Abstract
Signal transducer and activator of transcription-3 (STAT3) is an oncogenic transcription factor implicated in carcinogenesis, tumor progression, and drug resistance in head and neck squamous cell carcinoma (HNSCC). A decoy oligonucleotide targeting STAT3 offers a promising anti-tumor strategy, but achieving targeted tumor delivery of the decoy with systemic administration poses a significant challenge. We previously showed the potential for STAT3 decoy-loaded microbubbles, in conjunction with ultrasound targeted microbubble cavitation (UTMC), to decrease tumor growth in murine squamous cell carcinoma. As a next step towards clinical translation, we sought to determine the anti-tumor efficacy of our STAT3 decoy delivery platform against human HNSCC and the effect of higher STAT3 decoy microbubble loading on tumor cell inhibition. STAT3 decoy was loaded on cationic lipid microbubbles (STAT3-MB) or loaded on liposome-conjugated lipid microbubbles to form STAT3-loaded liposome-microbubble complexes (STAT3-LPX). UTMC treatment efficacy with these two formulations was evaluated in vitro using viability and apoptosis assays in CAL33 (human HNSCC) cells. Anti-cancer efficacy in vivo was performed in a CAL33 tumor murine xenograft model. UTMC with STAT3-MB caused significantly lower CAL33 cell viability compared to UTMC with STAT3-LPX (56.8±8.4% vs 84.5±8.8%, respectively, p<0.05). In vivo, UTMC with STAT3-MB had strong anti-tumor effects, with significantly less tumor burden and greater survival compared to that of UTMC with microbubbles loaded with a mutant control decoy and untreated control groups (p<0.05). UTMC with STAT3 decoy-loaded microbubbles significantly decreases human HNSSC tumor progression. These data set the stage for clinical translation of our microbubble platform as an imaged-guided, targeted delivery strategy for STAT3 decoy, or other nucleotide-based therapeutics, in human cancer treatment.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, with 49,670 cases in the United States and 600,000 cases globally in 2017 [1]
We previously demonstrated that ultrasound targeted microbubble cavitation (UTMC) treatment with signal transducer and activator of transcription-3 (STAT3) decoy-loaded cationic lipid microbubbles inhibits the growth of murine skin squamous cell carcinoma xenografts [23]
The main finding of this study is that lipid microbubbles loaded with a cyclic STAT3 decoy oligonucleotide, in the presence of image-guided therapeutic ultrasound, inhibit growth of human HNSCC tumors and suppress downstream target gene expression
Summary
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, with 49,670 cases in the United States and 600,000 cases globally in 2017 [1]. Despite advances in conventional therapies such as surgery, radiotherapy, and chemotherapy, the five-year survival rate of patients with HNSCC is ~40% and has improved only marginally over the past several decades [3,4,5]. Both tobaccoassociated and HPV-linked HNSCC are associated with hyperactivation of signal transducer and activator of transcription-3 (STAT3) [6]. STAT3 is considered an important therapeutic target for several reasons, including its role in suppressing cancer cell apoptosis and in multiple oncogenic pathways, such that its inhibition would effectively block the action of several upstream tyrosine kinases [11]
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