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Dual-Responsive Polyphosphoester-Doxorubicin Prodrug Containing a Diselenide Bond: Synthesis, Characterization, and Drug Delivery
ACS Biomaterials Science & Engineering ( IF 5.4 ) Pub Date : 2018-05-22 00:00:00 , DOI: 10.1021/acsbiomaterials.8b00429 Guoqing Ma 1 , Jie Liu 1 , Jinlin He 1 , Mingzu Zhang 1 , Peihong Ni 1
ACS Biomaterials Science & Engineering ( IF 5.4 ) Pub Date : 2018-05-22 00:00:00 , DOI: 10.1021/acsbiomaterials.8b00429 Guoqing Ma 1 , Jie Liu 1 , Jinlin He 1 , Mingzu Zhang 1 , Peihong Ni 1
Affiliation
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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-b-PBYP-Se]2 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-b-PBYP-Se]2 via the Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) “click” reaction to yield a pH/reduction-responsive polymeric prodrug, namely [PEEP-b-(PBYP-hyd-DOX)-Se]2. 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-b-PBYP-Se]2. 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.
中文翻译：
含二硒键的双反应性多磷酸酯-阿霉素前药：合成，表征和药物输送。
新型刺激响应性和可生物降解的多磷酸酯-抗癌前药的开发对于设计在药物递送领域中使用的水溶性前药具有重要意义。在这项研究中，重点是使用具有还原反应性的二（1-羟基苯癸基）二硒化物作为引发剂，聚合2-（but-3），合成具有生物相容性和可生物降解性的二硒化物的聚磷酸酯[PEEP - b -PBYP-Se] 2。 -yn-1-yloxy）-2-oxo-1,3,2-dioxaphospholane（BYP）和2-ethoxy-2-oxo-1,3,2-dioxaphospholane（EOP）。之后，将含有叠氮基的阿霉素（DOX）衍生物连接到[PEEP- b -PBYP-Se] 2的侧链上通过Cu（I）催化的叠氮化物-炔烃环加成（CuAAC）“点击”反应产生pH /还原反应性聚合物前药，即[PEEP- b-（PBYP- hyd -DOX）-Se] 2。通过核磁共振波谱，紫外可见分光光度计，傅立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，聚合前药NP是相对均匀的球体，可以在生理条件下保持稳定性，但在酸性或还原性介质中裂解。此外，通过在不同介质中体外药物释放来研究前药NP的pH和还原响应特性。事实证明，与在生理条件下相比，该药物在酸性或还原性培养基中有效释放。甲基噻唑基四唑鎓测定的结果证实了[PEEP-b -PBYP-Se] 2。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。该发现有助于新型的含二硒化物的聚磷酸酯-阿霉素的前药的设计。
更新日期：2018-05-22
中文翻译：
含二硒键的双反应性多磷酸酯-阿霉素前药：合成，表征和药物输送。
新型刺激响应性和可生物降解的多磷酸酯-抗癌前药的开发对于设计在药物递送领域中使用的水溶性前药具有重要意义。在这项研究中，重点是使用具有还原反应性的二（1-羟基苯癸基）二硒化物作为引发剂，聚合2-（but-3），合成具有生物相容性和可生物降解性的二硒化物的聚磷酸酯[PEEP - b -PBYP-Se] 2。 -yn-1-yloxy）-2-oxo-1,3,2-dioxaphospholane（BYP）和2-ethoxy-2-oxo-1,3,2-dioxaphospholane（EOP）。之后，将含有叠氮基的阿霉素（DOX）衍生物连接到[PEEP- b -PBYP-Se] 2的侧链上通过Cu（I）催化的叠氮化物-炔烃环加成（CuAAC）“点击”反应产生pH /还原反应性聚合物前药，即[PEEP- b-（PBYP- hyd -DOX）-Se] 2。通过核磁共振波谱，紫外可见分光光度计，傅立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，聚合前药NP是相对均匀的球体，可以在生理条件下保持稳定性，但在酸性或还原性介质中裂解。此外，通过在不同介质中体外药物释放来研究前药NP的pH和还原响应特性。事实证明，与在生理条件下相比，该药物在酸性或还原性培养基中有效释放。甲基噻唑基四唑鎓测定的结果证实了[PEEP-b -PBYP-Se] 2。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。该发现有助于新型的含二硒化物的聚磷酸酯-阿霉素的前药的设计。
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