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Renally Excreted Multimodal Core-Shell Silica Nanoparticles as Tumor-Selective Ra

肾排泄多峰核壳二氧化硅纳米颗粒作为肿瘤选择性 Ra

基本信息

批准号：
9084475
负责人：
Michelle S Bradbury
金额：
$ 49.31万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-12 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9084475
关键词：
Architecture Arginine Aspartic Acid Autoradiography Binding Biological Biological Assay Biological Availability Blood Circulation Caliber Cancer Center Cancer Diagnostics Cell Line Cells Chemicals Chemistry Clinic Clinical Clinical Trials Detection Diagnosis Disease Dyes Flow Cytometry Fluorescence Fluorescence Microscopy Fluorescence Spectroscopy Formulation Future Galactose Generations Glycine Goals Human Hybrids In Vitro Individual Institutes Institutional Review Boards Investigation Investigational Drugs Investigational New Drug Application Iodine Kinetics Label Length Ligand Binding Ligands Luciferases Malignant Neoplasms Measurement Melanocyte stimulating hormone Melanoma Cell Metastatic Melanoma Modeling Molecular Monitor Mus Nanotechnology New Drug Approvals New York Normal tissue morphology Optics Organ Outcome Particle Size Patients Peptides Performance Phase Polyethylene Glycols Positron-Emission Tomography Procedures Property Protocols documentation Quality Control RGD (sequence)Radiation therapy Radiolabeled Radionuclide therapy Renal clearance function Research Scientist Signal Transduction Silicon Dioxide Source Specificity Spectrum Analysis Staging Surface System Targeted Radiotherapy Technology Therapeutic Therapeutic Agents Therapy trial Time Tissues Toxic effect Tracer Translations Treatment Efficacy Tumor Tissue Tumor Volume Tyrosine United States Universities Ursidae Family Variant anticancer research base cancer diagnosis cancer therapy clinical practice cyanine dye 5 density design digital dosimetry fluorodeoxyglucose positron emission tomography improved in vivo innovation inter-institutional man melanoma nanomedicine nanoparticle novel optical imaging outcome forecast palliative particle peptide drug prognostic protocol development prototype radiotracer receptor receptor binding response success targeted treatment tool translational study treatment planning tumor

项目摘要

DESCRIPTION (provided by applicant): Metastatic melanoma has a very poor prognosis, with a median survival of less than 1 year. There are no satisfactory treatments for most patients; therapies are largely palliative and yield short-term benefit. Significant advances in the rapidly growing field of nanomedicine have the potential to profoundly impact cancer diagnosis and treatment. Multifunctional particle platforms that combine and deliver several functionalities to tumors offer distinct advantages over individual molecules, and are poised to move into clinical practice. By attaching tumor-selective peptides and therapeutic moieties to particle surfaces to create such platforms, cancers may be selectively targeted and treated. Fluorescent core-shell silica nanoparticles are clinically-promising non- toxic "lab-on-a-particle platforms" that demonstrate exceptional per particle brightness and stability, and have successfully integrated multiple functionalities for cancer diagnostics and radiotherapeutics. Tuned to sizes for renal clearance, the particle shows increased receptor binding potency and favorable targeting kinetics after small peptide ligands and radiolabels are attached to its surface to create a combined PET-optical probe. As such, it represents the only renally excretable, inorganic, PET-optical probe that simultaneously targets tumors in vivo without attendant toxicity issues. In addition to size considerations, optimal in vivo performance dictates that particle surface chemistry be well-controlled and reproducible. This requires collectively tailoring the number of peptide ligands and polyethylene glycol (PEG) chain lengths and grafting densities on particle surfaces to achieve favorable targeting and clearance profiles. For inorganic nanoparticles, it is not known how surface chemistry variations modulate biological properties. The long-term objective of this proposal is to develop and implement good surface designs for our FDA IND approved ~7-nm diameter core-shell silica nanoparticle architectures for detection, staging, and therapy planning of human metastatic melanoma. This proposal aims to: (1) determine the optimal tunable surface chemistry for targeted silica nanoparticles to achieve favorable melanoma receptor binding using variable numbers of cyclic arginine-glycine-aspartic acid-tyrosine (cRGDY) peptides, PEG chain lengths, and grafting densities; (2) investigate whether optimally formulated chemistries established for cRGDY-bound probes can be extended to alternative probes bearing melanoma-specific peptides (1-MSH); (3) assess in vivo tumor-selective accumulations of 124I-cRGDY-PEG- and 124I-1MSH-PEG-dots and feasibility of targeted radionuclide therapy; and (4) perform targeted radiotherapy and 18FDG PET response monitoring of tumors and normal tissues by attaching therapeutic radiolabels. The success of this study will enable the generation of investigational new drug applications for conducting future Phase I/II clinical trials in metastatic melanoma patients, offering the potential for wider application to other receptor-bearing malignancies. The efficiency of probe translation to the clinic may additionally be improved based upon the establishment of generalized templates for small ligand targeting platforms.

