Camptothecin-Containing Nanoparticles: Control Over Particle Size, Biodistributio

描述(申请人提供)：化疗药物纳米粒(NPs)介导的靶向癌症治疗尚未成功转化为临床应用。为了实现肿瘤靶向，NPs必须具有特定的特性，使其能够逃避肝和脾网状内皮细胞的非特异性吞噬作用，从而使NPs能够优先定位于实体瘤组织。绕过这一系统性障碍是具有挑战性的，在抗癌药物输送方面尚未实现。目前系统注射的大多数NPs，无论有没有表面共轭靶向配体，都会在非靶器官内积聚，特别是在肝脏或脾内。大量研究表明，纳米粒子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的大小与体内生物分布的相关性尚未建立。在控制NP尺寸和表面特性方面，NP配方仍然存在挑战。目前在许多临床前和临床研究中的聚合物纳米粒是通过纳米沉淀法(疏水药物和聚合物的共沉淀)或自组装过程(如胶束或囊化)形成的。然而，这些过程通常会导致纳米颗粒尺寸不均一。可以使用自上而下、模板导向的纳米制造技术来制备尺寸可控的NPS。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下制备千克量级的NPs用于人类临床研究时。自上而下的方法能否解决可伸缩性问题仍然是个未知数。非常重要和迫切需要新的系统/策略，允许制备尺寸精确控制的纳米颗粒，以便它们可以用于研究尺寸-生物分布相关性，并有可能以癌症特异性的方式提供化疗药物。在这项R21建议的研究中，我们的目标是开发尺寸可控的单分散二氧化硅纳米颗粒，并研究其在有无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生物分布曲线的相关性的大量信息。我们的目标还包括开发含有喜树碱、单分散、快速降解的二氧化硅纳米颗粒，根据先前研究收集的信息优化其尺寸和表面性质，然后在荷瘤小鼠身上测试这些纳米颗粒靶向癌症的能力。 公共卫生相关性：纳米颗粒的大小和表面性质对其在体内的生物分布和癌症靶向能力有很大影响。然而，颗粒大小和表面性质与其在体内的生物分布和肿瘤靶向的相关性仍然难以捉摸。在这项R21建议的研究中，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密度可控的二氧化硅纳米颗粒，以研究其生物分布特征和癌症靶向能力，然后利用收集的信息来开发含有喜树碱的、快速降解的用于体内癌症靶向的二氧化硅纳米颗粒。

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.