The purpose of this study was to develop a biodegradable
drug platform composed of
chitosan and
guar gum and to explore the possibility of using it for local adjuvant or
neoadjuvant therapy of
colorectal cancer.
Celecoxib (Cx), a chemopreventative
drug for
familial adenomatous polyposis (FAP) and under trial for reducing post surgical colorectal
malignancies, was selected as a model
drug for this topical system because of the
contraindications that are associated with its systemic administration. Films made of
chitosan (Ct) and
guar gum (GG) were prepared, characterized for equilibrium swelling, mucoadhesion, in vitro and in vivo degradation and loaded with Cx. Short term dosing studies in vitro were performed in the HT-29 colon
carcinoma cell line that was incubated with Cx using the MTT test to assess IC50. The impact of a single high dose was evaluated and compared with a repeating low-dose regimen. In vivo dosing experiments with Cx were performed in the perfused intestine of the anaesthetized rat. Measuring tissue LDH assessed epithelium injury. Mechanical, mucoadhesion and in vitro degradation of the
polysaccharide films were dictated by manipulating the ratios of Ct and GG. The addition of rat cecal contents to the dissolution medium increased the total Cx released from those films containing high amounts of GG. MTT reduction, a measure of cell proliferation, diminished as a function of increasing
drug concentration and exposure time in the HT-29 cell line studies. Local high concentrations of Cx were shown to impede the proliferation of
cancer cells directly, while
chemoprevention has been demonstrated with low Cx doses. Healthy cells were shown to be sensitive to high Cx doses. Maximum therapeutic efficiency in the context of minimal healthy tissue exposure would thus be predicted utilizing a local delivery system such as the proposed adhesive, biodegradable
polysaccharide composites.