PILOT STUDIES

试点研究

• 批准号: 7918222
• 负责人: ROBERT Samuel LANGER
• 金额: $ 22.66万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7918222
• 关键词: 3-Dimensional; Address; Adhesions; Advanced Malignant Neoplasm; Affinity; Aging; Allografting; Amino Acids; Ammonium; Animal Model; Animals; Antibodies; Antineoplastic Agents; Apoptotic; Applied Research; Arginine; Aspartate; Autologous Transplantation; Avidin; Aziridines; Behavior; Benchmarking; Binding; Biocompatible; Biological; Biological Assay; Biological Markers; Biomedical Engineering; Biophysics; Biopsy; Blinded; Blood; Blood Circulation; Blood Tests; Cadaver; Caliber; Cancer Cell Growth; Cancer Center; Cancer Detection; Cancer Etiology; Cancer Model; Cancer Patient; Cancer cell line; Carcinoembryonic Antigen; Cell Communication; Cell Count; Cell Culture Techniques; Cell Density; Cell Line; Cell Proliferation; Cell Separation; Cell Size; Cells; Cellular Membrane; Cessation of life; Charge; Chemical Engineering; Chemical Structure; Chemicals; Chemistry; Classification; Clinical; Clinical Medicine; Coculture Techniques; Collagen; Complement; Complex; Computers; Consultations; 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Viral; Water; Whole Blood; Work; Xenograft procedure; absorption; aged; base; biological systems; biomaterial compatibility; c-erbB-1 Proto-Oncogenes; cancer cell; cancer therapy; cantilever; cell behavior; cellular imaging; chemical synthesis; chemotherapy; clinical material; clinically relevant; copolymer; cost; cytotoxicity; density; design; di-block copolymer; drug development; drug efficacy; efficacy testing; electric field; fluid flow; gene delivery system; gene therapy; genetic analysis; human cancer mouse model; human disease; imaging probe; immunogenic; immunogenicity; improved; in vitro Model; in vivo; interest; light intensity; light transmission; magnetic beads; magnetic field; melanoma; men; metal oxide; molecular marker; monolayer; mutant; nano; nanoengineering; nanofiber; nanometer; nanoparticle; nanoscale; nanosurgery; nanowire; neoplastic cell; next generation; novel; novel strategies; novel therapeutics; professor; prognostic; programs; receptor-mediated signaling; repository; research study; response; sarcoma; scaffold; self assembly; single molecule; small molecule; success; surface coating; tool; tumor; tumor growth; tumor progression; uptake; voltage

PILOT PROJECTS During the preparation of this application, there has been a tremendous interest by research groups to join the consortium through pilot projects. We view these projects as an important adjunct of the CCNE's mission and from which full projects can emerge. The pilot projects also provide a mechanism by which to attract new researchers and to rapidly fund the most promising ideas. New pilot projects beyond year 02 will be chosen by the internal steering committee in consultation with the NCI program officer. The following section lists some of the current examples of pilot projects: Pilot project 1: Nanoparticle labels for high-sensitivity mass detection of cancer biomarkers Project Leader: Scott Manalis Ph.D, Associate Professor, MIT Department: Biological Engineering, MIT Background Despite progress in the development of new therapeutic agents for the treatment of cancer, there