Özet:
Due to their hydrophobic nature, most of the chemotherapy drugs have poor solubility in water. To increase their solubility, solubilizing agents are necessary, which can often cause side effects. Conversely, instead of using solubilizing agents, hydrophobic drugs can be doped into non-toxic polymeric micelles. Polymeric micelles are composed of a hydrophilic shell and a hydrophobic core. While the hydrophobic core carries the hydrophobic drug molecules, the hydrophilic shell reduces protein adsorption and increases their water solubility. However, micellar carriers have drawbacks such as premature disassembly and non-selective targeting. In this thesis, to overcome premature disassembly, micelles composed of dendron-polymer conjugates were core-crosslinked to increase their stability. Moreover, the micelles were tailored to bear tumor targeting groups on their surface, in order to increase their targeting efficiency. In particular, several micellar structures (non-core-crosslinked and core-crosslinked) were synthesized using novel polymer-dendron conjugates obtained by utilizing nucleophilic thiol-ene reaction between thiol end-functionalized p(PEGMEMA) polymers synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization and peripheral alkene-containing dendrons with maleimide group at their focal point. An amine group containing cyclic peptide cRGDfK was conjugated to N-hydroxy succinimide (NHS) ester obtained through activation of the carboxylic end group on the dendron-polymer conjugate. Micellar stabilities were measured using fluorescence spectroscopy and dynamic light scattering (DLS). Sizes of these micelles were found to be less than 200 nm, a size suitable for targeting various tumors. Micelles were core-crosslinked via radicalic thiol-ene reaction in the presence of a tetrathiol and a photoinitiator under UV-irradiation. Core-crosslinking of the micelles improved their stability as confirmed due to lack of disassembly upon dilution with water or addition an organic solvent like THF. Overall, core-crosslinked micelles with cyclic peptide based targeting groups were obtained using novel methodologies.
