Thesis

Novel non-viral delivery systems for cancer gene therapy

Creator
Rights statement
Awarding institution
  • University of Strathclyde
Date of award
  • 2016
Thesis identifier
  • T14543
Person Identifier (Local)
  • 201552254
Qualification Level
Qualification Name
Department, School or Faculty
Abstract
  • The non-viral gene delivery systems dendrimers have been widely studied for cancer therapy. However, due to lack of targeting efficacy, their therapeutic applications are still limited. In this present study, our aim was to investigate the efficacy of four formulations of modified generation- 3- diaminobutyric polypropyleneimine (DAB), by determining their physicochemical characteristics (measurement of particle size, Zeta potential, DNA condensation) and evaluating their in vitro transfection. Conjugation of targeting ligands such as transferrin and lactoferrin is an attractive tool to improve specificity and cellular uptake of carriers, and surface modification of dendrimers with hydrophilic polymers such as polyethylene glycol should facilitate lower systemic toxicity and promote the enhanced permeability and retention (EPR) effect, which should result in increasing DNA transportation into cells and improving the transfection efficacy. The modified dendrimers DAB-transferrin, DAB-lactoferrin, DAB-PEG-transferrin and DAB-PEG-lactoferrin complexed with plasmid DNA had sizes below 200 nm, which is suitable for exploiting passive targeting. In addition, their Zeta potentials were slightly positive. These dendrimers were able to condense more than 75% of DNA at dendrimer: DNA weight ratios of 20:1, 10:1 and 5:1. In vitro, these modified dendrimers led to a significant increase of gene expression compared to unmodified DAB, by 3.67- fold in DAB-PEG-transferrin: DNA ratio of 10:1 in DU145 cells, 3.46- fold in DAB-PEG-transferrin: DNA ratio of 10:1 in PC3 cells, and by 1.95- fold in DAB-PEG-Lactoferrin: DNA ratio of 20:1 in B16F10 cells, respectively. When the formulations modified with PEG were compared with formulations without PEG in three cell lines, DAB-PEG-transferrin showed higher gene expression compared to DAB-transferrin, unlike DAB-lactoferrin, which led to higher transfection compared to DAB-PEG-lactoferrin. Furthermore, modified dendrimers showed significantly higher gene expression level at their optimum dendrimer: DNA weight ratios, compared to the unmodified DAB in all the tested cancer cells. Novel targeted dendrimers transferrin-, lactoferrin-, transferrin-PEG- and lactoferrin-PEG- bearing generation 3 polypropyleneimine dendrimer are therefore promising gene delivery systems.
Resource Type
DOI
Date Created
  • 2016
Former identifier
  • 9912547592002996

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