New therapeutics that target gene expression such as nucleic acid (NA) based constructs show great promise for treating complex diseases more effectively. However a major roadblock to the implementation of these compounds for clinical use is their efficient delivery into tissues and cells which is impeded due to their highly charged nature and inability to pass across the plasma membrane. Here we propose to formulate and test a novel delivery system based on chemically modified gold nanoparticles (GNPs) for delivery of an NA-based compound (signal transducer and activator of transcription 3 decoy oligonucleiotide (STAT3d)) that has shown effectiveness in the treatment of head and neck squamous cell carcinoma (HNSCC). The novel carrier system is expected to overcome multiple limitations currently faced by this type of technology in that it (1) allows the therapeutic NA to be administered systemically after IV injection, (2) allows the NA to preferentially target cancer cells, (3) allows the NA to permeate the cell membrane, (4) allows the molecule to be tracked via fluorescence imaging, and (5) allows for the additive benefit of radiation sensitization to be conferred after uptake of the GNP-based delivery system in tumor cells. Development of the novel NA-based therapeutic (NA- GNP-STAT3d) will be accomplished through the following specific aims: (1) optimization and characterization of a nucleolin-targeted oligonucleotide (ODN)/gold nanoparticle (GNP) delivery system (NA-GNP-STAT3d), and (2) mapping the efficacy of the NA-GNP-STAT3d system in attenuating STAT3d-mediated gene expression in HNSCC and testing the combined effect of STAT3d and GNP-mediated radiosensitization on the viability of HNSCCs in culture.

Public Health Relevance

In order for newly developed drugs aimed at altering gene expression to be translated into clinical use, a safe and effective method for their delivery to diseased tissue in humans must be developed. In this study we aim to synthesize and test a new delivery system for a promising therapeutic (STAT3d) for treating head and neck cancers. The delivery system combines the safety and utility of chemically modified gold nanoparticles with a traceable fluorescent probe all in a formulation that is suitable for IV administration to humans, and which will be targeted to malignant cells in the body.

National Institute of Health (NIH)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Exploratory/Developmental Grants (R21)
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Clinical Molecular Imaging and Probe Development (CMIP)
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Tucker, Jessica
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University of Massachusetts Medical School Worcester
Schools of Medicine
United States
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Zhang, Surong; Gupta, Suresh; Fitzgerald, Thomas J et al. (2018) Dual radiosensitization and anti-STAT3 anti-proliferative strategy based on delivery of gold nanoparticle - oligonucleotide nanoconstructs to head and neck cancer cells. Nanotheranostics 2:1-11
Metelev, Valeriy; Zhang, Surong; Zheng, Shaokuan et al. (2017) Fluorocarbons Enhance Intracellular Delivery of Short STAT3-sensors and Enable Specific Imaging. Theranostics 7:3354-3368
Bogdanov Jr, Alexei A; Dixon, Adam J; Gupta, Suresh et al. (2016) Synthesis and Testing of Modular Dual-Modality Nanoparticles for Magnetic Resonance and Multispectral Photoacoustic Imaging. Bioconjug Chem 27:383-90
Bogdanov Jr, Alexei A; Gupta, Suresh; Koshkina, Nadezhda et al. (2015) Gold nanoparticles stabilized with MPEG-grafted poly(l-lysine): in vitro and in vivo evaluation of a potential theranostic agent. Bioconjug Chem 26:39-50