用于药物载体的多重响应型聚合物分子的设计与合成

利用原子转移自由基聚合(ATRP)法和连续ATRP法合成了温度敏感型聚合物和pH/温度双重敏感型聚合物。用紫外光谱考察聚合物在水溶液中的温敏行为,发现聚合物的低临界溶解温度(LCST)可以通过单体的比例进行调控,而且聚合物的温度响应行为非常敏感且具有可逆性。pH/温度双重敏感型聚合物还具有非常灵敏的pH响应行为,且不受单体比例的影响。最后,对聚合物胶束的体外释药动力学进行了研究,结果表明聚合物胶束的环境敏感性决定了药物的释放行为。

Design and Synthesis of Multi-Responsive Copolymers for Drug Carrier

A copolymer P(MEO₂MA_m-co-OEGMA_n)-b-PDPA_p (polydi(ethylene glycol) methyl ether methacrylate-co-oligo(ethylene glycol) methacrylate]-b-poly2-(diisopropylamino) ethyl methacrylate]) had been designed to have good stimuli-response for developing temperature/pH dual-responsive drug delivery systems. In this study, the copolymer was synthesized in two steps: atom transfer radical polymerization (ATRP) method, followed by the continuous ATRP method for P(MEO₂MA_m-co-OEGMA_n) and P(MEO₂MA_m-co-OEGMA_n)-b-PDPA_p, respectively. The data of proton nuclear magnetic resonance spectroscopy (¹H NMR) and gel permeation chromatography (GPC) showed that the chemical compositions of the two copolymers could be precisely controlled. The aqueous solution properties of the copolymers were investigated using a UV-visible spectrophotometer. Results showed that the former random copolymers had reversible temperature response, while the end product exhibited temperature/pH dual-responsive behaviors. Their lower critical solution temperatures (LCSTs) were found to be dependent on the ratios of the monomers. Firstly, the relationship between the monomer ratio and the low critical solution temperature (LCST) of P(MEO₂MA_m-co-OEGMA_n) was investigated. It was found that within the range of the experimental study (m + n = 100, 0 < n < 30), the LCST of the copolymer showed a linear relationship with the number of OEGMA units in each polymer chain. Then, the proportion of the two monomers (MEO₂MA_m and OEGMA) was fixed (m = 90, n = 10) and the random terpolymer P(MEO₂MA_m-co-OEGMA_n)-b-PDPA_p was synthesized. The LCSTs of P(MEO₂MA_m-co-OEGMA_n)-b-PDPA_p were found to be highly dependent on the DPA unit numbers in the range of 15 < p < 30 while their pH trigger points were not related to the chemical composition of the P(MEO₂MA_m-co-OEGMA_n)-b-PDPA_p. Finally, the copolymer P(MEO₂MA₉₀-co-OEGMA₁₀)-b-PDPA₂₂ with a LCST of 43 ℃ and a pH trigger point of 6.5 was carefully selected for preparing micelles, as a nanocarrier of doxorubicin (DOX) for an in vitro release study. The in vitro release kinetics of copolymer micelles were studied under different conditions. At pH 7.4, which mimics the normal physiological condition, the total release amount of DOX at 37 ℃ was about 25%, which was much higher than that at a higher temperature of 45 ℃ (approximately 5%). However, at pH 5.0, which mimics the intracellular environment, the cumulative release of the DOX quickly reached 95% at 37 ℃, while the cumulative release of the drug at 45 ℃ was only about 65% in the same period of time. For the latter, a slow and sustained release was observed and the cumulative drug release amount reached about 85% in 30 h. These results showed that the environmental stimuli response of the copolymer determined the drug release behavior of the micelles. This copolymer-based drug carrier could be expected to undergo bursting and sustained drug release in response to different conditions. Therefore, the results show potential for applications in the design and preparation of controllable drug transportation systems.