Single-chain polymer nanoparticles as drug delivery systems

Nanotechnology is focused on the development of synthetic techniques for producing nanoscale objects that enable precise size control and specific functionalization. For that purpose, single-chain polymer nanoparticles (SCNPs), created by the collapse or folding of polymer chains into structurally defined nanoparticles, are a dramaticly growing research topic in polymer science that has been developing over the last twenty-five years. SCNPs, which are ultra-small cross-linked nanoparticles, are obtained by individual folding or collapse of linear polymer chains by intra-chain cross-linking under high dilution conditions. SCNPs allow the formation of 1-20 nm sized polymer nanoparticles which are more smaller than traditional polymer nanoparticles. Finally, interest in this field continues to increase due to the various potential applications of SCNP, including catalysis, sensors, nanoreactors and biomedicine. As a result of the wide variety of applications, they are one of the promising nano carriers for any research topic in the field of biomedicine. A variety of synthetic methodologies have been applied to the formation of SCNPs. Most of the examples include postpolymerization functionalization reactions in dilute polymer solutions (typically <1 mg mL-1). Postpolymerization cross-linking reactions are typically selected based on their efficiency; reactions with low yields or side reactions are undesirable. Intrachain crosslinking consists of covalent, dynamic covalent and non-covalent interactions. In this thesis, 3 different studies were carried out with single-chain polymer nanoparticles as drug carrier systems. In the studies, drug molecules were selected to ensure intra-chain cross linking in SCNP formation, so that no drug loading would be required in SCNPs. First, SCNPs were formed using the cisplatin molecule as a cross-linker. For this purpose, poly[poly(ethylene glycol) methyl ether methacrylate-r-methacrylic acid] (P(PEGMA-r-MAA)) hydrophilic copolymer and poly(ethylene glycol)-b-poly(N-isopropylacrylamide-r-methacrylic acid) (PEG-b-P(NIPAM-r-MAA)) amphiphilic copolymer were synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization. At the same time, poly[(γ-benzyl-L-glutamate)-r-(Nε-benzylcarbonyl-L-lysine)] [P(Glu-r-Lyz)] hydrophilic copolymer and poly(ethylene glycol amine)-b-poly[(γ-benzyl-L-glutamate)-r-(L-alanine)] [PEG-b-P(Glu-r-Ala)] amphiphilic copolymer were synthesized using ring-opening polymerization. It was aimed to form SCNPs as a result of the reaction of these precursor polymers with cisplatin molecule under ultra-dilute conditions. In the second study, SCNPs were formed by using curcumin molecule as a cross linker. Firstly, poly[poly(ethylene glycol methyl ether methacrylate)-r-(bromomethacrylate)] (P(PEGMA-r-BrMA)) hydrophilic copolymer was synthesized by RAFT polymerization. Then, SCNPs were formed as a result of the reaction with the curcumin molecule under ultra-dilute conditions. In the last study, tadpole likesingle chain polymer nanoparticles (TSCNP) were formed by using the curcumin molecule as a crosslinker and micelles were formed from these TSCNPs. First, poly(ethylene glycol)-b-poly[(methyl methacrylate)-r-(methacrylic acid)] (PEG-b-P(MMA-r-MAA)) amphiphilic copolymers were synthesized by RAFT polymerization. Then, TSCNPs were formed as a result of the reaction with the curcumin molecule under ultra-dilute conditions. Doxorubicin-loaded micelles were formed by dialysis using the formed TSCNPs. All polymers obtained during thesis work were characterized by gel permeation chromatography (GPC), nuclear magnetic resonance spectroscopy (1H NMR), and differential scanning calorimetry (DSC) techniques. The obtained SCNPs and TSCNPs were characterized by GPC, DSC, dynamic light scattering (DLS), transmission electron microscopy (TEM) analyses and molecular weight, size, glass transition temperature and morphology that changed due to cross linking. Drug loading efficiency and release behavior were monitored by ultraviolet-visible light absorption spectroscopy and microplate reader. Cytotoxicity and cellular uptake of SCNPs, TSCNPs and micelles were investigated. Studies show that single-chain nanoparticles provide potential for drug delivery systems and promising studies can be presented.