Targeting aggressive prostate cancer with novel theranostic nanomedicine

利用新型治疗诊断纳米药物治疗侵袭性前列腺癌

• 批准号: 8336823
• 负责人: Jer-Tsong Hsieh
• 金额: $ 32.37万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-21 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8336823
• 关键词: Adopted; Adverse effects; Anatomy; Animals; Apoptosis; Area; Attention; Basal Cell; Biocompatible; Biotechnology; Cancer Etiology; Cell Line; Cell Nucleus; Cells; Cellular Stress; Cessation of life; Chelating Agents; Collaborations; Data; Dendrimers; Development; Diagnostic; Diagnostic Imaging; Disease; Down-Regulation; Drug Delivery Systems; Drug Kinetics; Drug Monitoring; Epithelial; Epithelium; Future; GTPase-Activating Proteins; Genes; Goals; Growth Factor; Hormones; Human; Human body; Image; Imaging Techniques; Imaging technology; Impotence; In Vitro; Incontinence; Investigational Therapies; Knock-out; Knowledge; Laboratories; Lead; Lesion; Location; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Medicine; Membrane; Metastatic Prostate Cancer; Metastatic to; Molecular; Molecular Medicine; Molecular Target; Monitor; Nanotechnology; Neoplasm Metastasis; Non-Malignant; One-Step dentin bonding system; Organ; Outcome Study; PC3 cell line; PSA screening; Pathologic; Patients; Peptides; Permeability; Pharmaceutical Preparations; Phenotype; Population; Positron-Emission Tomography; Pre-Clinical Model; Predictive Value; Progression-Free Survivals; Prostate; Protein Biochemistry; Proteins; Publications; Quality of life; Radiation; Reporting; Research; Risk; Screening procedure; Sensitivity and Specificity; Signal Pathway; Signal Transduction; Signaling Protein; Single Nucleotide Polymorphism; Site; Staging; Stimulus; Survival Rate; System; Tertiary Protein Structure; Testing; The Sun; Therapeutic; Therapeutic Agents; Therapeutic Index; Time; Tissues; Toxic effect; Tracer; Translating; Treatment Efficacy; Tumorigenicity; Ursidae Family; Work; base; cancer cell; cancer diagnosis; cancer imaging; cancer surgery; cancer therapy; cell growth; chemotherapy; clinical application; cytotoxicity; design; drug development; early onset; epithelial to mesenchymal transition; extracellular; flexibility; hormone therapy; imaging probe; improved; in vivo; insight; lymph nodes; men; molecular imaging; mortality; nanocarrier; nanomedicine; nanoparticle; neoplastic cell; novel; particle; prevent; response; small molecule; success; synthetic peptide; targeted delivery; theranostics; tumor

DESCRIPTION (provided by applicant): In this project, we proposed to develop a new drug delivery vehicle based on dendrimer nanotechnology for personalized medicine. This new nanoparticle contains imaging probe and molecular medicine with a cancer-specific targeting capability which is able to target cancer cells, monitor drug delivery and tumor response to achieve a "see and treat" strategy as a new concept of molecular medicine. This nanoparticle platform will be very flexible for adopting any new cell targeting molecule or any forms of therapeutic agents. One of the most exciting developments in molecular medicine has been the step-by-step construction of signaling cascades that trace the effect path of extracellular stimuli, including soluble growth factors, hormone, matrices, stress, and cell-cell contact, all the way from the external membrane to the cell nucleus. Altered signaling pathways are often found in malignant or non-malignant diseases. Knowledge from protein biochemistry has revealed specific functional motif associated with signaling protein responsible for this action. Thus, targeting these defective signal pathways with small molecule, particular small peptide or peptido-memtics, is now becoming an active research area of drug development because peptide is a natural compound in human body with less concern of side effect. In order to increase therapeutic index of these agents, we have designed a target-specific delivery system from a unique group of peptide with cell permeability. To date, the rapid evolving nanotechnology has yielded many biocompatible nanocarriers for imaging and/or therapeutic application. In this project, a dendrimer nanoparticle equipped cell specific cell permeable peptide was designed and synthesized to have molecular imaging capabilities and carry various therapeutic agents. This particle will be tested for locate target cell and monitor the drug response of tumor cells in a real-time manner. We believe that this experimental therapy has a great potential to translate into clinical application in an immediate future because all the materials do not expect to post any significant toxicity to human body. Most importantly, this proposal is to explore a new avenue of tailored molecular therapy for metastatic prostate cancer in contrast to conventional therapeutic strategy since prostate cancer has become the second leading cause of cancer death among US men. Most men died of prostate cancer are due to metastatic disease that has not been controlled effectively. Thus, the success outcome of this study will certainly bring one step close to the ultimate cure of this disease. This work is carried out by a team with highly productive collaborations with numbers of publications. The Simanek's laboratory will make dendrimers that bear a functional handle for the chelating agent provided by Dr. Sun and several peptides provided by Dr. Hsieh. Dr. Simanek's lab is responsible installing both the chelate and the peptides onto the dendrimer and characterizing the resulting materials before return to Drs. Sun's and Hsieh's laboratory for evaluating the application of molecular imaging and therapy.

描述（由申请人提供）：在此项目中，我们建议开发一种基于树枝状大分钟纳米技术的新药输送工具。这种新的纳米颗粒包含具有癌症特异性靶向能力的成像探针和分子医学，能够靶向癌细胞，监测药物递送和肿瘤反应，以实现“ SEE SEE and CRENT”策略作为分子医学的新概念。该纳米颗粒平台将非常灵活，用于采用任何新的细胞靶向分子或任何形式的治疗剂。分子医学中最令人兴奋的发展之一是信号级联的分步构造，这些层面是追踪细胞外刺激的效果路径，包括可溶性生长因子，激素，基质，压力，压力和细胞 - 细胞接触从外膜到细胞核。信号通路发生变化，通常在恶性或非恶性疾病中发现。来自蛋白质生物化学的知识揭示了与负责此作用的信号蛋白相关的特定功能基序。因此，将这些有缺陷的信号途径用小分子（特定的小肽或肽 - 膜剂）靶向，现在正成为药物发育的积极研究领域，因为肽是人体中一种天然化合物，对副作用的关注较少。为了增加这些药物的治疗指数，我们已经从具有细胞渗透率的独特肽组设计了一个特定于靶标的递送系统。迄今为止，快速发展的纳米技术产生了许多生物相容性纳米载体用于成像和/或治疗应用。在该项目中，设计并合成具有分子成像能力并携带各种治疗剂的树枝状聚合物纳米颗粒具有渗透性肽。该粒子将被测试以定位靶细胞并以实时方式监测肿瘤细胞的药物反应。我们认为，这种实验疗法具有在不久的将来转化为临床应用的巨大潜力，因为所有材料都不希望对人体发出任何明显的毒性。最重要的是，该建议是探索与常规治疗策略相比，探索针对转移性前列腺癌的量身定制分子疗法的新途径，因为前列腺癌已成为美国男性癌症死亡的第二大主要原因。大多数男性死于前列腺癌，是由于转移性疾病尚未受到有效控制。因此，这项研究的成功结果肯定会使该疾病的最终治疗接近一步。这项工作是由一个与大量出版物合作的团队进行的。 Simanek的实验室将使树枝状聚合物为Sun博士提供的螯合剂和HSIEH博士提供的几种肽提供功能性手柄。 Simanek博士的实验室负责将螯合物和肽同时安装到树枝状聚合物上，并在返回DRS之前对所得材料进行表征。 Sun和Hsieh的实验室，用于评估分子成像和治疗的应用。