Department of Radiology, Laboratory of Molecular Imaging Probes; Department of Radiation Oncology
Nanomedicine | Radiology
Constitutively activated signal transducer and activator of transcription 3 (STAT3) factor is an important therapeutic target in head and neck cancer (HNC). Despite early promising results, a reliable systemic delivery system for STAT3- targeted oligonucleotide (ODN) drugs is still needed for future clinical translation of anti-STAT3 therapies. We engineered and tested a novel ODN duplex/gold nanoparticle (AuNP)-based system carrying a therapeutic STAT3 decoy (STAT3d) payload. This strategy is two-pronged because of the additive STAT3 antagonism and radiosensitizing properties of AuNP. The specificity to head and neck cancer cell surface was imparted by using a nucleolin aptamer (NUAP) that was linked to AuNP for taking the advantage of an aberrant presentation of a nuclear protein nucleolin on the cell surface. STAT3d and nucleolin aptamer constructs were independently linked to AuNPs via Au-S bonds. The synthesized AuNP constructs (AuNP-NUAP-STAT3d) exhibited internalization in cells that was quantified by using radiolabeled STAT3d. AuNP-NUAP-STAT3d showed radiosensitizing effect in human HNC FaDu cell culture experiments that resulted in an increase of cell DNA damage as determined by measuring gamma-H2AX phosphorylation levels by flow cytometry. The radiosensitization study also demonstrated that AuNP-NUAP-STAT3d as well as STAT3d alone resulted in the efficient inhibition of A431 cell proliferation. While FaDu cells did not show instant proliferation inhibition after incubating with AuNP-NUAP-STAT3d, the cell DNA damage in these cells showed nearly a 50% increase in AuNP-NUAP-STAT3d group after treating with radiation. Compared with anti-EGFR humanized antibody (Cetuximab), AuNP-NUAP-STAT3d system had an overall stronger radiosensitization effect in both A431 and FaDu cells.
oligonucleotide, aptamer, gold nanoparticle, confocal microscopy, STAT3
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DOI of Published Version
Nanotheranostics. 2018 Jan 1;2(1):1-11. doi: 10.7150/ntno.22335. eCollection 2018. Link to article on publisher's site
Zhang S, Gupta S, Fitzgerald TJ, Bogdanov AA. (2018). Dual radiosensitization and anti-STAT3 anti-proliferative strategy based on delivery of gold nanoparticle - oligonucleotide nanoconstructs to head and neck cancer cells. Radiology Publications. https://doi.org/10.7150/ntno.22335. Retrieved from https://escholarship.umassmed.edu/radiology_pubs/375
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