toxic side effects. Recently, the use of nanoparticle‐based gas donors, especially self‐assembled polymeric gas donors, have emerged as a promising approach. In this review, we describe the development of conventional small gas donors and the challenges in their therapeutic applications. We then illustrate the concepts and critical aspects for designing self‐assembled polymeric gas donors and discuss the advantages of this approach in gasotransmistter delivery. We also highlight recent efforts to develop the delivery systems for those molecules based on self‐assembled polymeric nanostructures.

    This article is categorized under:

    Therapeutic Approaches and Drug Discovery > Emerging Technologies

     
    more » « less
  2. Abstract

    Hydrogen sulfide (H2S) is a gaseous molecule that has received attention for its role in biological processes and therapeutic potential in diseases, such as ischemic reperfusion injury. Despite its clinical relevance, delivery of H2S to biological systems is hampered by its toxicity at high concentrations. Herein, we report the first metal‐based H2S donor that delivers this gas selectively to hypoxic cells. We further show that H2S release from this compound protects H9c2 rat cardiomyoblasts from an in vitro model of ischemic reperfusion injury. These results validate the utility of redox‐activated metal complexes as hypoxia‐selective H2S‐releasing agents for use as tools to study the role of this gaseous molecule in complex biological systems.

     
    more » « less
  3. Abstract

    Hydrogen sulfide (H2S) is a gaseous molecule that has received attention for its role in biological processes and therapeutic potential in diseases, such as ischemic reperfusion injury. Despite its clinical relevance, delivery of H2S to biological systems is hampered by its toxicity at high concentrations. Herein, we report the first metal‐based H2S donor that delivers this gas selectively to hypoxic cells. We further show that H2S release from this compound protects H9c2 rat cardiomyoblasts from an in vitro model of ischemic reperfusion injury. These results validate the utility of redox‐activated metal complexes as hypoxia‐selective H2S‐releasing agents for use as tools to study the role of this gaseous molecule in complex biological systems.

     
    more » « less
  4. Abstract

    Hydrogen sulfide (H2S) is a gaseous signaling molecule in the human body and has attracted attention in cancer therapy due to its regulatory roles in cancer cell proliferation and migration. Accumulating evidence suggests that continuous delivery of H2S to cancer cells for extended periods of time suppresses cancer progression. However, one major challenge in therapeutic applications of H2S is its controlled delivery. To solve this problem, polymeric micelles are developed containing H2S donating‐anethole dithiolethione (ADT) groups, with H2S release profiles optimal for suppressing cancer cell proliferation. The micelles release H2S upon oxidation by reactive oxygens species (ROS) that are present inside the cells. The H2S release profiles can be controlled by changing the polymer design. Furthermore, the micelles that show a moderate H2S release rate exert the strongest anti‐proliferative effect in human colon cancer cells in in vitro assays as well as the chick chorioallantoic membrane cancer model, while the micelles do not affect proliferation of human umbilical vein endothelial cells. This study shows the importance of fine‐tuning H2S release profiles using a micelle approach for realizing the full therapeutic potential of H2S in cancer treatment.

     
    more » « less
  5. Abstract

    Diabetes is one of the most pressing healthcare challenges facing society. Dysfunctional insulin signaling causes diabetes, leading to blood glucose instability and many associated complications. While the administration of exogenous insulin is then essential for achieving glucose control, issues with dosing accuracy and timing remain. Hydrogel‐based drug delivery systems have been broadly explored for controlled protein release, including for applications in long‐lasting and oral insulin delivery. More recently, efforts have focused on injectable hydrogels with glucose‐directed controlled release of insulin and glucagon, aiming for more autonomous and biomimetic approaches to blood glucose control. These materials typically use protein‐based sensing mechanisms or glucose binding by synthetic aryl boronates for glucose‐directed release. Despite advancements in this area, there remains a need for more precise timing of therapeutic availability to afford healthy blood glucose homeostasis, providing an opportunity for further research and innovation. This review summarizes the current state of hydrogel‐based delivery of insulin and glucagon, with insights into the potential benefits, future directions, and challenges that must be overcome to achieve clinical impact.

     
    more » « less