Date of Award
2006
Degree Type
Thesis
Degree Name
Master of Science
Program
Pathology
Supervisor
Dr. Jim Koropatnick
Abstract
Targeted delivery and enhanced cellular internalization are two challenges impacting the therapeutic use of antisense drugs. Hyaluronan-antisense Oligodeoxynucleotide (HA-ODN) conjugates were developed to assess the capacity of HA to enhance uptake and subcellular localization of antisense reagents and target antisense ODNs to tumour cells overexpressing the HA receptor CD44. Conjugation of HA to antisense ODNs targeting thymidylate synthase (TS) mRNA facilitated ODN uptake into HeLa cells in the absence of cationic liposomes. HA-ODNs accumulated in the cytoplasm and did not reduce TS mRNA levels. However, transfection of ODNs with Lipofectamine 2000 (LFA2K) resulted in nuclear localization and decreased TS mRNA levels. These data provide direct evidence for nuclear localization as a requirement for effectiveness of antisense ODNs. Uptake of HA-ODNs is not dependent on CD44 as decreasing the level of CD44 or reducing HA-CD44 binding had no effect on the enhanced capacity of HA-ODNs to enter HeLa cells.
Recommended Citation
Fard, Shireen Fatemeh, "Enhanced uptake and targeted subcellular localization of hyaluronan- conjugated thymidylate synthase antisense oligodeoxynucleotides in human tumour cells" (2006). Digitized Theses. 5069.
https://ir.lib.uwo.ca/digitizedtheses/5069
