TRACEABLE CANCER-TARGETED NANOPARTICLES FOR LOCALIZED CHEMOTHERAPY

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心机构，不一定为研究者机构。纳米技术为位点特异性化疗的发展开辟了新的途径。我们正在设计携带化疗剂或磁共振成像造影剂的纳米颗粒，分别用于癌症治疗和诊断。纳米尺寸的颗粒已经显示出由于不成熟、渗漏的脉管系统而选择性地在肿瘤中积聚。我们的目标是通过在纳米颗粒表面添加靶向肽来增强这种选择性积累。迄今为止，我们的研究主要集中在制造均匀的人口约50，约250，和约500纳米的可生物降解的聚（dl-乳酸-共-乙醇酸）（PLGA）的纳米粒子。环肽，cLABL，已被证明具有高亲和力的特异性结合细胞内细胞粘附分子-1（ICAM-1），这是上调肺癌，胰腺癌，前列腺癌等，我们已经拴cLABL的表面的PLGA纳米颗粒和量化的表面密度通过检测的存在下，二硫键的肽通过一个ThioGlo荧光测定。为了增加cLABL对细胞表面上ICAM-1的可及性，我们将碳二亚胺或聚乙二醇间隔物连接到纳米颗粒表面，随后使cLABL与这些间隔物的远端反应。在一项平行研究中，我们与堪萨斯大学医学中心Hoglund脑成像中心的Mehmet Bilgen博士合作，测试我们将钆封装到PLGA纳米颗粒中作为MRI对比增强剂的能力。他已经证实了这些纳米颗粒制剂以浓度依赖性方式增强磁共振图像的能力。在正在进行的研究中，我们正在制造带有和不带有cLABL的荧光纳米颗粒。这些制剂将与癌性Caco-2或内皮细胞单层（HUVEC）一起孵育，以定量cLABL-纳米颗粒与未标记的纳米颗粒相比的粘附或内吞作用。同时，我们计划通过MRI比较cLABL-纳米颗粒与未标记纳米颗粒的生物分布。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Nanotechnology has opened new avenues toward the development of site specific chemotherapy. We are designing nanoparticles that carry either a chemotherapeutic or a contrast agent for magnetic resonance imaging for application in cancer treatment and diagnosis, respectively. Nanometer-sized particles have been shown to selectively accumulate in tumors due to immature, leaky vasculature. Our goal is to augment this selective accumulation by adding a targeting peptide to the nanoparticle surface. Our studies to date have focused on fabricating homogeneous populations of ~50, ~250, and ~500 nm nanoparticles of biodegradable poly(dl-lactic-co-glycolic acid) (PLGA). The cyclic peptide, cLABL, has been proven to bind with high affinity specificity to intracellular cell adhesion molecule-1 (ICAM-1), which is upregulated in lung cancer, pancreatic cancer, prostate cancer, etc. We have tethered cLABL to the surface of PLGA nanoparticles and quantified the surface density by a detecting the presence of the di-sulfide bond on the peptide via a ThioGlo fluorescence assay. To increase the accessibility of cLABL to ICAM-1 on the surface of cells, we have attached carbodiimide or polyethylene glycol spacers to the nanoparticle surface and subsequently reacted cLABL to the distal end of these spacers. In a parallel study, we have partnered with Dr. Mehmet Bilgen at the Hoglund Brain Imaging Center at the University of Kansas Medical Center to test our ability to encapsulate gadolinium into PLGA nanoparticles as an MRI contrast enhancing agent. He has verified the ability of these nanoparticle formulations to enhance magnetic resonance images in a concentration dependent manner. In ongoing studies, we are fabricating fluorescent nanoparticles with and without cLABL attached. These formulations will be incubated with cancerous Caco-2 or endothelial cell monolayers (HUVECs) to quantify the adhesion or endocytosis of cLABL-nanoparticles compared to unlabeled nanoparticles. In parallel, we plan to compare the biodistribution of cLABL-nanoparticles to unlabeled nanoparticles via MRI.