Cellular and molecular evaluation of oral delivery systems for chemotherapeutic agents
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.
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