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Researchers Develop Innovative Nitric Oxide Therapy for Skin Cancer

Researchers Develop Innovative Nitric Oxide Therapy for Skin Cancer



A team of researchers led by Dr. Mark Schoenfisch, Peter A. Ornstein Distinguished Professor at UNC-Chapel Hill, explores the potential of nitric oxide as a topical treatment for melanoma, offering hope for a more effective, less toxic alternative.

Mark Schoenfisch, Peter A. Ornstein Distinguished Professor at UNC-Chapel Hill, is co-author of the study.

January 30, 2025 | By Dave DeFusco

Melanoma, a highly aggressive form of skin cancer, has long posed significant challenges in both treatment and patient outcomes. Its increasing incidence and notorious resistance to conventional therapies highlight the need for innovative solutions. Traditional treatments like surgery, immunotherapy and chemotherapy have shown limited success, often accompanied by severe side effects and, in many cases, acquired resistance.

However, in a promising new study,Nitric Oxide-Releasing Topical Treatments for Cutaneous Melanoma,” published in the journal, Molecular Pharmaceutics, a team of researchers led by Dr. Mark Schoenfisch, Peter A. Ornstein Distinguished Professor at UNC-Chapel Hill, explores the potential of nitric oxide as a topical treatment for melanoma, offering hope for a more effective, less toxic alternative.

Nitric oxide, a naturally occurring gasotransmitter, has been gaining attention in cancer research for its dual role in regulating tumor biology. At low concentrations, nitric oxide can promote tumor growth but at higher levels, it exhibits powerful anticancer effects. Nitric oxide triggers apoptosis, or programmed cell death, enhances oxidative stress, inhibits metastasis and even sensitizes tumors to chemotherapy and immunotherapy. These tumor-suppressing effects make nitric oxide an attractive candidate for treating melanoma, which is notorious for its resistance to many conventional cancer therapies.

The key challenge with nitric oxide as a therapeutic agent is its reactivity and short half-life. To harness its full potential, scientists have turned to chemical nitric oxide donors—compounds that store nitric oxide and release it in a controlled manner. However, the efficacy of these nitric oxide donors has remained underexplored, particularly in the context of melanoma. This is where the new research originates, aiming to optimize the nitric oxide release for targeted melanoma treatment.

Dr. Schoenfisch and his collaborators investigate the use of macromolecular nitric oxide donors for the treatment of cutaneous melanoma. The study evaluated three different nitric oxide donor systems—cyclodextrin, mesoporous silica nanoparticles and hyaluronic acid—each with tunable nitric oxide-release kinetics. By analyzing their cytotoxicity against melanoma and healthy skin cells, as well as their ability to permeate the skin, the team sought to identify the most effective donor for topical melanoma therapy.

“Our approach focused on optimizing the delivery of nitric oxide directly to the tumor site, bypassing the need for systemic administration,” said Dr. Schoenfisch. “This topical approach could potentially reduce the adverse side effects commonly associated with traditional therapies and increase the concentration of the drug at the site of the tumor.”

The researchers found that the cytotoxicity of nitric oxide-releasing systems was primarily dependent on the nitric oxide payload and not the donor identity or the release kinetics. For example, the three nitric oxide donor systems—cyclodextrin, mesoporous silica nanoparticles and hyaluronic acid—differed in their release profiles, but their anticancer activity was largely determined by the amount of nitric oxide they could deliver.

Among these systems, cyclodextrin-based nitric oxide donors exhibited the largest therapeutic indices, meaning they were more toxic to cancer cells versus the healthy cells. hyaluronic acid-based nitric oxide donors also showed favorable results, with attractive therapeutic indices, while mesoporous silica nanoparticles had lower therapeutic indices. This suggests that biopolymer-based nitric oxide donors, such as cyclodextrin and hyaluronic acid, are more effective for melanoma treatment as they combine high nitric oxide payloads with better biocompatibility.

A significant challenge in developing topical treatments is ensuring that the therapeutic agents can penetrate the skin’s protective barrier. The study employed Franz diffusion cells to assess the skin permeation of the nitric oxide-releasing materials. Cyclodextrin-based nitric oxide donors, due to their small size and favorable charge characteristics, demonstrated the highest skin permeation. The researchers also found that smaller, more neutral donors were more successful at permeating the skin, a critical factor for the success of topical treatments.

The team used a Pluronic F127 organogel formulation to optimize the delivery of the cyclodextrin-based nitric oxide donor to tumors below the skin. This formulation not only improved the skin permeation of the nitric oxide donor but also showed promising results in reducing tumor growth in an in vivo model.

The final step in the study was to evaluate the in vivo efficacy of the most promising nitric oxide donor formulation. The results showed that the cyclodextrin-based nitric oxide donor, delivered through the optimized organogel formulation, significantly reduced tumor growth in a melanoma mouse model. This promising outcome suggests that the topical delivery of nitric oxide could be a viable therapeutic strategy for addressing cutaneous melanoma.

“The controlled delivery of nitric oxide through macromolecular donors offers a novel approach to overcoming the limitations of traditional melanoma therapies,” said Dr. Schoenfisch. “By reducing the risk of systemic toxicity and potentially overcoming drug resistance, nitric oxide-releasing topical treatments could revolutionize melanoma care, providing patients with a safer, more effective option for managing this aggressive cancer.”


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