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Multi-arm polymeric nanocarrier as a nitric oxide delivery platform for chemotherapy of head and neck squamous cell
Shaofeng Duan1, Shuang Cai, Qiuhong Yang
1Department of Pharmaceutical Chemistry, The University of Kansas, 2095 Constant Ave, Lawrence, KS 66047, United States.
Abstract:
Nitric oxide is a cell signaling molecule that can be a potent inducer of cell death in cancers at elevated concentrations. However, NO is also toxic to normal tissues and chronic exposure at low levels can induce tumor growth. We have designed a polymeric carrier system to deliver nitric oxide locoregionally to tumorigenic tissues at micromolar concentrations. A highly water solubility and biodegradable multi-arm polymer nanocarrier, sugar poly-(6-O-methacryloyl-d-galactose), was synthesized using MADIX/RAFT polymerization, and utilized to deliver high concentrations of nitric oxide to xenografts of human head and neck squamous cell carcinoma (HNSCC). The in vitro release of the newly synthesized nitric oxide donor, O(2)-(2,4-dinitrophenyl) 1-[4-(2-hydroxy)ethyl]-3-methylpiperazin-1-yl]diazen-1-ium-1,2-diolate and its corresponding multi-arm polymer-based nanoconjugate demonstrated a 1- and 2.3-fold increase in half-life, respectively, compared to the release half-life of the nitric oxide-donor prodrug JS-K. When administered to tumor-bearing nude mice, the subcutaneously injected multi-arm polymer nitric oxide nanoparticles resulted in 50% tumor inhibition and a 7-week extension of the average survival time, compared to intravenous JS-K therapy. In summary, we have developed an effective nitric oxide anti-cancer chemotherapy that could be administered regionally to provide the local disease control, improving prognosis for head and neck cancers.
Insights
Researchers developed a novel polymer nanocarrier for targeted nitric oxide (NO) delivery to head and neck cancers. This innovative chemotherapy demonstrated significant tumor inhibition and extended survival times in preclinical models.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Nitric oxide (NO) is a dual-acting molecule in cancer, inducing cell death at high concentrations but promoting tumor growth at low levels.
- Effective delivery of NO to tumor sites while minimizing systemic toxicity remains a challenge in cancer therapy.
Purpose of the Study:
- To design and synthesize a biodegradable, multi-arm polymer nanocarrier for locoregional delivery of high concentrations of nitric oxide to tumors.
- To evaluate the efficacy of this NO-releasing nanocarrier system in preclinical models of human head and neck squamous cell carcinoma (HNSCC).
Main Methods:
- Synthesis of a sugar-based poly-(6-O-methacryloyl-d-galactose) multi-arm polymer nanocarrier using MADIX/RAFT polymerization.
- Development of a novel NO-donor prodrug and its conjugation to the polymer nanocarrier.
- In vitro release studies and in vivo efficacy evaluation in HNSCC xenografts in nude mice.
Main Results:
- The polymer-based NO nanoconjugate exhibited a significantly longer release half-life compared to the free NO-donor prodrug JS-K.
- Subcutaneous administration of the NO nanoparticles resulted in 50% tumor inhibition in HNSCC xenografts.
- Treatment with the NO nanoparticles led to a 7-week extension in average survival time compared to intravenous JS-K therapy.
Conclusions:
- A novel polymer nanocarrier system effectively delivers high concentrations of nitric oxide to tumors.
- This NO-based chemotherapy demonstrates significant anti-cancer activity and improves survival in preclinical models of head and neck cancer.
- Regional administration of this nanocarrier system offers a promising strategy for local disease control and improved prognosis in HNSCC.
