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.

R01CA171785

2013-03-06

2019-02-28