描述（由申请人提供）：转移性黑色素瘤预后非常差，中位生存期不到1年。大多数患者没有满意的治疗方法；治疗在很大程度上是姑息性的，并产生短期效益。快速发展的纳米医学领域的重大进展有可能深刻影响癌症的诊断和治疗。多功能粒子平台结合并向肿瘤提供多种功能，比单个分子具有明显的优势，并准备进入临床实践。通过将肿瘤选择性肽和治疗部分附着在颗粒表面来创建这样的平台，癌症可能被选择性地靶向和治疗。荧光核壳二氧化硅纳米颗粒是一种具有临床前景的无毒“颗粒实验室平台”，它展示了卓越的每颗粒亮度和稳定性，并成功地将多种功能集成到癌症诊断和放射治疗中。调整到适合肾脏清除的大小，在小肽配体和放射性标签附着在其表面以形成组合pet光学探针后，颗粒显示出增强的受体结合效力和良好的靶向动力学。因此，它代表了唯一的肾脏可排泄的，无机的，pet光学探针，同时靶向肿瘤在体内没有随之而来的毒性问题。除了尺寸的考虑，最佳的体内性能决定了颗粒表面化学是良好的控制和可重复性。这需要共同调整肽配体的数量和聚乙二醇（PEG）链长以及颗粒表面上的接枝密度，以实现有利的靶向和清除剖面。对于无机纳米粒子，表面化学变化如何调节生物特性尚不清楚。本提案的长期目标是开发和实施良好的表面设计，用于FDA和IND批准的~ 7nm直径核壳二氧化硅纳米颗粒结构，用于人类转移性黑色素瘤的检测，分期和治疗计划。本研究旨在：(1)利用可变数量的环精氨酸-甘氨酸-天冬氨酸-酪氨酸（cRGDY）肽、PEG链长度和接枝密度，确定目标二氧化硅纳米颗粒的最佳可调表面化学，以实现良好的黑色素瘤受体结合；(2)研究为crgdy结合探针建立的最佳配方化学物质是否可以扩展到含有黑色素瘤特异性肽（1-MSH）的替代探针；(3)评估124I-cRGDY-PEG-和124I-1MSH-PEG-dots在体内的肿瘤选择性积累以及靶向放射性核素治疗的可行性；(4)通过贴附治疗性放射性标签对肿瘤和正常组织进行靶向放疗和18FDG PET反应监测。这项研究的成功将为未来转移性黑色素瘤患者的I/II期临床试验提供新的研究药物应用，为其他受体承载恶性肿瘤提供更广泛的应用潜力。基于小配体靶向平台的通用模板的建立，还可以提高探针转化到临床的效率。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Clinically-translated silica nanoparticles as dual-modality cancer-targeted probes for image-guided surgery and interventions.

临床翻译的二氧化硅纳米颗粒作为以癌为标志性的探针进行图像引导的手术和干预措施。

DOI：
10.1039/c2ib20174g
发表时间：
2013-01
期刊：
Integrative biology : quantitative biosciences from nano to macro
影响因子：
0
作者：
Bradbury MS;Phillips E;Montero PH;Cheal SM;Stambuk H;Durack JC;Sofocleous CT;Meester RJ;Wiesner U;Patel S
通讯作者：
Patel S

Cancer nanomedicines: closing the translational gap.