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Camptothecin-Containing Nanoparticles: Control Over Particle Size, Biodistributio

含喜树碱的纳米颗粒：控制粒径、生物分布

基本信息

批准号：
8215625
负责人：
Jianjun Cheng
金额：
$ 16.39万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-22 至 2012-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8215625
关键词：
Address Antineoplastic Agents Binding Biodistribution Bypass Camptothecin Cells Characteristics Clinical Clinical Research Correlation Studies Disease Drug Delivery Systems Drug Formulations Esters Ethylene Glycols Glutamate Carboxypeptidase II Gold Guidelines Hepatic Hour Human Kilogram LNCaP Label Laboratories Lead Ligands Liver Liver neoplasms Malignant Neoplasms Mediating Mission Modeling Mono-S Mus Nude Mice Organ Particle Size Pathway interactions Phagocytosis Pharmaceutical Preparations Polymers Polystyrenes Precipitation Preparation Process Radioactive Relative (related person)Reproducibility Silicon Dioxide Solid Solid Neoplasm Spleen Surface Surface Properties System Tail Techniques Technology Testing Time Tissues Translating Tumor Tissue Variant Veins Xenograft procedure aptamer base biomaterial compatibility cancer therapy chemotherapeutic agent clinical application cost density ethylene glycol in vivo nanofabrication nanomedicine nanometer nanoparticle nanoscale particle preclinical study public health relevance self assembly surface coating trimethoxysilane tumor

项目摘要

DESCRIPTION (provided by applicant): Targeted cancer therapy mediated by chemotherapeutic agent-incorporated nanoparticles (NPs) has yet to be translated successfully into clinical usage. To achieve cancer targeting, NPs must possess specific characteristics allowing for evasion of non-specific phagocytosis by hepatic and spleenic reticuloendothelial cells so that NPs can preferentially localize in solid tumor tissues. Bypassing this systemic barrier is challenging and has yet to be realized in cancer drug delivery. Most current NPs injected systemically, with or without surface conjugated targeting ligands, accumulate within non-target organs especially in the liver or spleen. Numerous studies suggested that the size and the surface properties of NPs can have direct correlation with their biodistribution in vivo. But because of the difficulty of controlling particles sizes precisely, the correlation of NP size with in vivo NP biodistribution has yet to be established. NP formulation challenges still exist for controlling NP sizes and surface characteristics. Polymeric NPs currently in numerous preclinical and clinical studies are formulated via nanoprecipitation (co-precipitation of hydrophobic drugs and polymers) or self- assembly processes (e.g., micellation or vesiclation). However, these processes usually lead to NPs with heterogeneous particle sizes. NPs with controlled sizes can be prepared using top-down, template-directed nanofabrication techniques. However, preparing NPs in large quantity is not practical using this top-down strategy, especially when attempting to prepare NPs in kilogram scale under GLP/GMP for human clinical studies. It still remains elusive whether the scalability issue can be addressed for the top-down approach. It is of great importance and urgent needs for new system/strategy that allows preparation of NPs with precisely controlled sizes so that they can be used to study size-biodistribution correlation and potentially to deliver chemotherapeutics in a cancer-specific manner. In this R21 proposed study, we aim to develop monodisperse silica NPs with controlled size and study their biodistribution with and without conjugated targeting ligand. We aim to gain substantial information with regard to the correlation of the size/targeting ligand density with NP biodistribution profiles. We also aim to develop camptothecin-containing, monodisperse, fast-degrading silica NPs with the size and surface property optimized based on information collected from the previous study and then test these NPs in tumor-bearing mice for their capability of targeting cancer. PUBLIC HEALTH RELEVANCE: The size and surface property of nanoparticles have dramatic effect on their in vivo biodistribution and capability of cancer targeting. However, the correlation of particle size and surface property with its in vivo biodistribution and cancer targeting still remains elusive. In this R21 proposed studies, we aim to develop silica NPs with discrete, close to mono-disperse sizes and controlled density of the surface-bound targeting ligand to study their biodistribution profiles and cancer targeting capability, and then use the information collected to develop camptothecin-containing, fast-degrading silica nanoparticles for in vivo cancer targeting.

描述（由申请人提供）：由掺入化疗剂的纳米颗粒（NP）介导的靶向癌症治疗尚未成功转化为临床应用。为了实现癌症靶向，NPs必须具有特定的特性，允许逃避肝脏和脾脏网状内皮细胞的非特异性吞噬作用，使得NPs可以优先定位于实体瘤组织中。克服这种全身屏障是具有挑战性的，并且在癌症药物递送中尚未实现。大多数目前全身注射的NP（有或没有表面缀合的靶向配体）在非靶器官内积累，特别是在肝或脾中。许多研究表明，纳米颗粒的大小和表面性质与其在体内的生物分布有直接的关系。但由于难以精确控制颗粒尺寸，NP尺寸与体内NP生物分布的相关性尚未建立。对于控制NP尺寸和表面特性而言，NP制剂仍然存在挑战。目前在许多临床前和临床研究中的聚合物NP通过纳米沉淀（疏水性药物和聚合物的共沉淀）或自组装过程（例如，胶束化或囊泡化）。然而，这些过程通常导致具有不均匀颗粒尺寸的NP。具有受控尺寸的NP可以使用自上而下、模板导向的纳米纤维技术来制备。然而，使用这种自上而下的策略大量制备NP是不实际的，特别是当试图根据GLP/GMP制备用于人类临床研究的千克规模的NP时。对于自顶向下的方法来说，可伸缩性问题是否能够得到解决仍然是难以捉摸的。这是非常重要的和迫切需要的新系统/策略，允许制备具有精确控制的尺寸的NP，使得它们可以用于研究尺寸-生物分布的相关性，并可能以癌症特异性的方式提供化疗药物。在这项R21提出的研究中，我们的目标是开发具有可控尺寸的单分散二氧化硅纳米颗粒，并研究它们在有和没有缀合的靶向配体的情况下的生物分布。我们的目标是获得大量的信息与NP的生物分布概况的大小/靶向配体密度的相关性。我们还旨在开发含有喜树碱，单分散，快速降解的二氧化硅纳米颗粒，其尺寸和表面性质根据先前研究收集的信息进行优化，然后在荷瘤小鼠中测试这些纳米颗粒靶向癌症的能力。公共卫生关系：纳米粒子的大小和表面性质对其体内分布和肿瘤靶向性有显著影响。然而，粒径和表面性质与其体内生物分布和癌症靶向的相关性仍然是难以捉摸的。在R21提出的研究中，我们的目标是开发具有离散的，接近单分散的尺寸和表面结合的靶向配体的受控密度的二氧化硅纳米颗粒，以研究其生物分布概况和癌症靶向能力，然后使用收集的信息开发含有喜树碱的快速降解的二氧化硅纳米颗粒用于体内癌症靶向。