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）：在本项目中，我们提出开发一种基于树状聚合物纳米技术的新型药物递送载体，用于个性化医疗。这种新型纳米粒子包含成像探针和具有癌症特异性靶向能力的分子药物，能够靶向癌细胞，监测药物递送和肿瘤反应，实现“看和治疗”策略，作为分子医学的新概念。这种纳米颗粒平台将非常灵活地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逐步构建信号级联，这些信号级联追踪细胞外刺激的作用路径，包括可溶性生长因子，激素，基质，应激和细胞-细胞接触，从外膜一直到细胞核。改变的信号通路通常在恶性或非恶性疾病中发现。蛋白质生物化学知识揭示了与负责这一作用的信号蛋白相关的特定功能基序。因此，用小分子，特别是小肽或肽记忆体靶向这些有缺陷的信号通路，现在正成为药物开发的活跃研究领域，因为肽是人体内的天然化合物，副作用较少。为了提高这些药物的治疗指数，我们从一组具有细胞渗透性的独特肽中设计了一种靶向特异性递送系统。迄今为止，快速发展的纳米技术已经产生了许多生物相容性纳米载体用于成像和/或治疗应用。在本项目中，设计并合成了一种配备细胞特异性细胞渗透肽的树枝状聚合物纳米颗粒，具有分子成像能力并携带各种治疗药物。该粒子将被测试用于定位靶细胞并以实时方式监测肿瘤细胞的药物反应。我们相信，这种实验性疗法具有很大的潜力，在不久的将来转化为临床应用，因为所有的材料都不会对人体产生任何显着的毒性。最重要的是，该建议是探索一种新的途径，定制的分子治疗转移性前列腺癌相比，传统的治疗策略，因为前列腺癌已成为美国男性癌症死亡的第二大原因。大多数死于前列腺癌的男性是由于转移性疾病没有得到有效控制。因此，这项研究的成功结果必将使这种疾病的最终治愈更近一步。这项工作是由一个团队进行的，该团队与许多出版物进行了富有成效的合作。Simanek的实验室将为Sun博士提供的螯合剂和Hsieh博士提供的几种肽制造带有功能手柄的树枝状聚合物。Simanek博士的实验室负责将螯合物和肽安装到树枝状聚合物上，并在返回Sun博士和Hsieh博士的实验室评估分子成像和治疗的应用之前对所得材料进行表征。