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Principal Investigator: Resham Bhattacharya
Organization: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
Fiscal Year: 2024
Award: $78,953
Funding agency: National Cancer Institute
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.
Terms: <Address><Adsorption><Angiogenesis Inhibition><Angiogenic Inhibition><Animal Model><Animal Models and Related Studies><Atrophic Arthritis><Binding><Bio-Informatics><Biodistribution><Bioinformatics><Biologic Models><Biological><Biological Function><Biological Models><Biological Process><Blood Plasma><Body Tissues><CDDP><Cancers><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cis-diammine-dichloroplatinum><Cis-diamminedichloridoplatinum><Cis-diamminedichloro Platinum (II)><Cis-dichloroammine Platinum (II)><Cis-platinous Diamine Dichloride><Cis-platinum II><Cis-platinum II Diamine Dichloride><Cisplatin><Cisplatina><Cisplatinum><Coupled><Cysplatyna><Data><Data Bases><Databases><Diabetic Retinopathy><Dichlorodiammineplatinum><Disease><Disease Outcome><Disorder><Drug resistance><Epithelium><Exposure to><Extracellular Signal-Regulated Kinase Gene><Fibroblasts><Gold><Heparin Binding Growth Factor><Human><In Vitro><Incubated><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Liquid substance><MAP Kinase Gene><MAPK><Macular degeneration><Macular degenerative disease><Malignant><Malignant - descriptor><Malignant Cell><Malignant Neoplasms><Malignant Ovarian Neoplasm><Malignant Ovarian Tumor><Malignant Pancreatic Neoplasm><Malignant Tumor><Malignant Tumor of the Ovary><Malignant neoplasm of ovary><Malignant neoplasm of pancreas><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Mesenchymal><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Methodology><Mitogen-Activated Protein Kinase Gene><Model System><Modeling><Modern Man><Molecular Configuration><Molecular Conformation><Molecular Interaction><Molecular Stereochemistry><Neoplasm Metastasis><Nodal><Normal Cell><Ovarian Tumor><Ovary Cancer><Ovary Neoplasms><Ovary Tumor><Pancreas Cancer><Pancreatic Cancer><Patients><Peyrone's Chloride><Peyrone's Salt><Plasma><Plasma Serum><Platinum Diamminodichloride><Process><Property><Protein Conformation><Proteins><Reporting><Resistance><Reticuloendothelial System, Serum, Plasma><Rheumatoid Arthritis><Scheme><Secondary Neoplasm><Secondary Tumor><Sequence Homology><Series><Short interfering RNA><Signal Transduction><Signal Transduction Systems><Signaling><Small Interfering RNA><Surface><Testing><Therapeutic><Tissues><Toxic effect><Toxicities><Treatment Efficacy><Tumor Promotion><Tumor Tissue><Validation><biologic><biological signal transduction><cancer cell><cancer metastasis><cancer microenvironment><cis dichlorodiammineplatinum><cis platinum compound><cis-Diaminedichloroplatinum><cis-Diamminedichloroplatinum><cis-Diamminedichloroplatinum(II)><cis-Dichlorodiammineplatinum(II)><cis-Platinum><clinical significance><clinically significant><conformation><conformational><conformational state><conformationally><conformations><data base><deliver short interfering RNA><deliver siRNA><deliver small interfering RNA><delivery system for siRNA><delivery system for small interfering RNA><delivery vector><delivery vectors for siRNA><delivery vehicle><drug resistant><drug-sensitive><experiment><experimental research><experimental study><experiments><fluid><gold nano particle><gold nanoparticle><in vivo><inhibitor drug><inhibitor therapeutic><inhibitor therapy><insight><intervention efficacy><interventional strategy><liposomal delivery><liposome delivery><liquid><malignancy><model of animal><nano gold><nano particle><nano toxicity><nano-sized particle><nanoGold><nanoparticle><nanoparticle therapy><nanosized particle><nanotoxicity><neoplasm/cancer><novel><ovarian cancer><ovarian neoplasm><pancreatic cancer model><pancreatic malignancy><pancreatic tumor model><personalization of treatment><personalized medicine><personalized therapy><personalized treatment><protein distribution><protein function><resistance to Drug><resistant><resistant to Drug><response><rheumatic arthritis><short interfering RNA delivery><siRNA><siRNA delivery><small interfering RNA delivery><small molecular inhibitor><small molecule inhibitor><therapeutic efficacy><therapeutic nanoparticles><therapeutic target><therapy efficacy><tumor cell metastasis><tumor growth><tumor microenvironment><validations>