has been very little progress in the development of molecular markers for the early detection of cancer. With the exception of the Prostate Specific Antigen (PSA) which is currently used to screen men for the presence of prostate cancer, most cancers have no molecular marker in clinical use. One possible reason is that early tumors are quite small, often under 10 mm in diameter. It is clear that the amount of protein secreted by such tumors will be also be small, requiring sensitive assays able to detect proteins in biological fluids at concentrations of 0.1 -1.0 ng/ml or less. Pilot project 2: Microfluidic Sorting of Circulating Tumor Cells Project Leader: Mehmet Toner, Ph.D., Professor HMS; Daniel Haber M.D, Professor, HMS Departments: NIGH Center for Engineering in Medicine and MGH Cancer Center Background Human cancers generate small numbers of cells that circulate in the vasculature. Some of these may be destined to seed sites of cancer metastasis, while the majority may not be viable but simply reflecting microvascular invasion at local sites of disease. The ability to identify, recover and study these cells offers a potentially accurate, affordable, reliable, and noninvasive screening and surveillance tool for early diagnosis and treatment monitoring. There are a growing number of reports on the isolation and characterization of CTC in cancer patients before the primary tumor is detected (1). There is also evidence that CTC are originated from the primary tumor. Thus, CTC may ultimately provide to be a very valuable source in providing diagnostic, prognostic, monitoring, as well as genetic and immunophenotypic information about the primary tumor. Equally important is the ability to use CTC for targeted therapies in cancer, such as non-small-cell lung cancer. Unfortunately, only about ten percent of patients with non-small-cell lung carcinoma have a robust clinical response to the tyrosine kinase inhibitor gefitinib. We and others have recently demonstrated that this subgroup of patients has specific mutations in the epidermal growth factor receptor (EGFR) gene (2-3). Thus, screening for EGFR mutations in lung cancers may identify patients who will have a response to a specific treatment. To this end, it is important to develop a noninvasive blood test such as the noninvasive isolation of CTC from blood of patients already diagnosed with lung cancer. Furthermore, the monitoring of the number of CTC of those patients with the EGFR mutation may provide invaluable information about the efficacy of the treatment with the tyrosine kinase inhibitor. The ability to use CTC to screen populations, to monitor therapies, to predict recurrence, and to identify patient subpopulations for targeted therapies, in combination with new molecular techniques, will likely result in significant progress toward improving survival rates in cancer. Pilot project 3: Nanomodels of Metastatic Cancer Project Leader: Sridhar Ramaswamy, Ph.D., Assistant Professor, HMS Department: MGH Cancer Center, Broad Institute Background Metastasis is the major cause of cancer-related deaths, but its molecular basis is poorly understood. As a result, current approaches to cancer drug development have not led to increased survival for most patients with advanced