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 在准备本申请的过程中，研究小组表现出极大的兴趣加入 该联盟通过试点项目。我们将这些项目视为 CCNE 的重要附属项目 使命，并从中产生完整的项目。试点项目还提供了一种机制， 吸引新的研究人员并快速资助最有前途的想法。 02 年之后的新试点项目 将由内部指导委员会与 NCI 项目官员协商后选出。这 以下部分列出了当前试点项目的一些示例： 试点项目 1：用于癌症生物标志物高灵敏度大规模检测的纳米颗粒标签 项目负责人：Scott Manalis 博士，麻省理工学院副教授 部门： 麻省理工学院生物工程 背景 尽管在开发用于治疗癌症的新治疗剂方面取得了进展，但 用于癌症早期检测的分子标记物的开发进展甚微。 前列腺特异抗原 (PSA) 除外，它是 目前用于筛查男性是否患有前列腺癌，大多数 癌症在临床上没有分子标记。一个可能的原因 早期肿瘤非常小，直径通常在 10 毫米以下。这是 显然，此类肿瘤分泌的蛋白质量也将是 小，需要能够检测生物中蛋白质的灵敏测定 浓度为 0.1 -1.0 ng/ml 或更低的液体。 试点项目2：循环肿瘤细胞的微流控分选 项目负责人：Mehmet Toner 博士，HMS 教授；丹尼尔·哈伯 (Daniel Haber) 医学博士，英国皇家医学院教授 部门： NIGH 医学工程中心和 MGH 癌症中心 背景 人类癌症产生少量在脉管系统中循环的细胞。其中一些可能 注定会成为癌症转移的种子部位，而大多数可能无法生存，但只是 反映局部病变部位的微血管侵犯。识别、恢复和研究的能力 这些细胞提供了一种潜在的准确、负担得起、可靠和无创的筛查方法 用于早期诊断和治疗监测的监测工具。越来越多的报道 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起源于原发肿瘤。因此，CTC最终可能 在提供诊断、预后、监测以及遗传方面提供非常有价值的来源 以及有关原发肿瘤的免疫表型信息。 同样重要的是能够使用 CTC 进行癌症靶向治疗，例如非小细胞肺癌 癌症。不幸的是，只有大约百分之十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烈临床反应。我们和其他人最近 证明该亚组患者的表皮生长因子具有特定突变 受体 (EGFR) 基因 (2-3)。因此，筛查肺癌中的 EGFR 突变可能会发现 对特定治疗有反应的患者。为此，重要的是开发一个 无创血液检测，例如从患者血液中无创分离 CTC 诊断患有肺癌。此外，对这些患者的 CTC 数量进行监测 EGFR 突变可能提供有关治疗效果的宝贵信息 酪氨酸激酶抑制剂。使用 CTC 筛选人群、监测治疗、预测的能力 复发，并结合新的治疗方法确定患者亚群以进行靶向治疗 分子技术可能会在提高癌症生存率方面取得重大进展。 试点项目 3：转移性癌症纳米模型 项目负责人：Sridhar Ramaswamy，博士，HMS 助理教授 科室：麻省总医院癌症中心、布罗德研究所 背景 转移是癌症相关死亡的主要原因，但对其分子基础知之甚少。作为 因此，目前的癌症药物开发方法 并未导致大多数晚期实体瘤患者的生存率增加 肿瘤 (1).转移主要是由于以下因素的相互作用造成的 获得性突变、表观遗传调控和遗传 (2)。 顺式和分子中高度复杂的细胞和分子相互作用 反式- 可能导致转移性癌症的临床特征 使其特别难以治疗；即肿瘤生长在 远处部位和对化疗的耐药性。这些互动， 然而，很难进行全面的功能检查 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）在很多方面都受到限制 包括低通量、高成本、低遗传复杂性，以及 与人类疾病的关系尚不清楚。体外建模 转移，通常仅限于癌细胞侵袭和迁移 检测虽然相对便宜且高通量，但不 充分概括了细胞和分子的复杂性 人类体内肿瘤。我们的目标是开发下一代 利用纳米技术新发展的体外癌症模型 更忠实地模仿转移人类的复杂性 肿瘤。我们的长期目标是利用这些系统来筛选 抑制限速步骤的小分子化合物 癌症转移：远处转移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背景 (4)。我们 假设成功的终末器官定植源于 癌细胞（具有特定突变）和 靶标中的宿主细胞（具有特定的遗传和表观遗传特征） 组织。我们正在实验性地探索广泛的 通过不同系统的共文化进行这种互动 人类癌细胞系（突变）与正常组 来自不同患者（遗传学）和器官的成纤维细胞 （表观遗传学）。这些二维共培养虽然很粗糙，但初步 证明癌细胞与不同的细胞之间的相互作用 成纤维细胞群可导致抑制、增强或无效 对体外癌症增殖的影响（图1）。这些结果 表明模拟多细胞的体外癌症模型 与单细胞相比，相互作用将产生对人类癌细胞行为截然不同的看法 模型，并且此类实验系统可以更准确地模拟体外肿瘤生物学。 