The Synthesis, Structures, Properties And Phase Transitions Of Thermo-pH Sensitive Copolymer-liposome

Since liposome was proposed as a drug carrier, many attentions have been paid to design stimuli-sensitive liposome. Among these stimuli, pH-sensitive liposome has attracted many researchers' attentions. As the pH of endosoma of the cancerous cell is lower than that of extracellular fluids, this feature has been exploited in the design of systems that facilitate the delivery of active compounds to the cytoplasm via a pH-dependent membrane-disruptive and/or fusogenic action. Recent studies have demonstrated that polymers have also investigated to confer pH-responsiveness to liposome. The addition of polymers can alter the composition of membrane or modify the surface of liposome, and it can exhibit prolonged circulation times in vivo and accumulate in tumors. Temperature sensitive liposome has been investigated to control release drug at phase transition temperature in many-studies. The phase transition temperature of the liposome can be changed by changing the hydrophilic or hydrophobic monomers of the polymer. However, to the best of our knowledge, the report regarding pH-temperature sensitive copolymer-liposome is scarce. The studies of synthesis and property of pH-temperature sensitive copolymer-liposome are hence of most importance and remains a challenging problem, and the research focuses on controlled drug release both spatially and temporally.In this thesis, we focused on synthesis of the pH-temperature sensitive copolymer and pH-temperature sensitive copolymer-liposome, the phase behaviors of the copolymer solution and copolymer-liposome solution, and the control drug release from the copolymer-liposome. The main results presented in this thesis are summarized below.1. Copolymer with various phase transition pH can be synthesized by controlling composition of the copolymer. The phase transition of the copolymer depends on the composition and concentration of the copolymer. The temperature-pH sensitivity of the copolymer solution increases with the MAA content in the copolymer. The lower critical solution temperature (LCST) and phase transition pH (pH*) of the copolymer solution decrease with the increasing MAA content. The LCST of the copolymer solution can reach a maximum at the pH*. The LCST decreases with the increasing copolymer concentration, but the pH* was not affected by the concentration.2. The critical micelle concentration (CMC) of the copolymer solution depends on the copolymer composition. The CMC decreases with increasing the hydrophobicity of the copolymer. The CMC increases with MAA content at the fixed ODA content.3. The micelle of the copolymer was not affected by the temperature and pH, when the temperature was below the LCST of the copolymer solution. The mean diameter of the micelle increases with temperature, and it can reach the minimum at pH*.4. The phase transition temperature and micelle size of the copolymer-liposome were affected by the copolymer and berberine hydrochloride (ber), and the mean diameter and phase transition temperature can reach the maximum at phase transition pH*. When the mass ration of the copolymer to SPC (w) was 1:2, the mean diameter and phase transition temperature was the maximum value. The copolymer-liposome was most stable at the pH* and w=1:2. The mean diameter and phase transition temperature were decreased by addition of berberine, but the pH* of the copolymer-liposome was not affected by addition of bererine.5. The berberine release from the copolymer-liposome was the maximum value at the phase transition temperature and pH* of the copolymer-liposome.