Synthesis and Properties of Aliphatic Polycarbonate Copolymers and EPR Imaging Contrast Agents
|School||Wuhan Institute of Technology|
|Keywords||Biodegradable polycarbonate ring-opening poly-merization 5-carboxy-1,1,3,3-tetramethyl-isoindoin-2-yloxyl (CTMIO) porphyrin drug controlled release EPR imaging|
Biodergradable aliphatic polycarbonates are the most attractivebiodegradable materials that have been widely used in the medical fields,such as suture, bone fixing and drug delivery systems due to their goodbiocompatibility and biodegradability in recent years.Electron paramagnetic resonance imaging (EPRI) is a relativelyrecent imaging technique, which provides potentially multidimensionalimaging of the spatial distribution of paramagnetic species. Thanks to theuse of stable spin probes, low frequency EPR imaging has recentlyallowed the use of large tissue samples or whole animals in vivo in thefield of biology and medicine. It is normally necessary to introduce priorintravenous or intramuscular infusion of stable or slowly metabolizablenon-toxic water-soluble paramagnetic materials, or stable implantableparticulate materials as spin probes to the system.In this thesis, the trends in the development of biodegradablepolycarbonates for medical application have been reviewed andemphasized on their synthesis structures and properties. The classificationand research progress of spin probes for EPRI at present were furtherdescribed briefly. The important potential approaches in water-solubleparamagnetic materials design including site-specific andmacromolecular conjugated nitroxides were also investigated here.A series of aliphatic polycarbonate copolymers have beensynthesized by the bulk ring-opening polymerization between2-phenyl-5,5-bis(oxymethyl) trimethylene carbonate (PTC) and trimethylenecarbonate (TMC) with aluminium iso-propylate and Sn(Oct)2as thecatalysts. These polycarbonate copolymers were further reduced by thepalladium/carbonate (Pd/C) catalyst to obtain the partly deprotectedpolycarbonate copolymers. These two type copolymers obtained werecharacterized by1H NMR, FT-IR, UV, gel permeation chromatography(GPC), differential scanning calorimetry (DSC) and automatic contactangle meter. The influences of the feed molar ratio of monomers, catalystconcentration and reaction time as well as reaction temperature on the copolymerization process were also studied. The copolymerization ofPTC and TMC monomers was a non-ideal copolymerization and thecopolymerization reactivity ratio of TMC was higher than that of PTC inthe polymerization process. In vitro degradation tests indicated that partlydeprotected polycarbonate copolymers possessed the faster degradationrates and more hydrophilicity than those of unreduced polycarbonatecopolymers. In vitro release profiles of5-Fu from copolymers showedthat these two type copolymers had the steady drug release rates and goodcontrolled release properties. Moreover, partly deprotected polycarbonatecopolymers had faster drug release rates than those of unreducedpolycarbonate copolymers.Poly-α, β-[N-(2-hydroxylethy1)-L-aspartamide](PHEA) and itsderivatives are water-soluble polymers which have been used as plasmaexpanding agents and drug carriers due to low-cytotoxicity andnon-immunogenicity, good biocompatibility and biodegradability, easychemical modification. The water soluble tumor-targeting EPRI contrastagents were synthesized by the incorporation of5-carboxy-1,1,3,3-tetramethyl-isoindoin-2-yloxyl (CTMIO) as spin probes and5-(4-amino-phenyl)-10,15,20-tris(4-sulfonatophenyl)-porphyrin (Na3APTSPP) asthe tumor-targeting groups into the side chains of PHEA carriers. Thesecompounds obtained were further characterized by FT-IR,1H NMR, UV,DSC and in vitro properties were also evaluated. The results of in vitrocytotoxicity assay and relaxivity test showed that these macromolecularEPRI contrast agents possessed lower cytotoxicities to HeLa cells andobviously higher relaxation effectiveness than that of CTMIO.