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Lymph-Directed Self-Immolative Nitric Oxide Prodrug for Inhibition of Intractable Metastatic Cancer
Taejeong Kim1, Jeeyeon Suh1, Jihoon Kim2
1Department of Chemistry Pohang University of Science and Technology (POSTECH) 77 Cheongam-ro, Nam-gu Pohang 37673 Republic of Korea.
Abstract:
There has been a significant clinical demand for lymph-directed anti-metastatic therapy as tumor-draining lymph nodes play pivotal roles in cancer metastasis which accounts for more than 90% of tumor-related deaths. Despite the high potential of nitric oxide (NO) in anti-cancer therapy owing to its biocompatibility and tumor cell-specific cytotoxicity, the poor stability and lack of target specificity of present NO donors and delivery systems have limited its clinical applications. Herein, a redox-triggered self-immolative NO prodrug that can be readily conjugated to various materials containing free thiol groups such as albumin, is reported. The prodrug and its conjugates demonstrate smart release of NO donor via intramolecular cyclization under reductive conditions, followed by spontaneously generating NO in physiological conditions. The albumin-prodrug conjugate inhibits tumor metastasis by inducing cytotoxicity preferentially on tumor cells after efficiently draining into lymph nodes. This novel prodrug can contribute to the development of on-demand NO delivery systems for anti-metastatic therapy and other treatments.
Insights
A new nitric oxide (NO) prodrug targets cancer metastasis by releasing NO in lymph nodes. This albumin-conjugated prodrug selectively kills tumor cells, offering a promising approach for anti-metastatic therapy.
Area of Science:
- Biomedical Engineering
- Oncology
- Drug Delivery Systems
Background:
- Tumor-draining lymph nodes are critical in cancer metastasis, driving over 90% of cancer-related deaths.
- Nitric oxide (NO) shows anti-cancer potential due to biocompatibility and tumor cell cytotoxicity.
- Current NO donors lack stability and target specificity, limiting clinical use.
Purpose of the Study:
- To develop a novel, redox-triggered, self-immolative nitric oxide (NO) prodrug for targeted anti-metastatic therapy.
- To create an albumin-prodrug conjugate for enhanced lymph node accumulation and NO release.
- To evaluate the efficacy of the conjugate in inhibiting tumor metastasis.
Main Methods:
- Synthesis of a redox-triggered self-immolative NO prodrug.
- Conjugation of the prodrug to albumin via thiol groups.
- In vitro and in vivo evaluation of NO release kinetics and anti-metastatic activity.
- Assessment of preferential cytotoxicity towards tumor cells within lymph nodes.
Main Results:
- The prodrug demonstrated smart NO release via intramolecular cyclization under reductive conditions.
- Albumin-prodrug conjugates efficiently drained into lymph nodes.
- The conjugate exhibited preferential cytotoxicity towards tumor cells, inhibiting metastasis.
- Stable NO generation under physiological conditions was achieved.
Conclusions:
- A novel self-immolative NO prodrug conjugated to albumin shows promise for targeted anti-metastatic therapy.
- This approach overcomes limitations of current NO donors, enabling on-demand NO delivery.
- The prodrug's ability to target lymph nodes and selectively kill tumor cells offers a new strategy for cancer treatment.
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