Application For Controlled Drug Release Of Biomedical Polymers And Their Safety Evaluation

This thesis mainly consists of two parts. One is about the study on poly(D,L-lactic)microspheres embedded in calcium alginate hydrogel beads as dual drug delivery dystems. Theother is about the effects of the gene carrier material polyethyleneimine (PEI) on the structureand function of blood componentsⅠ. Study on poly(D,L-lactic) microspheres embedded in calcium alginate hydrogel beadsas dual drug delivery dystems（the second charpter）This work is to develop a novel dual drug delivery system that can simultaneously load andrelease18b-glycyrrhetinic acid (GA, a hydrophobic drug) and bovine serum albumin (BSA,hydrophilic model drug) in a single formulation. The system consists of poly(D,L-lactic)(PDLLA) microspheres embedded in calcium alginate hydrogel beads. Scanning electronmicroscope (SEM) revealed that the PDLLA microspheres were homogeneously distributed inthe beads. Differential scanning calo-rimetry (DSC) measurement suggested certain interactionbetween GA and PDLLA, and the crystal structure of GA was influenced by the polymer. Thedual release in vitro showed a rapid BSA release but a sustained GA release in all the systems.Furthermore, the release rate of BSA was accelerated by increasing PDLLA/alginate ratio, whilethe release rate of GA was decreased, and the release of both hydrophobic and hydrophilic drugscould be adjusted by changing the ratio of PDLLA/alginate.This dual carrier system to deliver multiple drugs may find broad utility in complicatedclinical syndrome which needs several drugs to treat.Ⅱ. Effects of the gene carrier material polyethyleneimine on the structure and function ofblood components（the third and forth charpter）As a synthetic polycation, PEI is currently one of the most effective non-viral gene carriers.For in vivo applications, PEI will enter systemic circulation and interact with various bloodcomponents and then affect their individual bio-functions. Up to now, overall and systematicinvesti-gation on the interaction of PEI with multiple blood components at cellular, membrane,and molecular levels is lacking, even though it is critically important for the in vivo safety of PEI.In view of this, this dissertation investigated the effects of PEI with different molecular weight (MW,0.6kDa,1.8kDa,25kDa) and shape (branched or linear) on key blood components andfunction.1. Effects of the gene carrier polyethyleneimines on structure and function of plasma proteinsand blood cellsThis section investigated the effects of PEI with different molecular weight (0.6kDa,1.8kDa,25kDa) and shape (branched or linear) on RBC aggregation and morphological change,platelet activation, conformation change of albumin, and blood coagulation process. Additionally,more proteins from plasma were screened and identified to have associations with PEI by aproteomic analysis. It was found that, the PEIs have severe impact on RBC membrane structure,albumin conformation, and blood coagulation process, but do not significantly activate plateletsat low concentrations. Furthermore,41plasma proteins were identified to have some interactionwith PEI. This indicates that, besides albumin, PEI does interact with a variety of blood plasmaproteins, and could have unexplored effects on their structures and bio-functions.2. Effects of the gene carrier polyethyleneimines on structures and functions of plasma proteinand erythrocyte and whole bloodThis section investigated the effects of PEI with different molecular weight (0.6kDa,1.8kDa,25kDa) and shape (branched or linear) on fibrin polymerization test, the structure offibrinogen, the internal structure of blood clot, in vitro hemolytic, the morphology, surfaceroughness, membrane proteins, and enzyme activity on erythrocyte membrane. The results revealthat, the PEIs alter the struture and conformation of fibrinogen and then modify the fibrinpolymerization process. As a result, the clotting function of the PEIs-containing blood is alsoaffected. Besides, hemolysis induced by the PEIs, the PEIs also have severe impact on themorphology, roughness, and membrane proteins, and inhibit acetylcholinesterase activity oferythrocyte membrane.These results provide good insight into the molecular design and blood safety of PEI andother polycations for in vivo applications.