Exploiting gold nanoparticle as a probe to identify therapeutic targets

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Nanoparticles (NPs) have mostly been used as delivery vehicles for various biomedical applications. When exposed to biological fluids NPs interact with proteins forming a biological coating on their surface, termed protein corona. Protein corona around NPs have been investigated to address the biological responses including biodistribution, clearance and potential toxicity of NP. Previously, we along with others have demonstrated self- therapeutic property of gold nanoparticles (GNPs). In the current application, exploiting self-therapeutic GNP (ST-GNP) as a probe, we are proposing a unique concept of capturing, identifying and validating therapeutic targets responsible for tumor growth and therapy resistance in cancer. We demonstrated that ST-GNP inhibited functions of a number of tumor-promoting heparin-binding growth factors (HB-GFs) via binding through the HB-domain that altered protein conformations, whereas conformations and functions of non-HB-GFs remained unaltered. In addition, among various sizes, GNP of 20 nm size demonstrated highest therapeutic efficacy whereas GNP of 100 nm size was non self-therapeutic (NST- GNP). Importantly, ST-GNP inhibited tumor growth, metastasis and sensitized ovarian cancer cells to cisplatin by reversing epithelial-mesenchymal transition (EMT) and abrogating MAPK-signaling (Fig 1) In orthotopic model of pancreatic cancer, we reported that ST-GNP disrupted cross-talk between cancer cells and cancer associated fibroblasts (CAFs) and reprogrammed tumor microenvironment that inhibited tumor growth. Investigating protein enrichment on ST-GNP from ovarian cancer or normal cellular lysates, we identified SMNDC1 and PPA1, as potential new targets for tumor growth. Furthermore, we recently reported that non-toxic Auroliposome enhanced silencing efficacy of siRNA and more effectively inhibited ovarian tumor growth compared to traditional DOTAP-DOPE based liposomal delivery of siRNA. Based on these results, we hypothesize that functions of the proteins enriched on ST-GNP will be inhibited resulting in tumor growth inhibition and therapy resistance. Therefore, these ST-GNP-enriched proteins may serve as potential therapeutic targets. We will use specific aims below to test our hypothesis; Specific aim 1: Investigating protein enrichment on ST-GNP. Specific aim 2: Validating therapeutic targets in animal models. Impact: Protein corona around NPs is evolving as a unique signature for personalized medicine. Our findings support that the ST-GNP could be utilized to identify therapeutic targets not only for ovarian and pancreatic cancer but in diabetic retinopathy, macular degeneration and rheumatoid arthritis as well where others have reported ST property of GNP to inhibit angiogenesis in these models.