Huang Xiangxuan, Liao Wenbo, Zhang Gang, Kang Shimin, Zhang Can Yang
School of Chemical Engineering and Energy Technology, Dongguan University of Technology, Dongguan, People's Republic of China.
Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, WA, USA.
Int J Nanomedicine. 2017 Mar 21;12:2215-2226. doi: 10.2147/IJN.S130037. eCollection 2017.
A novel amphiphilic pH-sensitive triblock polymer brush (poly(β-amino esters)--cholesterol)--poly(ethylene glycol)--(poly(β-amino esters)--cholesterol) ((PAE--Chol)--PEG--(PAE--Chol)) was designed and synthesized successfully through a three-step reaction, and their self-assembled polymeric micelles were used as hydrophobic anticancer drug delivery carriers to realize effectively controlled release. The critical micelle concentrations were 6.8 μg/mL, 12.6 μg/mL, 17.4 μg/mL, and 26.6 μg/mL at pH values of 7.4, 6.5, 6.0, and 5.0, respectively. The trend of critical micelle concentrations indicated that the polymer had high stability that could prolong the circulation time in the body. The hydrodynamic diameter and zeta potential of the polymeric micelles were influenced significantly by the pH values. As pH decreased from 7.4 to 5.0, the particle size and zeta potential increased from 205.4 nm to 285.7 nm and from +12.7 mV to +47.0 mV, respectively. The p of the polymer was confirmed to be approximately 6.5 by the acid-base titration method. The results showed that the polymer had sharp pH-sensitivity because of the protonation of the amino groups, resulting in transformation of the PAE segment from hydrophobic to hydrophilic. Doxorubicin-loaded polymeric micelles were prepared with a high loading content (20%) and entrapment efficiency (60%) using the dialysis method. The in vitro results demonstrated that drug release rate and cumulative release were obviously dependent on pH values. Furthermore, the drug release mechanism was also controlled by the pH values. The polymer had barely any cytotoxicity, whereas the doxorubicin-loaded system showed high toxicity for HepG2 cells as free drugs. All the results proved that the pH-sensitive triblock polymer brush and its self-assembled micelle might be a potential delivery carrier for anticancer drugs with sustained release.
通过三步反应成功设计并合成了一种新型两亲性pH敏感三嵌段聚合物刷（聚（β-氨基酯）-胆固醇）-聚乙二醇-（聚（β-氨基酯）-胆固醇）（（PAE-Chol）-PEG-（PAE-Chol）），其自组装聚合物胶束用作疏水性抗癌药物递送载体以实现有效控释。在pH值为7.4、6.5、6.0和5.0时，临界胶束浓度分别为6.8μg/mL、12.6μg/mL、17.4μg/mL和26.6μg/mL。临界胶束浓度的趋势表明该聚合物具有高稳定性，可延长其在体内的循环时间。聚合物胶束的流体动力学直径和zeta电位受pH值的显著影响。随着pH从7.4降至5.0，粒径和zeta电位分别从205.4nm增加到285.7nm，从+12.7mV增加到+47.0mV。通过酸碱滴定法确定该聚合物的p约为6.5。结果表明，由于氨基的质子化，该聚合物具有敏锐的pH敏感性，导致PAE链段从疏水性转变为亲水性。采用透析法制备了载药量高（20%）和包封率高（60%）的载阿霉素聚合物胶束。体外结果表明，药物释放速率和累积释放明显依赖于pH值。此外，药物释放机制也受pH值控制。该聚合物几乎没有细胞毒性，而载阿霉素体系对HepG2细胞显示出与游离药物一样的高毒性。所有结果证明，pH敏感三嵌段聚合物刷及其自组装胶束可能是一种潜在的抗癌药物缓释递送载体。
