Camptothecin-Containing Nanoparticles: Control Over Particle Size, Biodistributio

描述（由申请人提供）：由化疗药物结合纳米颗粒（NPs）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必须具有特异性特征，允许逃避肝脏和脾脏网状内皮细胞的非特异性吞噬，以便NPs可以优先定位于实体肿瘤组织。绕过这一系统性屏障是具有挑战性的，在癌症药物输送中尚未实现。目前大多数全身注射的NPs，无论有无表面共轭靶向配体，都在非靶器官内积累，特别是在肝脏或脾脏。大量研究表明，NPs的大小和表面性质与其在体内的生物分布有直接关系。但由于难以精确控制颗粒大小，NP大小与体内NP生物分布的相关性尚未建立。NP配方在控制NP尺寸和表面特性方面仍然存在挑战。目前，在许多临床前和临床研究中，聚合物NPs是通过纳米沉淀（疏水药物和聚合物的共沉淀）或自组装过程（例如，微泡或囊泡）制成的。然而，这些过程通常会导致颗粒大小不均匀的NPs。具有控制尺寸的纳米粒子可以使用自上而下的、模板导向的纳米制造技术制备。然而，使用这种自上而下的策略大量制备NPs是不现实的，特别是当试图在GLP/GMP下以千克为单位制备NPs用于人体临床研究时。对于自顶向下的方法，可伸缩性问题能否得到解决仍然是一个难以捉摸的问题。这是一个非常重要和迫切需要的新系统/策略，允许制备具有精确控制尺寸的NPs，以便它们可以用于研究尺寸-生物分布的相关性，并有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控制尺寸的单分散二氧化硅NPs，并研究它们在有和没有共轭靶向配体的情况下的生物分布。我们的目标是获得关于大小/靶向配体密度与NP生物分布概况的相关性的大量信息。我们的目标是开发含有喜树碱的、单分散的、快速降解的二氧化硅NPs，并根据先前的研究收集的信息优化其大小和表面性质，然后在肿瘤小鼠中测试这些NPs靶向癌症的能力。

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.