Exploiting gold nanoparticle as a probe to identify therapeutic targets

利用金纳米颗粒作为探针来识别治疗靶点

• 批准号: 10374481
• 负责人: Resham Bhattacharya
• 金额: $ 39.9万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-15 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10374481
• 关键词: Address; Animal Model; Binding; Biodistribution; Bioinformatics; Biological; Biological Models; Biological Process; Cells; Cisplatin; Coupled; Data; Databases; Diabetic Retinopathy; Disease; Disease Outcome; Drug resistance; Epithelial; Exposure to; Fibroblasts; Gold; Heparin Binding Growth Factor; Human; In Vitro; Incubated; Intervention; Liquid substance; MAP Kinase Gene; Macular degeneration; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of ovary; Malignant neoplasm of pancreas; Mass Spectrum Analysis; Mesenchymal; Methodology; Modeling; Molecular Conformation; Neoplasm Metastasis; Nodal; Normal Cell; Patients; Plasma; Process; Property; Protein Conformation; Proteins; Reporting; Resistance; Rheumatoid Arthritis; Scheme; Sequence Homology; Series; Signal Transduction; Small Interfering RNA; Surface; Testing; Therapeutic; Tissues; Toxic effect; Treatment Efficacy; Tumor Tissue; Validation; angiogenesis; base; cancer cell; clinically significant; delivery vehicle; drug-sensitive; experimental study; in vivo; inhibitor therapy; insight; liposomal delivery; nanoGold; nanoparticle; novel; ovarian neoplasm; pancreatic cancer model; personalized medicine; protein distribution; protein function; response; siRNA delivery; small molecule inhibitor; therapeutic nanoparticles; therapeutic target; tumor; tumor growth; tumor microenvironment

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.

纳米颗粒（NPs）主要用作各种生物医学应用的递送载体。当 暴露于生物流体的NP与蛋白质相互作用，在其表面上形成生物涂层，称为蛋白质 电晕。已经研究了NP周围的蛋白质冠，以解决生物反应，包括 NP的生物分布、清除率和潜在毒性。以前，我们沿着与别人展示自我- 金纳米颗粒（GNP）的治疗特性。在当前的应用中，开发自我治疗GNP （ST-GNP）作为探针，我们提出了一个独特的概念，捕获，识别和验证治疗 靶点负责肿瘤生长和癌症的治疗抗性。 我们证明，ST-GNP抑制了许多促肿瘤的肝素结合蛋白的功能。 生长因子（HB-GFs）通过HB结构域结合改变蛋白质构象，而 非HB-GF的构象和功能保持不变。此外，在各种规模中，GNP为20 纳米尺寸的GNP显示出最高的治疗功效，而100纳米尺寸的GNP是非自我治疗的（NST-100）。 GNP）。重要的是，ST-GNP抑制肿瘤生长、转移和对顺铂敏感的卵巢癌细胞 通过逆转上皮-间充质转化（EMT）和废除MAPK信号传导（图1）， 在胰腺癌模型中，我们报道了ST-GNP破坏了癌细胞和癌细胞之间的相互作用， 相关的成纤维细胞（CAF）和抑制肿瘤生长的重编程肿瘤微环境。 通过研究卵巢癌或正常细胞裂解物中ST-GNP的蛋白富集，我们发现 SMNDC 1和PPA 1是肿瘤生长的潜在新靶点。此外，我们最近报告说，无毒 金脂质体增强siRNA沉默效果，更有效地抑制卵巢肿瘤生长 与传统的基于DOTAP-DOPE的siRNA脂质体递送相比。基于这些结果，我们 假设ST-GNP上富集的蛋白质的功能将被抑制，导致肿瘤生长 抑制和治疗抗性。因此，这些富含ST-GNP的蛋白质可作为潜在的治疗剂。 目标的我们将使用下面的具体目标来测试我们的假设; 具体目标1：研究ST-GNP上的蛋白富集。 具体目标2：在动物模型中验证治疗靶点。 影响：NP周围的蛋白质冠正在演变为个性化医疗的独特特征。我们的研究结果 支持ST-GNP不仅可用于确定卵巢和胰腺癌的治疗靶点， 糖尿病性视网膜病变、黄斑变性和类风湿性关节炎， 报道了在这些模型中GNP抑制血管生成的ST性质。