Nanotheranostics for Early Colorectal Cancer Detection and Treatment

描述(申请人提供)：结直肠癌(CRC)被认为是通过多种独立的途径发生的，其中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)。尽管起源如此多样化，但大多数癌遵循相似的形态路线--从正常粘膜到腺瘤，再到高度发育不良的腺瘤，再到癌。特别值得注意的是，在50岁人群的常规结直肠癌筛查中，最常见的早期肿瘤是腺瘤性息肉。虽然这些息肉中的绝大多数不是恶性的，但据报道，在切除息肉后，CRC的发病率和晚期肿瘤性息肉的频率显著和持续地下降，这表明西半球95%的CRC病例是由腺瘤性息肉的恶变(M-T)引起的。[1-4]为了减少CRC的发生率，在息肉M-T之前，需要对结直肠腺瘤性息肉及其前驱病变进行早期的检测/监测和预防/根除的方法。不幸的是，最有效的抑制腺瘤性息肉形成/生长的药物--非类固醇抗炎药(NSAIDs)--靶向性差，而且受到剂量依赖的不良胃肠道/心脏/肝脏后遗症的限制。为了克服目前药物治疗中的这些不足，并使息肉/肿瘤疾病的原位M-T分期成为可能，我们将合成生物相容的MCM-41介孔二氧化硅纳米颗粒(MSN)并使其具有三功能，用于靶向、内窥镜可追踪的传统非甾体抗炎药的输送。然后，我们将使用人结直肠癌细胞系和小鼠大肠息肉/癌症模型，通过体外/活体荧光成像/内窥镜和体外组织病理学分析，评估我们的三功能MSN的靶向性、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的用途，其内部用pH触发的可释放非甾体抗炎药(舒林酸硫化物、塞来昔布或乙酰水杨酸)贴砖，其外部覆盖有针对M-T分期依赖的异常息肉/糖蛋白表达的凝集素/适配子/肽(粘蛋白MUc1和MUC15、粘蛋白样肿瘤相关糖蛋白TAG-72和粘蛋白表面糖蛋白�-L-岩藻糖)。我们将研究这些纳米平台的同时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应用，以及F�Rster共振能量转移(FRET)-药物和给药平台之间-在体外和体内药物释放动力学表征中的应用。我们推测，这些用于口服和息肉靶向给药的纳米平台的功能化将为腺瘤性息肉在M-T之前的预防、检测、分期和非手术根除提供一种手段。

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.