solid tumors (1). Metastasis mostly results from the interplay of acquired mutation, epigenetic regulation, and inheritance (2). Highly complex cellular and molecular interactions in cis- and trans- likely cause the clinical features of metastatic cancer that make it particularly difficult to treat; namely, tumor growth at distant sites and resistance to chemotherapy. These interactions, however, are difficult to functionally examine in a comprehensive way using traditional approaches. This hinders the development of effective chemotherapy for advanced cancer (3). Animal models of metastasis (autograft, allograft, xenograft, or genetically-engineered), for example, are limited in many ways including low-throughput, high cost, low-genetic complexity, and unclear relation to human disease. In vitro modeling of metastasis, usually limited to cancer cell invasion and migration assays, while relatively inexpensive and high-throughput, do not adequately recapitulate the cellular and molecular complexity of human tumors in vivo. Our aim is to develop next-generation in vitro cancer models using new developments in nanotechnology to more faithfully mimic the complexity of metastatic human tumors. Our long-term goal is to use these systems to screen for small-molecule compounds that inhibit the rate-limiting step in cancer metastasis: survival and growth of metastatic cancer cells at distant sites. Cancer cell behavior is highly dependent on micro-environmental cues and context (4). We hypothesize that successful end-organ colonization results from interactions between cancer cells (with particular mutations) and host cells (with specific genetic and epigenetic features) in target tissues. We are experimentally exploring a wide spectrum of such interactions through the systematic co-culture of different human cancer cell lines (mutations) with panels of normal fibroblasts from different patients (genetics) and organs (epigenetics). These 2-D co-cultures, albeit crude, preliminarily demonstrate that interactions of a cancer cell with different fibroblast populations can result in inhibitory, enhancing, or null effects on in vitro cancer proliferation (Figure 1). These results suggest that in vitro cancer models that mimic multi-cellular interactions will yield very different views of human cancer cell behavior compared with unicellular models, and that such experimental systems might more accurately model tumor biology in vitro. Pilot project 4: Hybrid Integrated Circuit / Microfluidic chips for the manipulation of cells Project Leaders: Robert Westervelt Ph.D, Professor Harvard University; Donhee Ham, Ph.D. Assistant Professor, Harvard Department: Division of Engineering and Applied Sciences, Harvard University Background The manipulation of biological systems using spatially patterned magnetic and electric fields is an important tool. Conventional approaches use relatively simple methods to create the electromagnetic fields, limiting the range of their applications. Pilot project 5: Ultrasensitive chemical probing at the single molecule level using surface enhanced Raman scattering in local optical fields of gold nanoparticles Project Leaders: Katrin Kneipp Ph.D, Associate Professor, Harvard Department: Wellman Center for Photomedicine, MGH