18. Oral colon cancer targeting by chitosan nanocomposites

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Oral colon cancer targeting by chitosan nanocomposites
Anirbandeep Bose¹ and Tin Wui Wong^2
1Acharya and BM Reddy College of Pharmacy, Bangalore, India, ²iPROMISE, Universiti Teknologi MARA Selangor, Puncak Alam, Selangor, Malaysia

1. Introduction

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Colon cancer is a lethal disease evolved from the abnormal changes of epithelial lining of the colon or rectum of the gastrointestinal tract. The most common cause of colon cancer is due to the mutations in the Wnt signaling pathway which lead to mutations of the epithelial cells and finally result in colon cancer [1 3] (Fig. 18.1). The colon cancer can be initiated via the demutation of the adenomatous polyposis coli (APC) gene, which is mainly responsible for the synthesis of APC protein. The major function of the APC protein is to prevent the accumulation of β-catenin pro- tein. In absence of the APC protein, β-catenin accumulates to high levels and binds to the specific area of DNA which is solely responsible for the activation of the transcription of the proto-oncogenes. Although these genes are working for the renewal and differentiation of the stem cell, an uncontrolled expression at high β-catenin concentrations can cause cancer. In some cases of cancers, the β-catenin level is increased due to mutations in β-catenin (CTNNB1) and other genes such as AXIN1, AXIN2, TCF7L2, or NKD1 [4].
There are a number of proteins which cause programed cell death such as TGF-β and deleted in colorectal cancer and are found to be deactivated in colon cancer. Among them, TGF-β is found to be in a deactivating mutation stage for around half of the cases of colon cancer. Sometimes instead of deactivation of TGF-β, a down- stream protein named SMAD is found deactivated [5].
Genome-scale analysis indicates that colon carcinoma can be categorized into hypermutated and nonhypermutated tumors. In addition to the oncogenic and inactivating mutations described for the genes earlier, nonhypermutated samples are characterized by mutated CTNNB1, FAM123B, SOX9, ATM, and ARID1A. Progressing through a distinct set of genetic events, hypermutated tumors display mutated forms of ACVR2A, TGFBR2, MSH3, MSH6, SLC9A9, TCF7L2, and BRAF. The common theme among these genes, across both tumor types, is their involvement in Wnt and TGF-β signaling pathways, which results in increased activity of MYC, a central player in colon cancer [5,6].
Applications of Nanocomposite Materials in Drug Delivery. DOI: https://doi.org/10.1016/B978-0-12-813741-3.00018-2
© 2018 Elsevier Inc. All rights reserved.

410 Applications of Nanocomposite Materials in Drug Delivery
Figure 18.1 TGF-β/BMP and Wnt pathways.
H
Figure 18.2 Chemical structure of chitosan.

The most common format of TGF-β/Wnt cross-talk occurs in the nucleus, where the Smad and Lef/β-catenin synergistically regulate a set of shared target genes. TGF-β/BMP and Wnt can determine the ligand production of each other. TGFβ or BMP ligands specifically bind to type II receptors to engage the related type I receptor to instigate a flow of events leading to phosphorylation of their particular receptor-Smads (R-Smads). Protein interactions in the cytoplasm (such as Smad7- Axin binding) are implicated in these two pathways in association with various can- cers including colon cancer [6].

Chitosan is a partially deacetylated biopolymer of N-acetyl glucosamine that can be obtained through alkaline deacetylation of chitin. It consists of a β-(1,4)-linked- D-glucosamine residue with the amine groups acetylated randomly (Fig. 18.2). Chitosan is safe and nontoxic. Due to the presence of free amine and hydroxyl groups, chitosan possesses special functional moieties that can be exploited in chemical modification. Being polycationic, chitosan can interact with polyanions to form various complexes [7].
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2.