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

• 批准号: 8447326
• 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
• 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/8447326
• 关键词: A/J Mouse; APC Gene Inactivation; Acetic Acids; Adenomatous Polyps; Affinity; Age-Years; Area; Aspirin; Binding; Biocompatible; Biodistribution; Biological Assay; Breast; Cancer cell line; 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; Glycoproteins; Growth; HT29 Cells; 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; Modeling; Monitor; Mucin-1 Staining Method; Mucins; Mucous Membrane; Mus; 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; Relative (related person); Reporting; Research; Route; Secure; Silicon Dioxide; Specificity; Staging; Sulindac Sulfide; Surface; TAG-72 Antigen; Therapeutic; Tissue Harvesting; Toxic effect; Transgenic Mice; Treatment Efficacy; Tumor Suppressor Genes; Work; adenoma; cancer cell; cancer therapy; celecoxib; colorectal cancer screening; cytotoxicity; fluorescence imaging; fluorophore; glycosylation; in vitro Assay; in vivo; inhibitor/antagonist; minimally invasive; mouse model; nanoparticle; nanotheranostics; novel; polyposis; public health relevance; response; salicylate; targeted delivery; tumor; uptake

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）被认为是通过多种独立的途径发生的，包括许多癌基因和肿瘤抑制基因的突变和改变（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——从正常粘膜到腺瘤，到高度发育不良的腺瘤，再到癌。特别值得注意的是，在50岁以下人群的常规CRC筛查中，最常发现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，切除后CRC的发病率和晚期肿瘤性息肉的频率显著持续下降，这表明西半球95%的CRC病例是由腺瘤性息肉的恶性转化（M-T）引起的。[1-4]为了降低结直肠癌的发病率，需要在息肉M-T发生前及早发现/监测和预防/根除结直肠腺瘤性息肉及其前体。不幸的是，抑制腺瘤性息肉形成/生长最有效的药物——非甾体类抗炎药（NSAIDs）——靶向性差，并且受到剂量依赖性不良胃肠道/心脏/肝脏后遗症的限制。为了克服目前药物治疗的这些缺陷，并使息肉/肿瘤疾病的微创M-T原位分期成为可能，我们将合成并三功能化生物相容性MCM-41介孔二氧化硅纳米颗粒（MSNs），用于靶向、内镜下可追踪的常规非甾体抗炎药的递送。然后，我们将利用人类结直肠癌细胞系和小鼠结直肠息肉病/癌症模型，通过体外/体内荧光成像/内窥镜和体外组织病理学分析，评估我们的三功能化MSN的靶向特异性、摄取、毒性、药物释放动力学、治疗效果和平台排泄。特别是，我们将描述荧光msn的实用性，其内部覆盖有ph触发的可释放的非甾体抗炎药（sulindac sulfide，塞来昔布或乙酰水杨酸），其外部覆盖有凝集素/适体/肽，靶向M-T阶段依赖的异常息肉多糖/糖蛋白表达（粘蛋白MUC1和MUC15，粘蛋白样肿瘤相关糖蛋白TAG-72，粘蛋白表面聚糖-l -聚焦）。我们将研究这些纳米平台的同步荧光强度和寿命成像/内窥镜在评估息肉M-T分期和治疗反应中的效用，以及在体外和体内药物释放动力学表征中使用F¿rster共振能量转移(FRET) -在药物和传递平台之间。我们假设，这些纳米平台的功能化将为非甾体抗炎药的口服给药和息肉靶向给药提供一种预防、检测、分期和非手术根除腺瘤性息肉的方法。