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Nanotheranostics for Early Colorectal Cancer Detection and Treatment

用于早期结直肠癌检测和治疗的纳米治疗学

基本信息

批准号：
9015793
负责人：
JEFFREY S. SOURIS
金额：
$ 32.79万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-03-06 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9015793
关键词：
A/J Mouse APC gene Acetic Acids Adenomatous Polyps Affinity Age-Years ApcMin/+ mice Area Aspirin Binding Biocompatible Biodistribution Biological Assay Breast Cancerous Carcinoma Cardiac Cell Line Colon Colorectal Colorectal Adenoma Colorectal Cancer Colorectal Polyp Contrast Media Contrast Sensitivity Coupled Detection Disease Dose-Limiting Drug Addiction Drug Delivery Systems Drug toxicity Drug usage Electrostatics Endoscopy Energy Transfer Excision Excretory function Flow Cytometry Fluorescein-5-isothiocyanate Fluorescence Fluorescence Microscopy Fluorescent Dyes Frequencies Fucose Gene Silencing Glycoproteins Growth HCT116 Cells HT29 Cells Health HepG2 Hepatic Histology Human Image In Situ In Vitro Incidence Incubated K-ras Oncogene Label Lectin MCF7 cell Malignant - descriptor Malignant Neoplasms Mass Spectrum Analysis Measurement Membrane Glycoproteins Methods Monitor Mucin 1 protein Mucins Mucous Membrane Mutation Neoplasms Neoplastic Polyp Non-Steroidal Anti-Inflammatory Agents Oncogene Activation Oral Oral Administration PTGS1 gene PTGS2 gene Pathway interactions Peptide aptamers Pharmaceutical Preparations Pharmacotherapy Plasma Polyps Polysaccharides Prevention Reporting Research Route Salicylic Acids Secure Silicon Dioxide Specificity Staging Sulindac Sulfide Surface TAG-72 Antigen TP53 gene Therapeutic Tissue Harvesting Toxic effect Transgenic Mice Treatment Efficacy Tumor Suppressor Genes Work adenoma cancer cell cancer therapy celecoxib colon cancer cell line colorectal cancer screening cytotoxicity fluorescence imaging fluorophore glycosylation histological studies in vitro Assay in vivo inhibitor/antagonist minimally invasive mouse model nanoparticle nanotheranostics novel polyposis response targeted delivery treatment response tumor uptake

项目摘要

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is postulated to arise via multiple independent pathways that include mutations and alterations in numerous oncogenes and tumor suppressor genes (e.g., APC gene inactivation, K-ras oncogene activation, and p53 mutation). Despite such diversity of origin, most CRCs follow a similar morphological route - evolving from normal mucosa, to adenoma, to highly-dysplastic adenoma, to carcinoma. Of particular note is the observation that the most frequently found early neoplasms during routine CRC screenings of people >50 years of age are adenomatous polyps. While the overwhelming majority of these polyps are not malignant, significant and sustained reductions in the incidence of CRC and the frequency of advanced neoplastic polyps have been reported following their resection, suggesting that >95% of all CRC cases in the Western Hemisphere arise from the malignancy transformation (M-T) of adenomatous polyps.[1-4] To reduce the incidence of CRC, early methods of detection/monitoring and prevention/eradication of colorectal adenomatous polyps and their precursors are needed, prior to polyp M-T. Unfortunately the most effective drugs at inhibiting adenomatous polyp formation/growth - nonsteroidal anti-inflammatory drugs (NSAIDs) - are poorly targeted and limited by dose-dependent adverse GI/cardiac/hepatic sequelae. To overcome these deficiencies in current drug therapy and enable minimally invasive M-T staging of polyp/neoplastic disease in situ, we will synthesize and tri-functionalize biocompatible MCM-41 mesoporous silica nanoparticles (MSNs) for the targeted, endoscopically-traceable, delivery of conventional NSAIDs. We will then employ both human CRC cell lines and murine models of colorectal polyposis/cancer to evaluate our tri-functionalized MSN's targeting specificity, uptake, toxicity, drug releasing dynamics, therapeutic efficacy, and platform excretion via in vitro/vivo fluorescence imaging/endoscopy and ex vivo histopathological analyses of harvested tissues. In particular we will characterize the utility of fluorescent MSNs whose interiors are tiled with pH-triggered releasable NSAIDs (sulindac sulfide, celecoxib, or acetylsalicylic acid) and whose exteriors are covered with lectins/aptamers/peptides that target M-T stage-dependent, aberrant polyp glycan/glycoprotein expression (mucins MUC1 and MUC15, mucin-like tumor-associated glycoprotein TAG-72, and mucin surface glycan �-L-fucose). We will investigate the utility of concurrent fluorescence intensity and lifetime imaging/endoscopy of these nanoplatforms in the assessment of polyp M-T staging and therapeutic response, as well as the use of F�rster resonance energy transfer (FRET) - between drug and delivery platform - in the characterization of drug releasing dynamics, both in vitro and in vivo. We postulate that functionalization of these nanoplatforms for oral administration and polyp-targeted delivery of NSAIDs will provide a means for the prevention, detection, staging, and non-surgical eradication of adenomatous polyps prior to their M-T.

