382349 Controlled and Targeted Drug Delivery to Tumor Cells Via Mucoadhesive Chitosan and Chlorotoxin
The aim of this research is to develop a localized drug delivery system consisting of non-ionic surfactant vesicles (niosomes) with chlorotoxin (CTX) embedded in a chitosan hydrogel with enhanced targeting ability for the treatment of cancerous tumors. We found the specific accumulation of chitosan on the surface of ovarian epithelial carcinoma cells known to have high expression of mucin antigen MUC1. This behavior was not observed on the normal ovarian epithelial cells. This finding indicates the capability of chitosan to target tumor cells expressing MUC1. Besides, the incorporation of CTX (a 36-amino acid peptide capable of specific binding to tumor cells of neuroectodermal origin but not to normal cells) along with niosomes into the chitosan hydrogel has been used as the second targeting strategy to further improve the specific delivery of drugs to tumor cells such as glioma.
Attenuated Total Reflectance-Fourier Transform Infra-Red (ATR-FTIR) spectroscopy was used to investigate the possible molecular interaction between the chitosan hydrogel and various cell lines. Cell based Enzyme Linked Immunosorbent Assay (Cell-ELISA) was used for quantitative analysis of the expression level of MUC1 in different cell lines in order to understand the mechanism involved in interactions between chitosan and specific tumor cells. To examine the effect of CTX on the release rates, in vitrorelease studies were performed. Transmission Electron Microscopy (TEM) was used to assess the morphology of CTX and nisomes as well as chitosan hydrogel embedded with niosomes and CTX.
Preliminary results of Cell-ELISA revealed approximately 1.5 fold higher expression level of MUC1 in ovarian epithelial carcinoma cell line (OV2008) when compared to normal ovarian epithelial cell line (MCC3) implicating higher affinity of chitosan for OV2008 than MCC3 cell lines. This finding is consistent with ATR-FTIR results as well as the previously observed higher chitosan accumulation on the surface of OV2008 compared to MCC3, confirming the mucoadhesive property of chitosan and indicating its specificity in targeting MUC1 overexpressing tumor cells. In vitrorelease studies indicate that embedding CTX along with the niosomes does not disturb the controlled release from the chitosan network. In fact, attachment of CTX to the surface of niosomes shown by TEM imaging improves the stability of niosomes resulting in extended release rates.
Based on these findings, it is anticipated that the drug delivery system described here would improve the uptake of drugs into epithelial and neuroectodermal origin tumor cells due to the enhanced tumor targeting and its controlled and sustained drug release.
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