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Abstract 3933: NADPH oxidases 4 inhibition using a hyaluronic acid nanoparticle drug delivery system sensitized therapeutic response to chemo and radiotherapy in drug resistant breast cancer

Objectives: Resistance to therapy is the major unmet challenge in clinical management of breast cancer. NADPH oxidases 4 (NOX4) is a critical NADPH oxidase subunit because it constitutively reacts with hydrogen peroxide (H2O2), generating ROS that is associated with tumorigenesis, metastasis, and invasion. A high level of NOX4 activity has been associated with drug resistance in human cancers. To improve the therapeutic efficacy, we have developed a hyaluronic acid nanoparticle (HANP) carrying a NOX4 inhibitor and examined the anti-tumor effect in combination with radiotherapy (RT) or chemotherapy. Methods: Biodegradable polymeric HANP was synthesized and encapsulated with GKT831 (HANP/GKT831), a novel inhibitor of NOX4. Targeted delivery of GKT831 with HANP was first studied by optical imaging in an orthotopic human breast cancer patient tissue derived xenograft (PDX) model. Subsequently, the ability of HANP/GKT831 in inhibition of tumor cells and sensitization of tumor cells to chemotherapy and RT was evaluated in breast PDX models following intravenous administration of HANP/GKT831 (containing 5 mg/kg equivalent dose of GKT831) in combination with Doxorubicin (DOX, 5 mg/kg) and RT (2 Gy) for 5 times, once per week. Furthermore, mechanism of NOX4 inhibition on improving therapeutic response in breast cancer was investigated. Results: We have developed HANP/GKT831 with drug loading efficiency of 15% (w/w) determined by high performance liquid chromatography (HPLC). The selective accumulation of HANP/GKT831 in breast PDX tumors following systemic delivery was demonstrated by optical imaging. Following five treatments, nude mice bearing breast PDX tumors that received HANP/GKT831 in combination with DOX or RT had significant stronger tumor growth inhibition compared with either DOX or RT alone (73.71±13.87% and 79.33±19%, respectively) as well as the non-treatment control group (86.33±16.25% and 78.15±14.27%, respectively). Examination of tumor tissues revealed that the level of poly (ADP-ribose) polymerase (PARP) expression was reduced in tumors treated with HANP/GKT831 in combination of RT or DOX, which induces cell death through DNA damage. Conclusions: We have developed a polymeric HANP carrying a NOX4 inhibitor (HANP/GKT831). We found that HANP/GKT831 could be efficiently delivered into tumors following systemic administration and significantly enhanced tumor response to Dox treatment or radiotherapy in two multi-drug resistant breast PDX tumor models. Therefore, HANP/GKT831 is a promising therapy agent for targeted therapy of breast cancer. Currently, mechanism of the effect on chemo- and radiotherapy sensitization is under investigation. One of the possible mechanisms is the downregulation of DNA-damage repairing functions, such as downregulation of DNA damage repair enzyme PARP. Citation Format: Lei Zhu, Yi Zhao, Wei Ping Qian, Dazhi Wang, Bing-Hua Jiang, Lily Yang. NADPH oxidases 4 inhibition using a hyaluronic acid nanoparticle drug delivery system sensitized therapeutic response to chemo and radiotherapy in drug resistant breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3933.