The Synthesis, Characterization And In Vivro Drug Delivery Behavior Of Poly(ε-caprolactone) Copolymers Bearing Ketone Groups

Poly(ε-caprolactone) (PCL) have drawn considerable attention due to its excellent biodegradability, biocompatibility and drug permeability since 1990s. Especially, over the last several years, with the rapid development of nano self-assembly techniques, amphiphilic copolymer composed of hydrophobic poly(ε-caprolactone) (PCL) and hydrophilic polymers have been extensively studied in the field of drug delivery. Nowadays, the preparation of biocompatible, biodegradable and intelligent stimulus responsive drug delivery system is the current research focus and development trends. Base on this back ground and development trends, a functional poly(e-caprolactone) copolymer bearing reactive ketone groups (P(OPD-co-CL)) was developed using 2-oxepane-1,5-dione (OPD) as research starting point, and block copolymer and graft copolymer contain hydrophilic chain were also synthesized by further functional modification. All the amphiphilic polymers underwent self-assemble to form micelles and their loaded hydrophobic drug doxorubicin (DOX), oleic acid modified Fe3O4 nanoparticles and 5-fluorouracil (5-Fu) micelles were prepared by utilizing the charateristics of core. In addition, the drug release behavior of drug-loaded polymer micelles was also studied. Four sections of work were carried out as follows:1. A amphiphilic functional block poly(ε-caprolactone) copolymer bearing ketone groups (MPEG-b-P(OPD-co-CL)) was synthesized.2-oxepane-1,5-dione (OPD) synthesized by Baeyer-Villiger oxidation of 1,4-cyclohexaedione was copolymerized withε-caprolatone (ε-CL) in which methoxy poly(ethylene glycol) (MPEG) and stannous octoate were used as initiator and catalyst, respectively. Both bulk and solution polymerization were adopted to investigate the effect of temperature on the structure of the copolymers. All the polymers were characterized by 1H-NMR, DSC, TGA and contact angle measurement. It demonstrated that the amphiphilic block copolymer with functional groups (MPEG-b-P(OPD-co-CL)) were successfully synthesized by solution polymerization. In constrast, the copolymers obtained by bulk polymerization were inclined to degrade due to the high reaction temperature.2. Blank and DOX-loaded micelles of (MPEG-b-P(OPD-co-CL)) were prepared by a dialysis method. The effects of micelle preparation conditions and content of OPD on the critical micelle concentration (CMC) and size of polymer micelles were investigated. The polymer micelles showed uniform manodispersed spherical. The presence of ketone groups on PCL bolck is favorable to increase the thermodynamic stability of polymer micelles and sustained-release effect of drug-loaded polymer micelles in physiological environment (pH7.4).3. With uniform size, regularly spherical shape, good magnetic responsiveness and stability of loaded oleic acid modified nano-Fe3O4 MPEG-b-(OPD-co-CL) micelles and loaded nano-Fe3O4 and DOX MPEG-b-(OPD-co-CL) micelles were carried out by a dialysis method. The drug release behavior of magnetic DOX-loaded polymer micelles was investigated. The magnetic polymer micelles and magnetic DOX-loaded polymer micelles were characterized by hysteresis loop, XRD and TGA. It was found that the polymer micelles containning oleic acid modified nano-Fe3O4 and DOX package leaded to a change in their crystalline, this result confirmed that the nano-Fe3O4 and DOX were loaded in the core of micelles; The content of nano-Fe3O4 increased with that of ketone groups increased in the hydrophobic chain, but the polymer micelles containning DOX package had little effect on the content of nano-Fe3O4. In addition, the polymer micelles containning oleic acid modified nano-Fe3O4 package also had no impact on the DLC and DEE, but are benificial to increase sustained-release effect of DOX-loaded polymer micelles in physiological environment (pH7.4).4. The amphiphilic graft copolymers containing PCL as the hydrophobic main chain and poly(N-isopropylacrylamide) (PNIPAM) as the temperature-sensitive side chain on the side were synthesized. We use hydroxyethyl hydrazine and p-nitrophenyl chloroformate as space molecule and couping agent, respectively. The structure of copolymers was confirmed by 1H NMR, FTIR and GPC. The self-assembly of graft copolymer in the selective solvent was also investigated by 1H NMR in D2O, TEM, DLS, fluorescence spectroscopy and UV-Vis spectrometer. The micelles exhibited thermo-and pH-sensitivity. In addition, the 5-Fu-loaded micelles also showed thermo-and pH-sensitive release characteristics in the drug release system.