Preparation and characterization of tumor targeted polymer micelles via polymerization induced self-assembly (PISA) method

Polymeric drug delivery systems attract attention as an alternative to traditional use of drugs. Especially polymeric micelles are widely studied because they have properties such as small particle size, structural stability, high drug loading capacity, water solubility, low toxicity. Micelles that are suitable for stability or functionalization are ideal for drug delivery systems with targeting capability. Micelles are obtained by self-assembly of amphiphilic block copolymers synthesized with hydrophilic and hydrophobic monomers. The copolymer forms aggregates in selective solvent for one of the blocks. This formation creates self-assembly. Self-assembly of the polymers by conventional methods is carried out in dilute solution (<1%) which generally limits the polymeric morphologies to occur. Polymerization-induced self-assembly (PISA) as an effective method removes this limitation. The PISA method is based on the polymerization of the insoluble block from the monomer dispersed or dissolved in a solvent selective for the initiator polymer. The polymerization degree of the insoluble block where chain elongation begins controls the spontaneous assembly process. The process of formation of polymeric structures in a wide variety of morphologies such as spheres, rods, vesicles, lamellar structures by self-assembly and rearrangements is observed. In this study, random copolymers were synthesized to form a hydrophilic block by using hydroxyethyl methacrylate (HEMA) and glycidyl methacrylate (GMA) monomers by reversible addition-fragmentation chain transfer (RAFT) polymerization. HEMA and functionalizable GMA units are polymerized in different proportions. First, for functionalization, polymers were azited from GMA units. Then, folic acid (FA) functionalized with propargyl was attached to the azidated units by "click" reaction. Polymerization of methyl methacrylate monomer that will form the hydrophobic block with the azide functional macro initiators (M-CTA) obtained was achieved by RAFT-PISA method. PISA reactions with different variables have been tried. Doxorubicin (dox) loaded micelles were prepared using the same method with the most stable parameters. The polymers obtained in the study were characterized by FT-IR, 1H NMR, UV-Vis and DSC. The average particle size of micelles obtained by PISA was measured by DLS. By comparing the results, the effects of the variables on the micelle sizes were examined.