(20f) Folate Receptor-Targeted Aminoglycoside-Derived Polymers for Transgene Expression in Cancer Cells

Authors: 
Godeshala, S., Arizona state university
Nitiyanandan, R., Arizona State University
Thompson, B., Arizona State University
Goklany, S., Arizona State University
Nielsen, D. R., Arizona State University
Rege, K., Arizona State University
Targeted delivery of anticancer drugs can overcome the limitations of poor drug bioavailability, drug resistance, and unintended side effects associated with current chemotherapeutic regimens. Folate-receptors are overexpressed in several epithelial malignancies, including ovarian, renal, lung, triple-negative breast and bladder cancers, making these attractive targets for the targeted delivery of small molecule and/or nucleic acid therapeutics to cancer cells. Aminoglycosides are hydrophilic molecules that contain multiple sugars, amines and hydroxyls, and are attractive as monomers for generating diverse libraries of macromolecules. We first cross-linked aminoglycosides with diglycidyl ethers and subsequently derivatized these polymers with folic acid resulting in the formation of folate-targeted polymers. These folic acid-conjugated aminoglycoside-derived polymers were investigated for transgene delivery and expression in triple negative breast and bladder cancer cells at different polymer: plasmid DNA weight ratios. The targeted folic acid-conjugated polymers demonstrated significantly higher levels of luciferase expression in cancer cells compared to their parental polymers. Competitive inhibition of the folate receptor using free folic acid significantly inhibited transgene expression activity, indicating a role for the receptor in transgene expression. The targeted polymers were employed for the delivery of a newly constructed pEF-TRAIL plasmid, which expresses the TNF-alpha Related Apoptosis Inducing Ligand (TRAIL) protein, which is known to iduce death selectively in cancer cells. Cancer cell death following delivery of the pEF-TRAIL plasmid was investigated as a single-agent treatment as well as with other chemotherapeutics resulting in a combination treatment approach. Our results indicate that folate-targeted, aminoglycoside-derived polymers may be promising new materials for delivering nucleic acids to cancer cells in several malignancies.
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