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: 10540753
• 负责人: Resham Bhattacharya
• 金额: $ 38万
• 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/10540753
• 关键词: Address; Adsorption; Angiogenesis Inhibition; Animal Model; Binding; Biodistribution; Bioinformatics; Biological; Biological Models; Biological Process; Cells; Cisplatin; Coupled; Data; Databases; Diabetic Retinopathy; Disease; Disease Outcome; Drug resistance; Epithelium; 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 Promotion; Tumor Tissue; Validation; cancer cell; clinically significant; delivery vehicle; drug-sensitive; experimental study; in vivo; inhibitor therapy; insight; liposomal delivery; nanoGold; nanoparticle; nanotoxicity; novel; ovarian neoplasm; pancreatic cancer model; personalized medicine; protein distribution; protein function; response; siRNA delivery; small molecule inhibitor; therapeutic nanoparticles; therapeutic target; 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（NP）主要用作各种生物医学应用的输送车辆。什么时候 暴露于生物流体的NP与在其表面形成生物涂层的蛋白质相互作用，称为蛋白 电晕。已经研究了NP周围的蛋白质电晕，以解决包括 NP的生物分布，清除和潜在毒性。以前，我们和其他人一起表明了自我 金纳米颗粒（GNP）的治疗特性。在当前的应用中，利用自我治疗的GNP （ST-GNP）作为探测器，我们提出了一个独特的捕获，识别和验证治疗的概念 导致癌症肿瘤生长和治疗性抗药性的靶标。 我们证明了ST-GNP抑制了许多促肿瘤肝素结合的功能 生长因子（HB-GFS）通过通过HB膜结合改变蛋白质构象，而蛋白质的结合，而 非HB-GF的构象和功能保持不变。另外，在各种尺寸中，GNP为20 NM大小显示出最高的治疗功效，而100 nm大小的GNP是非自我治疗的 GNP）。重要的是，ST-GNP抑制了肿瘤的生长，转移和敏化卵巢癌细胞对顺铂 通过逆转上皮 - 间质转变（EMT）并在原位上废除MAPK信号（图1） 胰腺癌模型，我们报道了ST-GNP破坏了癌细胞与癌症之间的串扰 相关的成纤维细胞（CAF）和重编程的肿瘤微环境，抑制了肿瘤的生长。 研究来自卵巢癌或正常细胞裂解物的ST-GNP的蛋白质富集，我们确定了 SMNDC1和PPA1是肿瘤生长的潜在新目标。此外，我们最近报道了无毒的 耳脂体增强了siRNA的沉默功效，并更有效地抑制了卵巢肿瘤的生长 与传统的siRNA基于DOTAP的脂质体递送相比。基于这些结果，我们 假设富集在ST-GNP上的蛋白质的功能将受到抑制，从而导致肿瘤生长 抑制和耐药性。因此，这些富含ST-GNP的蛋白可以用作潜在的治疗 目标。我们将在下面使用特定目标来检验我们的假设； 特定目标1：研究ST-GNP上的蛋白质富集。 特定目标2：验证动物模型中的治疗靶标。 影响：NP周围的蛋白质电晕正在发展为个性化医学的独特签名。我们的发现 支持ST-GNP不仅可以用于识别卵巢和胰腺的治疗目标 癌症，但在糖尿病性视网膜病变，黄斑变性和类风湿关节炎中也 报告了GNP的ST特性抑制这些模型的血管生成。