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    Cellular and molecular evaluation of oral delivery systems for chemotherapeutic agents

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    Date
    2004-05
    Author
    Blanchette, James Otto, 1976-
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    Abstract
    The development of carriers to deliver a variety of cancer therapeutics orally would represent a significant advance in the treatment of this disease. This delivery system is based on hydrophilic polymer carriers to deliver therapeutic agents to the upper region of the small intestine in response to the pH increase when passing from the stomach. Methacrylic acid (MAA) and ethylene glycol (EG) combined in a 1:1 molar ratio were reacted to form P(MAA-g-EG) nanospheres by UV-initiated free radical polymerization. MAA and EG were chosen to give the nanospheres pH-responsive swelling behavior and mucoadhesive properties as has been shown by previous work in our lab with oral delivery of proteins. Bleomycin, chosen as a chemotherapeutic agent with desirable properties, was loaded into the nanospheres by in situ polymerization or imbibition. Release studies were carried out in conditions modeling the gastrointestinal tract. Results showed that bleomycin is preferentially released at a higher pH due to the increased mesh size of the swollen hydrogel carrier. The potential cytotoxicity of bleomycin on the small intestine was investigated with the use of Caco-2 cells (human colon adenocarcinoma). Studies done with bleomycin concentrations ranging from 0.01 – 1.0 mg/ml showed maintenance of both viability and proliferation in treated cells compared to control cells. The presence of the nanospheres decreases the transepithelial electrical resistance (TER) across Caco-2 cell monolayers. This decrease is thought to be the result of calcium binding by the nanospheres and removal of calcium aids transport of bleomycin across a Caco-2 model of the intestinal epithelium. Bleomycin efficacy studies show activity of the drug against a DLD-1 cell (human colon carcinoma) tumor model following loading and release from the nanospheres.
    Department
    Biomedical Engineering
    Description
    text
    Subject
    Cancer--Chemotherapy
    Oral medication
    Drug delivery systems
    URI
    http://hdl.handle.net/2152/12748
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