# Delivery of H2S: Supramolecular and Enzyme-Triggered Strategies for Controlled Release

> **NIH NIH R01** · VIRGINIA POLYTECHNIC INST AND ST UNIV · 2021 · $293,845

## Abstract

PROJECT SUMMARY/ABSTRACT
 Despite its reputation as a toxic and foul-smelling gas, hydrogen sulfide (H2S) is an important signaling
molecule that plays a role in nearly every organ in the body. H2S therapy is a growing area of research, with
studies showing efficacy in many animal models of disease, including cardiovascular disease, neurological
diseases, and cancer. However, outcomes appear to depend heavily on the duration and rate of H2S delivery.
To fully understand the physiological roles of H2S, to measure its effects on different organs and systems, and
to achieve its therapeutic potential, novel methods for delivering H2S with control over the timing, location, rate,
and duration of delivery are needed. The long-term goal of this project is to treat diseases by delivery of
exogenous H2S; however, chemical tools must first be developed that will enable controlled delivery. These
tools, which will provide methods to probe H2S physiology in a variety of diseases, include both enzyme-
triggered H2S-releasing prodrugs (control over timing and location of delivery) and H2S releasing micelles with
tunable release rates (control over rate and duration of delivery). Through the following specific aims these
new chemical tools will be prepared and tested in a biologically relevant application of H2S in cancer therapy:
1. Synthesize enzyme-triggered H2S prodrugs with high specificity
 This aim will focus on synthesis of small molecules that release H2S only in the presence of specific
 enzymes, including proteases, esterases, and azoreductases, all of which are upregulated in response to
 specific diseases that may benefit from H2S treatment.
2. Develop biodegradable H2S-releasing polymer micelles with tunable release rates
 In this aim H2S release rate will be controlled using a polymer micelle platform. Micelles were chosen due
 to the many factors that can be controlled to tune H2S release kinetics, including size, shape, critical
 micelle concentration, and unimer exchange rates.
3. Use these tools to answer controversial biological questions regarding the roles of H2S in the
 inhibition/promotion of cancer cell proliferation
 The role of H2S in cancer is complex—it can either inhibit or promote cancer cell growth depending on the
 rate, dose, and duration of release. The prodrugs and micelles will be tested as anti-cancer agents to
 measure how release rate affects toxicity and selectivity toward cancer cells over normal cells.
 The H2S delivery methods proposed here will increase our understanding of the signaling roles that
endogenous H2S plays in mammalian biology. Also, we expect that these strategies for controlling timing,
location, rate, and duration of H2S delivery will inspire new methods for controlled delivery of other signaling
gases. In summary, the studies proposed here will elevate the therapeutic potential of H2S, furthering a
research program that may lead to H2S therapies with low toxicity, few side effects, and high efficacy.

## Key facts

- **NIH application ID:** 10092182
- **Project number:** 5R01GM123508-05
- **Recipient organization:** VIRGINIA POLYTECHNIC INST AND ST UNIV
- **Principal Investigator:** John B Matson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $293,845
- **Award type:** 5
- **Project period:** 2017-04-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10092182

## Citation

> US National Institutes of Health, RePORTER application 10092182, Delivery of H2S: Supramolecular and Enzyme-Triggered Strategies for Controlled Release (5R01GM123508-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10092182. Licensed CC0.

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