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Published on: June 13, 2014
Self-Assembled Core-Shell Nanoscale Coordination Polymer Nanoparticles Carrying a Sialyltransferase Inhibitor for
Xiang Zhang1, Cheng-Hao Xu1, Juan Mo1
1State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, and Chemical Biology Center, Peking University, Beijing 100191, China.
Abstract:
Despite hypersialylation of cancer cells together with a significant upregulation of sialyltransferase (ST) activity contributes to the metastatic cascade at multiple levels, there are few dedicated tools to interfere with their expression. Although transition state-based ST inhibitors are well-established, they are not membrane permeable. To tackle this problem, herein, we design and construct long-circulating, self-assembled core-shell nanoscale coordination polymer (NCP) nanoparticles carrying a transition state-based ST inhibitor, which make the inhibitor transmembrane and potently strip diverse sialoglycans from various cancer cells. In the experimental lung metastasis and metastasis prevention models, the nanoparticle device (NCP/STI) significantly inhibits metastases formation without systemic toxicity. This strategy enables ST inhibitors to be applied to cells and animals by providing them with a well-designed nanodelivery system. Our work opens a new avenue to the development of transition state-based ST inhibitors and demonstrates that NCP/STI holds great promise in achieving metastases inhibition for multiple cancers.
Insights
New nanoparticles deliver sialyltransferase (ST) inhibitors into cancer cells, effectively reducing metastasis. This nanodelivery system overcomes previous limitations, showing promise for multiple cancer types without toxicity.
Area of Science:
- Biomedical Engineering
- Cancer Research
- Nanotechnology
Background:
- Cancer cell hypersialylation and elevated sialyltransferase (ST) activity promote metastasis.
- Existing transition state-based ST inhibitors lack membrane permeability, limiting their therapeutic application.
- There is a need for effective tools to target ST activity in cancer metastasis.
Purpose of the Study:
- To design and construct a novel nanodelivery system for transmembrane delivery of ST inhibitors.
- To evaluate the efficacy of the developed nanoparticle system in inhibiting cancer metastasis.
- To assess the safety profile of the nanodelivery system in preclinical models.
Main Methods:
- Development of core-shell nanoscale coordination polymer (NCP) nanoparticles encapsulating a transition state-based ST inhibitor.
- Characterization of the NCP nanoparticles for stability and drug loading.
- In vitro testing of sialoglycan stripping from cancer cells.
- In vivo evaluation in experimental lung metastasis and metastasis prevention mouse models.
Main Results:
- The NCP nanoparticles successfully achieved transmembrane delivery of the ST inhibitor.
- The nanoparticle-ST inhibitor conjugate (NCP/STI) potently stripped sialoglycans from various cancer cells.
- NCP/STI significantly inhibited lung metastasis formation and prevented metastasis in preclinical models.
- No significant systemic toxicity was observed with the NCP/STI treatment.
Conclusions:
- The developed NCP nanodelivery system enables effective intracellular delivery of ST inhibitors.
- This strategy overcomes the membrane permeability issue of transition state-based ST inhibitors.
- NCP/STI demonstrates significant potential for inhibiting metastasis in multiple cancer types with a favorable safety profile.