描述（由申请人提供）：结肠直肠癌（CRC）被认为是通过多个独立的途径产生的，这些途径包括许多癌基因和肿瘤抑制基因（例如，APC基因失活、K-ras癌基因激活和p53突变）。尽管起源如此多样，但大多数CRC遵循相似的形态学途径-从正常粘膜演变为腺瘤，高度发育不良的腺瘤，再到癌。特别值得注意的是，在>50岁的人的常规CRC筛查期间最常见的早期肿瘤是腺瘤性息肉。虽然绝大多数这些息肉不是恶性的，但据报道，在切除后CRC的发病率和晚期肿瘤性息肉的频率显著和持续降低，这表明西半球>95%的CRC病例来自腺瘤性息肉的恶性转化（M-T）。[1-4]为了降低CRC的发病率，在息肉M-T之前，需要早期检测/监测和预防/根除结直肠腺瘤性息肉及其前体的方法。不幸的是，抑制腺瘤性息肉形成/生长的最有效药物-非甾体抗炎药（NSAID）-靶向性差，并受到剂量依赖性不良GI/心脏/肝脏后遗症的限制。为了克服目前药物治疗中的这些缺陷，并使息肉/肿瘤疾病的微创M-T分期原位，我们将合成和三功能化生物相容性MCM-41介孔二氧化硅纳米颗粒（MSN），用于靶向，内窥镜可追踪，传统NSAID的交付。然后，我们将采用人CRC细胞系和结肠直肠息肉病/癌症的鼠模型来评估我们的三官能化MSN的靶向特异性、摄取、毒性、药物释放动力学、治疗功效和平台排泄，通过体外/体内荧光成像/内窥镜检查和对收获的组织的离体组织病理学分析。特别是，我们将表征荧光MSN的效用，其内部铺有pH触发的可释放NSAID（舒林酸硫化物，塞来昔布或乙酰水杨酸），其外部覆盖有靶向M-T阶段依赖性异常息肉聚糖/糖蛋白表达的凝集素/适体/肽（粘蛋白MUC 1和MUC 15，粘蛋白样肿瘤相关糖蛋白TAG-72和粘蛋白表面聚糖β-L-岩藻糖）。我们将研究这些纳米平台的并发荧光强度和寿命成像/内窥镜检查在评估息肉M-T分期和治疗反应中的效用，以及使用药物和递送平台之间的F rster共振能量转移（FRET）在体外和体内表征药物释放动力学。我们假设，这些用于口服给药和非甾体抗炎药息肉靶向递送的纳米平台的功能化将提供一种在M-T之前预防、检测、分期和非手术根除腺瘤性息肉的方法。