Background Cancer is currently being missed at its earliest stages. With regard to this situation , the objective of this project is to explore and to develop a novel method based on ultrasensitive molecular structural probing and imaging inside living cells for the discovery of cellular changes during the development of cancer. The method has also the potential capability to monitor the "chemical" response of ceils to therapy and interventions. The applied approach exploits the phenomenon of surface enhanced Raman scattering (SERS), where Raman scattering takes place in the local optical fields of silver and gold nanostructures resulting in the increase of Raman signals up to 14 orders of magnitude. This allows molecular structural information from single molecules and from nanometer scaled volumes. Pilot project 6: Functionalized linear-Dendritic Diblock Copolymers for Targeted, Tumor-Selective Nucleic Acid Delivery Project Leaders: Paula Hammond Ph.D, M. Hyman Associate Professor MIT; Dane Wittrup, PhD, J. Mares Professor MIT Department: Chemical Engineering and Bioengineering, MIT Background The application of nucleotide-based therapeutics in clinical medicine has the potential to revolutionize the treatment of human disease. The success of gene therapy is dependent upon the ability to deliver genes that express key proteins when and where they are needed. To address this challenge, a spectrum of viral and non-viral delivery systems has been developed. One of the most promising delivery approaches involves the use of cationic polymers, and a range of linear, branched, and dendritic polymers have been explored, including poly (b-amino esters), poly (ethylenimines), and poly (amidoamines), respectively. Unlike viral delivery systems, which are often highly immunogenic, prone to insertional mutagenesis, and refractory to repeated administrations, non-viral (polymeric) delivery systems can be synthesized with low immunogenicity and toxicity, though they frequently suffer from cytotoxicity, poor tissue targeting, rapid clearance from circulation, and low expression efficiency (1-2). Pilot project 7: Targeted Nanoparticles for siRNA Delivery in Cancer Project Leader: Clark Cotton Ph.D, Professor, MIT Department: Chemical Engineering, MIT Background We have developed novel nanoparticles that have promise for siRNA delivery to tumor cells. The nanoparticles are composed of a unique alternating copolymer backbone consisting of hydrophilic polyethylene glycol (PEG) segments and hydrophobic trifunctional linkers to which are bound hydrophobic side chains terminated with hydrophobic, hydrophilic, or charged moieties. When placed into water above its critical micelle concentration, 8 to 12 of these amphiphilic polymer chains self assemble into a micelle structure with the linker forming the surface of a sphere, the PEG chains externalized as loops and the hydrophobic side chains internalized. Typically the micelles have a molecular weight about 200 and a hydrodynamic diameter about 5 nm. When mixed with contrast agents or drugs that are encapsulated as cargo, nanosphere size increases to as much as 50 nm. In addition to encapsulation of cargo, the side chain or terminal group can be replaced with a covalently bound agent. These