Synthesis of stimuli sensitive and biodegradable amphiphilic copolymers, investigation of sol-gel phase transition and drug release behaviors

In this study, temperature and pH sensitive, biocompatible and biodegradable amphiphilic copolymers with different compositions were synthesized and characterized. These copolymers can be used for controlled drug delivery. The micelle forming behavior, the sol-gel phase transition properties and drug release behavior of these copolymers were determined. In the first part of this study, amphiphilic copolymers were synthesized in three different architecture by using ε-caprolactone (ε-CL), methoxy poly(ethylene glycol) (mPEG) and different amines and diacrylate compounds: triblock copolymers, methoxy poly(ethylene glycol)-b-poly(ε-caprolactone)-b-poly(β-aminoester) (mPEG-b-PCL-b-PBAE); graft copolymers, poly(β-aminoester)-g-poly(ε-caprolactone)-b-methoxy poly(ethylene glycol) (PBAE-g-PCL-b-mPEG) and star copolymers, poly(ethylene oxide) (PEO) coated 4 armed poly(ε-caprolactone)-b-poly(ε-caprolactone) (PEO coated 4YPCL-b-PBAE). The structures, average molecular weights and polydispersities of these amphiphilic copolymers were characterized by Fourier Transform Infrared Spectroscopy (FTIR), Proton Nuclear Magnetic Resonance (1H-NMR) and Gel Permeation Chromatography (GPC). Polymeric micelles were prepared by dialysis method and critical micelle concentration of these micelles were determined by Fluorescence Spectrophotometer. The particle size, particle size distribution and charge of the micelles were measured by Dynamic Light Scattering (DLS) technique. The pH sensitivity of the copolymers was found by acid base titration method and the micelle morphology was characterized by Scanning Electron Microscope (SEM). In addition, surface characterization of PEO coated star copolymers were identified by X-Ray Photoelectron Spectroscopy (XPS). The increase in ether (-CO-) signal in the C1s envelope proved that PEO chains effectively bind to the nanoparticle surface. The results obtained from characterization studies were showed that the amphiphilic copolymers were successfully synthesized and they were able to form micelles at low concentrations (0,001 to 0,068 mg/mL). The particle size measurements showed that the micelle size of block copolymers was 60 to 92 nm, the micelle size of graft copolymers was 95 to 121 nm and the micelle size of star copolymers was between 110 to 160 nm. Biodegradation behavior of the synthesized copolymers were performed in phosphate buffer solution at pH 7.4 and hydrolytic degradation of approximately 50% of the copolymers was observed within 2-3 days. In the second stage, the sol-gel phase transition properties of the synthesized copolymers were analyzed. The copolymer solutions were prepared at certain concentrations and the gel forming properties were determined at different temperature and pH values by tube inverting method. It was observed that all the copolymers at a concentration of 25% can form a gel. By adjusting the length of each block, the conditions of copolymer solution for injection at room temperature and gel formation under physiological environment (37°C and pH 7.4) were detected. In the last part of this study; an anticancer drug, etoposide that was poorly soluble in water and highly toxic when used directly was loaded to copolymers in two different ways. In the first way, etoposide at diffrent concentrations (5, 10, 15, 20 mg/mL) was encapsulated in the hydrophobic core of the polymeric micelles that self assembly in water with dialysis method. The second way was direct mixing of etoposide with copolymers and the drug effectively loaded to the polymeric carrier during gel formation. The drug loading efficiency of these carriers were determined by UV-VIS spectrophotometer and the optimum etoposide loading content was found to be 10 mg/mL. In vitro release studies of etoposide from polymeric micelles and nanoparticles were evaluated in three different phosphate buffer media: acidic pH (5.0 and 6.5) and physiological pH (7.4). In vitro release studies of etoposide from gels were evaluated in physiological pH. The drug release properties of these two different carriers were compared. In conclusion; it was shown that etoposide can be administered orally to the body which is an efficient and easy release way when loaded polymeric micelles. Also, etoposide can be administered by injection because of the advantage of sol-gel phase transition of the copolymers.