Synthesis And Characterization Of Polyester Based Polymers As Drug Carriers

Polyester based polymers are of growing interest in pharmaceutical field as drug carriers. These polymers are attractive due to their excellent biocompatibility and biodegradability. In this dissertation, a series of homopolymers and copolymers were synthesized by ring-opening polymerization of several cyclic monomers such asε-caprolactone (ε-CL), trimethylene carbonate (TMC), L-lactide (LLA) and p-dioxanone (PDO), with lipase or SnOct2 as the catalyst. Their corresponding structures, compositions, molecular weights, thermal properties, crystallinities, hydrolytic degradation, enzymatic degradation and applications as drug carriers were then investigated in detail.Lipase-catalyzed synthesis and characterization of several polyester based polymers were investigated: (1) Thiol end-functionalized poly(ε-caprolactone) (HS-PCL) was synthesized via ring-opening polymerization ofε-caprolactone (ε-CL) using Novozym 435 as biocatalyst, and 2-mercaptoethanol as initiator. ¹H-NMR and GPC results showed that Novozym 435 had high catalytic activity for the ring-opening polymerization ofε-CL and the thiol end-functionalized fraction could achieve 99%. The benefit of using a chemoselective lipase as catalyst was that protecting and deprotecting steps are unnecessary. (2) In the presence of methoxy poly(ethylene glycol) (mPEG), amphiphilic mPEG-PCL and mPEG-PTMC copolymers were synthesized via the lipase-catalyzed ring-opening polymerization ofε-CL and TMC, respectively. The structures of the copolymers were identified by ¹H-NMR and GPC. The mPEG-PCL and mPEG-PTMC copolymers could self-assemble into nano-sized micelles in aqueous solution. (3) NH2-PEG-PCL was prepared through lipase-catalyzed esterification of the carboxy end-groups of NH2-PEG-COOH with the hydroxy end-groups of PCL-OH. Then the amino groups of NH2-PEG-PCL were conjugated with the carboxylic groups of the folate. The resulting folate-conjugated PEG-PCL (FA-PEG-PCL) copolymers were characterized by ¹H-NMR and GPC and the results confirmed that the product had expected structure.A series of monodispersed high molecular weight homopolymers such as PCL, PTMC, PLLA and PPDO, and copolymers such as poly(TMC-ran-CL) (PTC), poly(LLA-ran-CL) (PLC) and poly(PDO-ran-CL) (PDC) were synthesized by ring-opening polymerization of appropriate monomers using SnOct2 as catalyst. The resulting polymers were characterized by using ¹H-NMR, ¹³C-NMR, ATR-FTIR and GPC, which confirmed the random characteristic of the copolymers. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) revealed the amorphous state of the copolymers.Furthermore, the degradation behaviors of the PTC, PLC and PDC copolymers were investigated. Non-enzymatic hydrolysis experiments of the polymers were performed in water solutions with different pH values (1.0, 7.4 and 9.0) at 37°C. Enzymatic degradation of the polymers was investigated in PBS (pH 7.4) containing 0.02% lipase from porcine pancreas (PPL). It was found that: (1) PTC copolymers exhibited a faster degradation rate than PCL and it degraded fastest in aqueous media at pH 7.4. The degradation of PTC copolymers was accelerated according to surface erosion mechanism in the presence of PPL. ¹H-NMR data showed that the composition of PTC remained almost unchanged during hydrolytic degradation. However, the CL content decreased in the enzymatic degradation. (2) Degradation of PLC was found to be much faster than that of PCL. The degradation rate was faster for copolymers with higher molecular weight or higher LLA content. In addition, PLC degraded fastest in aqueous media at pH 1.0. The degradation of polymers was accelerated via PPL catalyzing the hydrolysis of ester bond. ¹H-NMR data showed that the LLA content decreased during hydrolytic degradation. In contrast, the CL content decreased in the enzymatic degradation. (3) PDC had a faster degradation rate than PCL, and PDC degraded fastest in aqueous media at pH 1.0. The water uptake and weight loss of the PDC copolymers increased with the PDO content. Overall, it could be concluded that the degradation rate can be adjusted by varying the composition of the copolymers.In another work, the application of polymers in the pharmaceutical field was investigated: (1) Paclitaxel loaded mPEG-PCL nanoparticles were prepared by emulsion/solvent evaporation technique with mPEG-PCL-1 (PEG wt%=18.5%) as drug carrier and mPEG-PCL-2 (PEG wt%=77.6%) as the emulsifier. The mean hydrodynamic diameters of the mPEG-PCL nanoparticles ranged from 70 to 100 nm. Paclitaxel loaded FA-PEG-PCL nanoparticles were prepared by nano-precipitation technique with FA-PEG-PCL and mPEG-PCL-2 as drug carriers. The fabricated paclitaxel loaded FA-PEG-PCL nanoparticles reached the highest encapsulation efficiency of 48.8% when the feed ratio was 5%. TEM investigations exhibited that both mPEG-PCL nanoparticles and FA-PEG-PCL nanoparticles had fine spherical shape and narrow particle size distribution. The paclitaxel loaded FA-PEG-PCL nanoparticles could achieve a sustained drug release for 6 days. (2) A series of cylindrical 5-FU loaded PCL implants with different drug loadings (25% and 50%) and same diameter (2 mm) were prepared by hot-melt extrusion. The in vitro release results showed that, for the implants with the same diameter, the release of drug from the implants with 50% drug loading was faster than that from the implants with 25% drug loading. SEM images revealed that 5-FU release took place gradually from the exterior region to the interior region of the implants. The GPC results suggested that PCL matrix degradation was very slow during the period of the study.