micelle nanoparticles have advantages over other approaches because 1) their small size enhances access to cells within a tumor, 2) their chemical structure can be easily modified, and they are synthesized by a straight forward chemo-enzymatic method that is more practical and economical than the complex protection-deprotection schemes needed for purely chemical synthesis of such structures, and 3) a single platform can accommodate a wide variety of bound or encapsulated agents useful for improved imaging of tumor cells and drug delivery to tumor cells. We are currently investigating different tumor targeting peptides (e.g. those developed by Ruoslahti (Project 2) or the Weissleder group (Project 5)). The peptides are bound to the free hydroxyl end groups of the PEG. As a consequence, large numbers of the nanoparticles are rapidly taken up selectively by tumor cells. Pilot project 8: Nanowire, nanolaser as optical probe for high resolution cellular imaging and manipulation Project Leaders: Yu Huang, PhD Department: MIT Material Science and Engineering/LLNL Backqround Nanotechnology can enable many unique tools to probe/image biosystems at an unprecedented molecular level and reveal new phenomena. For example, scanning near-field optical microscopy (SNOM) is an interesting technique in biophysics for the visualization of biological objects, e.g. cellular membrane, with high spatial resolution. This technique represents a powerful approach for high resolution imaging of bio-species by combining topographic information with optical fluorescence or light transmission imaging. However, the metallic coated probe is limited in several ways. First, only a tiny fraction (<0.01% for 100 nm tip) of the light coupled into the fiber is emitted by the aperture because of the cutoff of propagation of the waveguide modes. The low light throughput and the finite skin depth of the metal are the limiting factors for resolution. Many applications require spatial resolutions that are not obtainable with the aperture technique. Moreover, the aperture technique has other practical complications: (1) it is difficult to obtain a smooth metal coating on nano scale which introduces irreproducibility in probe fabrication, as well as measurements; (2) the absorption of light in the metal coating causes significant heating and poses a problem for biological applications. To address these issues, significant efforts have been devoted to searching for alternative probes such as aperture-less probe including metallic probes or fluorescence active probes. They represent exciting new directions, but often suffer from low signal-to-noise ratio due to low light intensity.

试点项目 在准备此应用程序期间，研究小组有很大的兴趣加入 通过试点项目的财团。我们将这些项目视为CCNE的重要辅助 任务并从中可以从中出现完整的项目。飞行员项目还提供了一种机制 吸引新的研究人员，并迅速为最有希望的想法提供资金。超过02年的新试点项目 内部指导委员会将与NCI计划官员协商。这 以下部分列出了试点项目的一些当前示例： 试点项目1：用于癌症生物标志物高敏性质量检测的纳米颗粒标签 项目负责人：麻省理工学院副教授Scott Manalis Ph.D 部门：麻省理工学院生物工程 背景 尽管开发了新的治疗剂治疗癌症，但仍有 在癌症早期发现分子标记的发展方面，几乎没有进展。 除前列腺特异性抗原（PSA）外 目前用来筛查男性的前列腺癌，大多数 癌症在临床用途中没有分子标记。一个可能的原因 是早期肿瘤很小，通常直径为10毫米。这是 清楚地表明，这种肿瘤分泌的蛋白质也将是 小，需要能够检测生物学中蛋白质的敏感测定 浓度为0.1 -1.0 ng/ml或更少的流体。 试点项目2：循环肿瘤细胞的微流体分选 项目负责人：Mehmet Toner博士，HMS教授； HMS教授Daniel Haber M.D 部门：医学和MGH癌症中心的工程中心 背景 人类癌症会产生少量的脉管系统循环的细胞。其中一些可能 注定要进入癌症转移的种子部位，而大多数可能不可行，而是简单 反映疾病当地部位的微血管入侵。