Luminal delivery and dosing considerations of local celecoxib administration to colorectal cancer.
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.
The Hebrew University of Jerusalem, Faculty of Medicine, School of Pharmacy, P.O. Box 12065, Jerusalem 91120, Israel.
Sue
S
Haupt
Tamar
T
Zioni
Irith
I
Gati
Jackie
J
Kleinstern
Abraham
A
Rubinstein
D000268:Adhesiveness; D000818:Animals; D000068579:Celecoxib; D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D048271:Chitosan / Q000737:chemistry* / Q000378:metabolism; D015179:Colorectal Neoplasms; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D005243:Feces / Q000737:chemistry; D005685:Galactans / Q000737:chemistry* / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D008297:Male; D008351:Mannans / Q000737:chemistry* / Q000378:metabolism; D010316:Particle Size; D053149:Plant Gums / Q000737:chemistry* / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013449:Sulfonamides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology
D016861:Cyclooxygenase Inhibitors; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D005685:Galactans; D008351:Mannans; D053149:Plant Gums; D011720:Pyrazoles; D013449:Sulfonamides; D048271:Chitosan; C007894:guar gum; D000068579:Celecoxib