试点项目4：用于细胞操纵的混合集成电路/微流控芯片 项目负责人：Robert Westervelt 博士，哈佛大学教授；韩东熙博士 哈佛大学助理教授 院系： 哈佛大学工程与应用科学部 背景 使用空间图案的磁场和电场来操纵生物系统是一种 重要的工具。传统方法使用相对简单的方法来产生电磁 领域，限制了其应用范围。 试点项目 5：利用表面在单分子水平上进行超灵敏化学探测 金纳米颗粒局部光场的增强拉曼散射 项目负责人：Katrin Kneipp 博士，哈佛大学副教授 科室： 麻省总医院韦尔曼光医学中心 背景 目前，癌症的早期阶段都被忽视了。针对这种情况，本次活动的目的 该项目旨在探索和开发一种基于超灵敏分子结构的新方法 活细胞内部的探测和成像，以发现细胞发育过程中的变化 癌症。该方法还具有监测细胞“化学”反应的潜在能力。 治疗和干预。 所应用的方法利用了表面增强拉曼散射（SERS）现象，其中 拉曼散射发生在银和金纳米结构的局部光场中，从而产生 拉曼信号增加高达 14 个数量级。这允许分子结构信息 来自单分子和纳米级体积。 试点项目 6：用于靶向、肿瘤选择性的功能化线性树枝状二嵌段共聚物 核酸递送 项目负责人：Paula Hammond 博士、M. Hyman 麻省理工学院副教授；戴恩·维特鲁普 (Dane Wittrup)，博士，J. 麻省理工学院马雷斯教授 部门： 麻省理工学院化学工程与生物工程 背景 基于核苷酸的疗法在临床医学中的应用具有彻底变革的潜力 人类疾病的治疗。基因治疗的成功取决于传递的能力 在需要的时间和地点表达关键蛋白质的基因。为了应对这一挑战， 已经开发了一系列病毒和非病毒递送系统。 最有前途的交付方法之一涉及使用 阳离子聚合物，以及一系列线性、支化和树枝状聚合物 已被探索，包括聚（b-氨基酯）、聚（乙烯亚胺）、 和聚(酰氨基胺)。与病毒传递系统不同， 通常具有高度免疫原性，容易发生插入突变，并且 难以重复给药、非病毒（聚合）递送 尽管可以合成具有低免疫原性和毒性的系统 它们经常遭受细胞毒性、组织靶向性差、快速 从循环中清除，表达效率低 (1-2)。 试点项目 7：用于癌症中 siRNA 递送的靶向纳米颗粒 项目负责人：Clark Cotton 博士、麻省理工学院教授 部门： 麻省理工学院化学工程 背景 我们开发了新型纳米粒子，有望将 siRNA 递送至肿瘤细胞。这 纳米粒子由独特的交替共聚物主链组成，主链由亲水性 聚乙二醇 (PEG) 片段和疏水性三官能连接基 以疏水性、亲水性或带电部分封端的疏水性侧链。放置时 在高于其临界胶束浓度的水中，这些两亲性聚合物链中的 8 至 12 个会自 组装成胶束结构，连接体形成球体表面，即 PEG 链 外化为环，疏水侧链内化。通常，胶束具有 分子量约200，流体动力学直径约5nm。当与对比混合时 作为货物封装的药剂或药物，纳米球尺寸增加至 50 nm。在 除了封装货物外，侧链或末端基团可以用共价键取代 绑定代理。这些胶束纳米粒子比其他方法具有优势，因为 1) 小尺寸增强了对肿瘤内细胞的接触，2）它们的化学结构可以轻松修改， 它们是通过直接的化学酶法合成的，更实用且更容易。 比纯化学合成所需的复杂保护-脱保护方案更经济 此类结构，以及3）单个平台可以容纳各种绑定或封装的 可用于改善肿瘤细胞成像和向肿瘤细胞递送药物的试剂。我们目前 研究不同的肿瘤靶向肽（例如由 Ruoslahti（项目 2）或 Weissleder 小组（项目 5））。肽与 PEG 的游离羟基端基结合。作为 结果，大量纳米颗粒被肿瘤细胞迅速选择性地吸收。 试点项目 8：纳米线、纳米激光作为高分辨率细胞成像的光学探针 操纵 项目负责人：黄宇 博士 部门： 麻省理工学院材料科学与工程/LLNL 背景 纳米技术可以使许多独特的工具 以前所未有的分子探针/图像生物系统 水平并揭示新现象。例如，扫描 近场光学显微镜（SNOM）是一种有趣的技术 用于生物可视化的生物物理学技术 对象，例如细胞膜，具有高空间分辨率。 该技术代表了一种强大的方法来实现高 结合地形的生物物种分辨率成像 具有光学荧光或光传输的信息 成像。然而，金属涂层探头的局限性在于 有几种方法。首先，只有一小部分（100 nm <0.01%） 尖端）耦合到光纤的光由 由于传播的截止而产生的孔径 波导模式。低光通量和有限的 金属的集肤深度是分辨率的限制因素。 许多应用程序需要的空间分辨率不是 可以通过孔径技术获得。此外， 孔径技术还有其他实际复杂性：(1) 难以获得纳米级光滑的金属涂层 这也导致了探针制造的不可重复性 作为测量； (2)金属对光的吸收 涂层会导致显着发热并造成问题 生物学应用。为了解决这些问题，重大 一直致力于寻找替代探针 例如无孔探头，包括金属探头或 荧光活性探针。他们代表着令人兴奋的新事物 方向，但经常遭受低信噪比的影响 到低光强度。