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: 8092399
• 负责人: Jer-Tsong Hsieh
• 金额: $ 33.76万
• 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/8092399
• 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. PUBLIC HEALTH RELEVANCE: Today, nanotechnology has produced many unique drug delivery platforms that can be integrated into a "theranostic" agent. Non-invasive molecular imaging techniques have advantages over anatomic imaging techniques to better define the location and extent of disease and to better assess the response of target tissue or organ to drugs in a real-time manner. By teaming up experts from various areas, the goal of this project is to invent mechanism-specific targeting agents using dendrimer then test their translational ability into future clinical application, which has many potentials to spin off a new biotechnology entity and further revolutionize current cancer therapy.

描述（由申请人提供）：在该项目中，我们提出开发一种基于树枝状大分子纳米技术的新型药物递送载体，用于个性化医疗。这种新型纳米粒子含有成像探针和分子医学，具有癌症特异性靶向能力，能够靶向癌细胞，监测药物输送和肿瘤反应，实现“即见即治”的分子医学新概念。该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。分子医学最令人兴奋的发展之一是逐步构建信号级联，全程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、应激和细胞间接触从外膜到细胞核。信号通路的改变经常出现在恶性或非恶性疾病中。蛋白质生物化学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，用小分子，特别是小肽或肽模因靶向这些有缺陷的信号通路，现在正成为药物开发的一个活跃研究领域，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，我们设计了一种由一组独特的具有细胞渗透性的肽组成的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用于成像和/或治疗应用的生物相容性纳米载体。在该项目中，设计并合成了配备有细胞特异性细胞渗透性肽的树枝状聚合物纳米颗粒，其具有分子成像功能并携带各种治疗剂。该颗粒将用于定位靶细胞并实时监测肿瘤细胞的药物反应。我们相信，这种实验疗法在不久的将来具有转化为临床应用的巨大潜力，因为所有材料预计不会对人体产生任何明显的毒性。最重要的是，由于前列腺癌已成为美国男性癌症死亡的第二大原因，该提案旨在探索一种与传统治疗策略不同的针对转移性前列腺癌的定制分子治疗的新途径。大多数男性死于前列腺癌是由于转移性疾病未得到有效控制。因此，这项研究的成功结果必将为该疾病的最终治愈迈出一步。这项工作是由一个与许多出版物进行高效合作的团队完成的。 Simanek 的实验室将制造带有孙博士提供的螯合剂和谢博士提供的几种肽的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 Drs 之前对所得材料进行表征。孙和谢的实验室用于评估分子成像和治疗的应用。 公共健康相关性：如今，纳米技术已经产生了许多独特的药物输送平台，可以集成到“治疗诊断”剂中。非侵入性分子成像技术比解剖成像技术具有优势，可以更好地确定疾病的位置和范围，并更好地实时评估靶组织或器官对药物的反应。通过联合来自不同领域的专家，该项目的目标是使用树枝状聚合物发明机制特异性靶向剂，然后测试其在未来临床应用中的转化能力，这有可能衍生出新的生物技术实体并进一步彻底改变当前的癌症治疗。