Degradable Long-lasting Drug-loaded Ultrasound Contrast Agents

Ultrasound contrast agents is a kind of chemical agent, it can reinforce ultrasound backscattering strength obviously. The range of size distribution is 2-8μm, and it can through the pulmonary circuit. Generally, biodegradable polymer materials are fabricated as shell of ultrasound contrast agents. Biodegradable polymer materials can degrade through simple biological chemical reactions or enzyme catalysis reactions in organism. The degradation products of this material are nontoxic and harmless monomers, these can be absorbed by organism and can also generate CO2 and H2O by participating in the metabolism. Such kind of biodegradable polymer materials are nontoxic and harmless for human body. Due to their good biocompatibility, high degradation performance, low biological toxicity, degradation speed and the chemicophysical properties can be adjusted etc. Biodegradable polymer materials have drawn great attention in physic field.Due to tri-block copolymer PLGE (PLGA-PEG-PLGA) based on the lactide, glycolide and polyethylene glycol (PEG) contains hydrophilic PEG segment, it can accelerate the speed of degradation. Using PLGE as drug carrier for drugs embedding, it can accomplish drug targeting and controlled release.Tri-block copolymer poly (lactide-co-glycolide) -b-poly(ethylene oxide)-b-poly (lactide-co-glycolide) (PLGE) were synthesized by copolymerization method and characterized by gel permeation chromatography (GPC), nuclear magnetic resonance (NMR). Rhodamine B(RhB)-loaded PLGE microspheres were fabricated by solvent evaporation method(O/W) and urokinase(UK)-loaded PLGE microspheres were prepared by double emulsion solvent evaporation method (W/O/W). Surface morphology of microspheres was characterized by scanning electron microscopy (SEM). Actual drug loading(DL) and encapsulation efficiency(EE) were measured by uv-vis spectrophotometer. Influence of the preparation methods, the added steps of external water, drug concentration, ethanol volume, species of solvent, chain length of PEG on microsphere morphology, DL and EE from RhB-loaded PLGE microspheres were studied. Influence of the polymer molecular weight, organic solvents volume, internal waters phase volume, ethanol volume, PVA concentration on microsphere morphology, DL and EE from urokinase-loaded PLGE microspheres were also studied. Drug release behavior under ultrasonic of RhB-loaded microspheres and degradation behaviors of RhB-loaded microsphere were studied.The results show that the influence of preparation conditions on RhB-loaded microspheres, RhB-loaded microspheres fabricated by W/O/W are easily ruptured, and the EE is lower. RhB-loaded microspheres size distribution and DL increased by increasing RhB concentration. DL and EE improved obviously by using toluene as solvent. Microparticle size distribution fabricated with two-step is smaller and more equal than one-step, but the microspheres fabricated with two-step are also easily ruptured and EE is much lower than one-step. Microspheres size distribution decreased by increasing ethanol volume. When ethanol volume increases to 1ml, microspheres are easily ruptured. Microspheres size, pore size and EE increased by increasing the PEG chain length.The influence of preparation conditions on urokinase-loaded microspheres, microspheres size distribution increased by increasing polymer molecular weight. Microspheres size distribution decreased by increasing methylene chloride volume. But microsphere will not be spherical when methylene chloride volume is too large. Microsphere size increase by increasing the internal water phase volume. Microspheres size distribution decreased by increasing ethanol volume, pore size also decreased and the surface of microspheres was smoother. There is few influence of PVA concentration on microspheres size distribution.Results of drug release behavior under ultrasonic show that the ultrasound effect was not obvious. And the reseaon is that RhB drugs was not loaded in the internal of PLGE microspheres, but dispersed in the surface of microspheres uniformly. Results of degradation experiment show that the degradation of microspheres beganfrom microsphere surface firstly. The pore on the surface was disappeared gradually with degradating, the microspheres were not spherical and size dispersion became smaller. It accelerated degradation speed by increasing the PEG segments length.