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

• 批准号: 8637013
• 负责人: Michelle S Bradbury
• 金额: $ 54.99万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-12 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8637013
• 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; Drug Formulations; Dyes; Flow Cytometry; Fluorescence; Fluorescence Microscopy; Fluorescence Spectroscopy; 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; 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; man; melanoma; nanomedicine; nanoparticle; novel; optical imaging; outcome forecast; palliative; particle; prognostic; protocol development; prototype; radiotracer; receptor; receptor binding; response; success; therapeutic target; tool; translational study; treatment planning; tumor

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）：转移性黑色素瘤的预后非常差，中位生存期不到1年。大多数患者没有令人满意的治疗方法;治疗主要是姑息性的，并产生短期效益。在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。多功能颗粒平台结合联合收割机并向肿瘤提供多种功能，与单个分子相比具有明显的优势，并有望进入临床实践。通过将肿瘤选择性肽和治疗部分附着到颗粒表面以产生这样的平台，可以选择性地靶向和治疗癌症。荧光核-壳二氧化硅纳米颗粒是临床上有前途的无毒“粒子实验室平台”，其表现出优异的每粒子亮度和稳定性，并且已经成功地整合了用于癌症诊断和放射治疗的多种功能。调整到肾清除的大小，该颗粒显示出增加的受体结合效力和有利的靶向动力学后，小肽配体和放射性标记物连接到其表面，以创建一个组合的PET-光学探针。因此，它代表了唯一的肾可排泄的无机PET光学探针，其同时靶向体内肿瘤而没有伴随的毒性问题。除了尺寸考虑之外，最佳的体内性能要求颗粒表面化学是良好控制和可再现的。这需要共同定制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特性。对于无机纳米颗粒，尚不清楚表面化学变化如何调节生物学特性。该提案的长期目标是为我们的FDA IND批准的直径约7 nm的核-壳二氧化硅纳米颗粒架构开发和实施良好的表面设计，用于人转移性黑色素瘤的检测、分期和治疗计划。 该提案旨在：（1）确定靶向二氧化硅纳米颗粒的最佳可调表面化学，以使用可变数目的环状精氨酸-甘氨酸-天冬氨酸-酪氨酸（cRGDY）肽、PEG链长和接枝密度实现有利的黑素瘤受体结合;（2）研究为cRGDY结合探针建立的最佳配制化学是否可以扩展到携带黑素瘤特异性肽（1-MSH）的替代探针;（3）评估124 I-cRGDY-PEG-和124 I-1 MSH-PEG-点的体内肿瘤选择性累积和靶向放射性核素治疗的可行性;和（4）通过连接治疗性放射性标记物来进行肿瘤和正常组织的靶向放射治疗和18FDG PET响应监测。 这项研究的成功将使研究性新药申请的产生，用于在转移性黑色素瘤患者中进行未来的I/II期临床试验，为其他携带受体的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，可以另外提高探针翻译到临床的效率。