Drug Delivery Properties And Blood Compatibility Of Polyeletrolyte Microcapsules

Polyeletrolyte microcapsules possess unique structure and variable properties. Theyhave many merits, such as finely controlled wall thickness, dimension and permeability. Therange for choosing wall materials is considerably wide and many kinds of naturalmacromolecules have been successfully used in the preparation of microcapsules.Polyeletrolyte microcapsules have attractive future application prospects; however, they haveto face the problem of blood compatibility in terms of in vivo application. Therefore, thiswork mainly studies the blood compatibility, the controlled drug release, and the targeteddelivery of microcapsules.Polyeletrolyte microcapsules and the corresponding polyeletrolyte multilayer have thesame physical and chemical structure. The results obtained from multilayer can beanalogically applied to microcapsules. Compared to microcapsules, however, the methodsand instruments to analyze the multilayer are more abundant. Therefore, poly(styrenesulfonate) /poly(allylamine hydrochloride) multilayers were assembled on silicone wafers viathe technique of layer-by-layer assembly. Their surfaces were further modified eitherphysically or chemically with bovine serum albumin (BSA), heparin and polyethylene glycol(PEG). Protein adsorption on these surfaces was investigated by quartz crystalmicrobalance-dissipation (QCM-D), ellipsometry and atomic force microscopy (AFM). Thedynamic adsorption process of BSA on these multilayers was monitored by QCM-D,revealing that the adsorption equilibrium was rapidly achieved within 3min on the controland heparin adsorbed multilayer surfaces, and within 5-10 min on the chemically bondedBSA and PEG surfaces, but more than 80min on the BSA physically modified surface. Afteradsorption of BSA or fibrinogen, all the modified multilayers became smoother due to theeffect of "surface valley adsorption". Ellipsometry characterization found that the adsorbedmount of BSA, fibrinogen and plasma proteins on all the modified multilayers were smallerthan that of the unmodified control multilayers. The platelet adsorption on the multilayerswas analyzed by SEM, revealing that the number of the adsorbed platelets on all the modifiedsurfaces except of the heparin modified one was significantly reduced. The prothrombin time(PT) of all the modified multilayers was prolonged compared with that of the unmodifiedmultilayers, but there was no significant difference between all the samples. Furthermore, the blood compatibility of the polyeletrolyte microcapsules was studied.PAH/PSS microcapsules were fabricated and their surfaces were further modified eitherphysically or chemically with bovine serum albumin (BSA), heparin and polyethylene glycol(PEG). Protein adsorption on the surfaces was investigated by fluorescence microscopy,scanning force microscopy (SEM) and AFM. The amount of BSA adsorbed on theunmodified control microcapsules and the BSA physically modified microcapsules arecomparatively larger than that on other capsules. The plasma recalcifation time (PRT) and thewhole blood coagulation time (CT) of microcapsules with the chemically bonded BSA andPEG outmost surfaces were prolonged than than that of the unmodified controlmicrocapsules.Subsequently, carboxymethyl cellulose (CMC)-doped CaCO₃ microparticles with anaverage diameter of 5μm were prepared and coated by chitosan and alginate multilayers. Theprepared CaCO₃ microparticles had a dominant phase of vaterite and a spherical morphologywith nanopores on their surface. These particles could spontaneously load positively chargeddoxorubicin (DOX) molecules, whose amount was 475 mg DOX/g CaCO₃ for theCaCO₃(CMC) microparticles. The loading was almost completed within 5 h, with a finalencapsulation efficiency of＞95%. Confocal laser scanning microscopy (CLSM) alsoconfirmed the deposition and even distribution of DOX into the inner core of microparticles.Bunauer-Emmett-Teller (BET) method was used to analyze the specific surface area and thepore size distribution of the CaCO₃(CMC) microparticles before and after DOX loading.After DOX loading, S_BET and pore volume were reduced obviously, and the volume ofsmaller pores less than 9 nm decreased significantly, whereas that of larger pores wereincreased. The increase of the volume of larger pores was explained by an electric chargescreening effect. DOX release from the CaCO₃ microparticles in pH 5 was relatively smallwithin the first 15 h, and could be sustained to more than 150 h The release amount at lowerpH was larger at the same time. In pH7.4 PBS buffer, DOX would not be released from themicroparticles. This would be a safe advantage to normal tissue for future in vivo applicationprospects. Coating of the CaCO₃(CMC) microparticles with the chitosan/alginate multilayerscould obviously assuage the initial burst release and reduce the release rate.To enhance the utilization efficiency of loaded drugs and reduce their side-effects, the targeted delivery of the folic acid (FA)-modified microcapsules was also studied. (PAH/GA)₃microcapsules were fabricated on the dextran sulfate (DS)-doped CaCO₃ microparticlesthrough the chemical bonding of PAH with glutaraldehyde (GA). Then FA was immobilizedon the microcapsules through the linkage of diamino terminated poly(ethylene glycol) (PEG)under the catalysis of l-ethyl-3-(3-dimethylamino-propyl) carbodiimide (EDAC)/N-hydroxysuccinimide (NHS). The chemical bonding reaction did not affect the surface morphology ofthe microcapsules as evidenced by SEM and AFM. The morphology of the microcapsuleswould not deter the cell uptake. The infrared spectroscopy (IR) and the ultravioletspectroscopy (UV) confirmed the chemical bonding of PEG and FA on the microcapsules.The amount of FA bonding on capsules was increased as the reaction time prolonged. Thenon-special adherence of capsules bonding with PEG on cells reduced obviously comparedwith that of unmodified capsules. The FA modified microcapsules could selectively adsorbonto HepG2 tumor cells with folate receptor mediated specific recognition. The amount of FAmodified microcapsules ingested by HepG2 cells were larger than that of capsulesunmodified with FA. Also the amount of FA modified capsules ingested by HepG2 cellsincreased with the increased amount of FA on the surface.