识别，恢复和学习的能力 这些细胞提供了潜在的准确，负担得起，可靠和无创筛查，并且 用于早期诊断和治疗监测的监视工具。越来越多的报告 关于在检测到原发性肿瘤之前癌症患者中CTC的分离和表征（1）。 也有证据表明CTC起源于原发性肿瘤。因此，CTC可能最终 提供提供诊断，预后，监测以及遗传的非常有价值的来源 以及有关原发性肿瘤的免疫表型信息。 同样重要的是能够将CTC用于癌症的靶向疗法，例如非小细胞肺 癌症。不幸的是，只有大约10％的非小细胞肺癌患者患有 对酪氨酸激酶抑制剂吉非替尼的强大临床反应。我们和其他人最近有 证明该亚组患者在表皮生长因子中具有特定的突变 受体（EGFR）基因（2-3）。因此，筛查肺癌中的EGFR突变可能会识别 对特定治疗的反应的患者。为此，建立一个 非侵入性血液测试，例如已经从患者血液中脱离CTC的非侵袭性分离 被诊断为肺癌。此外，监测那些患者的CTC数量 EGFR突变可能会提供有关治疗功效的宝贵信息 酪氨酸激酶抑制剂。使用CTC筛选种群，监测疗法，预测的能力 复发，并确定靶向疗法的患者亚群，结合新的 分子技术可能会导致在提高癌症存活率方面取得重大进展。 试点项目3：转移性癌的纳米模型 项目负责人：Sridhar Ramaswamy博士，HMS助理教授 部门：Broad Institute MGH癌症中心 背景 转移是癌症相关死亡的主要原因，但其分子基础知之甚少。作为 结果，目前的癌症药物开发方法具有 大多数晚期固体患者的生存率不会增加 肿瘤（1）。转移主要是由 获得的突变，表观遗传调节和遗传（2）。 顺式和分子相互作用高度复杂 转移可能引起转移性癌的临床特征， 使治疗特别困难；即肿瘤生长 遥远的部位和对化学疗法的抵抗力。这些互动， 但是，很难在全面检查功能 使用传统方法的方式。这阻碍了发展 晚期癌症的有效化疗（3）。动物 转移模型（自体移植，同种异体移植，异种移植或 例如，基因工程）在许多方面受到限制 包括低通量，高成本，低遗传复杂性和 与人类疾病的关系不清楚。体外建模 转移，通常仅限于癌细胞侵袭和迁移 测定虽然相对便宜且高通量，但不要 充分概括了细胞和分子复杂性 体内人类肿瘤。我们的目的是发展下一代 使用纳米技术的新发展的体外癌症模型 更忠实地模仿转移性人的复杂性 肿瘤。我们的长期目标是使用这些系统筛选 小分子化合物抑制限速步骤 癌症转移：遥远部位转移性癌细胞的存活和生长。 癌细胞行为高度依赖于微环境线索和上下文（4）。我们 假设成功的最终器官定植是由 癌细胞之间的相互作用（特定突变）和 靶标的宿主细胞（具有特定的遗传和表观特征） 组织。我们正在实验探索广泛的范围 通过不同的共同文化的这种相互作用 与正常面板的人类癌细胞系（突变） 来自不同患者（遗传学）和器官的成纤维细胞 （表观遗传学）。这些2-D的共同培养，尽管是原油 证明癌细胞与不同的相互作用 成纤维细胞种群可能导致抑制，增强或无效 对体外癌症增殖的影响（图1）。这些结果 建议在体外癌症模型中模仿多细胞 与单细胞相比 模型，这种实验系统可能会在体外更准确地对肿瘤生物学进行建模。 试点项目4：混合整合电路 /微流体芯片用于操纵细胞 项目负责人：哈佛大学教授罗伯特·韦斯特维尔特（Robert Westervelt Ph.D）； Donhee Ham博士 哈佛大学助理教授 部门：哈佛大学工程和应用科学系 背景 使用空间图案的磁场和电场对生物系统进行操作是一种 重要工具。传统方法使用相对简单的方法来创建电磁 字段，限制其应用程序的范围。 试点项目5：使用表面在单分子水平上进行超敏化化学探测 金纳米颗粒的局部光场中的拉曼散射增强 项目负责人：哈佛大学副教授Katrin Kneipp Ph.D 部门：MGH摄影医学中心 背景 目前在其最早的阶段被错过了癌症。关于这种情况，目的 项目是探索和开发基于超敏分子结构的新方法 在活细胞内部探测和成像，以发现在开发过程中发现细胞变化 癌症。该方法还具有监视天花板对“化学”响应的潜在能力 治疗和干预措施。 应用的方法利用了表面增强的拉曼散射（SER）的现象，其中 拉曼散射发生在当地的银和金纳米结构的光场中，导致 拉曼信号的增加最多14个数量级。这允许分子结构信息 来自单分子和纳米尺度的体积。 试点项目6：靶向肿瘤选择性的官能化线性树枝状二嵌段共聚物 核酸递送 项目负责人：Paula Hammond Ph.D，M。Hyman副教授MIT； Dane Wittrup，博士，J。 母马教授麻省理工学院 部门：麻省理工学院化学工程和生物工程 背景 基于核苷酸的疗法在临床医学中的应用有可能革新 人类疾病的治疗。基因疗法的成功取决于交付的能力 表达关键蛋白的基因在需要的时间和地点。为了应对这一挑战， 已经开发了病毒和非病毒输送系统的光谱。 最有希望的交付方法之一是使用 阳离子聚合物以及一系列线性，分支和树突聚合物 已经探索了包括聚（B-氨基酯），聚（乙基亚胺）， 和聚（胺）分别。与病毒输送系统不同， 通常是高度免疫原性的，容易插入诱变，并且 对重复管理，非病毒（聚合物）交付的难治性 系统可以与低免疫原性和毒性合成，但是 他们经常患有细胞毒性，组织靶向差，快速 循环清除和低表达效率（1-2）。 试点项目7：针对癌症中siRNA递送的靶向纳米颗粒 项目负责人：MIT教授Clark Cotton Ph.D 部门：麻省理工学院化学工程 背景 我们已经开发了新型的纳米颗粒，这些纳米颗粒有望向肿瘤细胞递送siRNA。这 纳米颗粒由由亲水性组成的独特交替共聚物主链组成 聚乙烯乙二醇（PEG）段和疏水三功能连接器与之结合 疏水侧链，终止于疏水，亲水或带电的部分。放置时 进入其临界胶束浓度以上的水，其中8至12个两亲聚合物链自我 组装成胶束结构，接头形成球的表面，钉链 外部为环和疏水侧链内部化。通常，胶束有一个 分子量约200，流体动力直径约5 nm。当与对比混合时 封装为货物的药物或药物，纳米球大小增加到多达50 nm。在 除了货物的封装外，侧链或终端组可以共价替换 约束代理。这些胶束纳米颗粒比其他方法具有优势，因为1） 小尺寸可增强肿瘤内进入细胞的访问，2）可以轻松修饰其化学结构， 它们是通过直接的化学酶方法合成的，该方法更实用，并且 比纯粹的化学合成所需的复杂的保护侵占方案 这样的结构和3）单个平台可以容纳多种绑定或封装 药物可用于改善肿瘤细胞成像和药物输送到肿瘤细胞的成像。我们目前 研究靶向肽的不同肿瘤（例如，Ruoslahti（项目2）或 Weissleder Group（项目5））。肽与PEG的游离羟基末端组结合。作为 结果是，大量纳米颗粒被肿瘤细胞选择迅速吸收。 试点项目8：纳米线，纳米剂作为高分辨率蜂窝成像的光学探针和 操纵 项目领导者：Yu Huang，博士 部门：麻省理工学院材料科学与工程/LLNL 后方 纳米技术可以使许多独特的工具能够 探针/图像生物系统在前所未有的分子 水平并揭示新现象。例如，扫描 近场光学显微镜（SNOM）很有趣 生物物理学的技术可视化生物学 对象，例如细胞膜，具有高空间分辨率。 该技术代表了高度的强大方法 通过结合地形来对生物种类的分辨率成像 具有光荧光或光传输的信息 成像。但是，金属涂层探针在 几种方式。首先，只有很小的分数（100 nm的0.01％ 尖端）耦合到纤维中的尖端是由 孔，是因为传播的临界值 波导模式。低光吞吐量和有限的 金属的皮肤深度是解决的限制因素。 许多应用需要空间决议 可以使用光圈技术获得。而且， 孔技术还有其他实际并发症：（1）是 难以在纳米尺度上获得光滑的金属涂层 这也引入了探针制造中的不可重复性 作为测量； （2）金属中的光吸收 涂层会引起大量加热，并提出问题 生物应用。为了解决这些问题，重大 努力一直致力于寻找替代探针 例如包括金属探针或 荧光活性探针。他们代表令人兴奋的新 方向，但经常遭受低信噪比的影响 低光强度。