Ma Guoqing, Liu Jie, He Jinlin, Zhang Mingzu, Ni Peihong
College of Chemistry, Chemical Engineering and Materials Science, State and Local Joint Engineering Laboratory for Novel Functional Polymeric Materials, Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, Suzhou Key Laboratory of Macromolecular Design and Precision Synthesis, Soochow University, Suzhou 215123, P. R. China.
ACS Biomater Sci Eng. 2018 Jul 9;4(7):2443-2452. doi: 10.1021/acsbiomaterials.8b00429. Epub 2018 Jun 8.
The development of novel stimuli-responsive and biodegradable polyphosphoester-anticancer prodrugs is of importance in designing water-soluble prodrugs utilized in the field of drug delivery. In this study, the focus is on the synthesis of biocompatible and biodegradable diselenide-containing polyphosphoester [PEEP--PBYP-Se] using reduction-responsive di(1-hydroxylundecyl) diselenide as an initiator to polymerize 2-(but-3-yn-1-yloxy)-2-oxo-1,3,2-dioxaphospholane (BYP) and 2-ethoxy-2-oxo-1,3,2-dioxaphospholane (EOP). After that, a doxorubicin (DOX) derivative containing an azide group was linked onto the side chain of [PEEP--PBYP-Se] via the Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) "click" reaction to yield a pH/reduction-responsive polymeric prodrug, namely [PEEP--(PBYP--DOX)-Se]. The chemical structures of various polymers were characterized by nuclear magnetic resonance spectroscopy, ultraviolet-visible spectrophotometer, Fourier transform infrared spectroscopy, and high-performance liquid chromatography. The self-assembly behavior measured by dynamic light scattering and transmission electron microscopy clearly supported the formation of the prodrug nanoparticles (NPs). The results indicated that the polymeric prodrug NPs were relatively uniform spheres that could maintain stability in a physiological condition but be cleaved in acidic or reductive medium. Furthermore, the pH- and reduction-responsive properties of the prodrug NPs were investigated via drug release in vitro in different media. It turned out that the drug was efficiently released in acidic or reductive medium compared with that under physiological conditions. The results of methyl thiazolyl tetrazolium assays confirmed the favorable biocompatibility of [PEEP--PBYP-Se]. Moreover, the cell cytotoxicity and intracellular uptake experiments were carried out to verify the efficient cellular proliferation inhibition. This finding contributes to the design of a novel diselenide-containing polyphosphoester-doxorubicin prodrug.
新型刺激响应性和可生物降解的聚磷酸酯-抗癌前药的开发对于设计用于药物递送领域的水溶性前药具有重要意义。在本研究中，重点是使用还原响应性二（1-羟基十一烷基）二硒化物作为引发剂，聚合2-（3-丁炔-1-基氧基）-2-氧代-1,3,2-二氧杂磷环戊烷（BYP）和2-乙氧基-2-氧代-1,3,2-二氧杂磷环戊烷（EOP），合成具有生物相容性和可生物降解性的含二硒化物聚磷酸酯[PEEP--PBYP-Se]。之后，通过铜（I）催化的叠氮化物-炔烃环加成（CuAAC）“点击”反应，将含叠氮基的阿霉素（DOX）衍生物连接到[PEEP--PBYP-Se]的侧链上，得到一种pH/还原响应性聚合物前药，即[PEEP--(PBYP--DOX)-Se]。通过核磁共振光谱、紫外可见分光光度计、傅里叶变换红外光谱和高效液相色谱对各种聚合物的化学结构进行了表征。通过动态光散射和透射电子显微镜测量的自组装行为清楚地支持了前药纳米颗粒（NPs）的形成。结果表明，聚合物前药NPs是相对均匀的球体，在生理条件下可以保持稳定，但在酸性或还原介质中会被裂解。此外，通过在不同介质中的体外药物释放研究了前药NPs的pH和还原响应特性。结果表明，与生理条件下相比，药物在酸性或还原介质中能有效释放。甲基噻唑基四氮唑测定结果证实了[PEEP--PBYP-Se]具有良好的生物相容性。此外，进行了细胞毒性和细胞内摄取实验以验证有效的细胞增殖抑制作用。这一发现有助于设计一种新型的含二硒化物聚磷酸酯-阿霉素前药。
