还原和温度双重敏感P(NIPAM-AA)纳米凝胶的合成及载药性能

Synthesis and Drugloading Properties of Dual Thermo and Redox Sensitive P(NIPAM-AA ) Nnanogels

以N-异丙基丙烯酰胺(NIPAM)和丙烯酸(AA)为单体,N,N'-双丙烯酰胱胺(BAC)为交联剂,采用自由基沉淀聚合方法制备了一系列温度和还原敏感聚N-异丙基丙烯酰胺-丙烯酸(PNA)纳米凝胶.利用红外光谱、拉曼光谱、动态光散射、紫外-可见光谱和扫描电子显微镜等方法表征了纳米凝胶的结构、粒径、Zeta电位和形貌等,研究了PNA纳米凝胶对阿霉素盐酸盐(DOX)的负载和释放行为.结果表明,BAC的浓度对PNA纳米凝胶的温敏性和还原敏感性及载药率和药物缓释性能有较大影响.当BAC的浓度为0.32和1.6mmol/L时,PNA纳米凝胶具有很好的载药率,但BAC的浓度为0.32 mmol/L时,纳米凝胶交联密度较低,低温时DOX也能轻易扩散出来,释放4 h时,25和37℃的释放率分别为56%和58%,温度控制释放不明显.当BAC的浓度为1.6 mmol/L时,释放4 h时,25和37℃及模拟细胞还原微环境下[37℃,二硫苏糖醇(DTT)浓度为4 mmol/L]的释放率分别为56%,61%和77%,可见PNA纳米凝胶有一定的温度和还原敏感性,能很好地控制药物释放,适合作为药物载体.

Although doxorubicin（DOX） has been widely used in the treatment of different types of cancer, the muhi-drug resistance is still a bottle for its further clinical applications. Nanogels with high loading capaci- ty, good stability, environmental responsiveness（such as ionic strength, pH, temperature, reducing agent）, are promising therapeutic nanocarriers for targeting delivery of drugs in a controllable way. In this study, a series of thermo- and redox- sensitive P （NIPAM-AA） nanogels was developed by free radical precipitation polymerization of N-isopropylacrylamide （NIPAM） and acrylic acid （AA） as monomers in the presence of N, N＇-bis （acryloyl） cystamine （BAC） as crosslinking agent. The structures, particle size, Zeta potential, mor- phology, encapsulation efficiency and drug cumulative release [ using doxorubicin （DOX） as an anticancer model drugl of the prepared composite nanogels were characterized by FTIR, Raman spectrum, dynamic light scattering（ DLS ）, scanning electron microscopy （ SEM ） and ultraviolet-visible （ UV-Vis ） techniques. DLS study showed that BAC concentrations had great influence on thermo-sensitivity of nanogels as well as their Zeta potentials. UV-Vis study showed that when concentration of BAC was 1.6 and 0. 32 mmol/L, nanogels had good drug encapsulation efficiency（64.9% and 53.5% , respectively）. In vitro release study showed that temperature controlled DOX release was not obviously（ DOX cumulative release at 4 h was 56% and 58% at 25 and 37 ℃ , respectively） for the 0. 32 mmol/L BAC-crosslinking system, probably because of the loose structure of the nanogels at low crosslinking degree that allows for rapid DOX diffusion from the nanogels at both temperatures. When BAC concentration was increased to 1.6 mmol/L, DOX cumulative release at 4 h was 56% and 61% at 25 and 37 ℃, respectively. The release rate can be further accelerated in a medium mimicking the intracellular reductive environment （ 37 ℃ and in the presence of 4 mmol/L D, L-dithiothrei- tol）. The nanogels with good thermo- and redox-sensitivity can act as a good platform for delivery of various kinds of therapeutics, beyond anticancer drugs.