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, College of Chemistry, Chemical Engineering and Materials Science , Soochow University , Suzhou 215123 , P. R. China.
ACS Appl Mater Interfaces. 2019 Mar 6;11(9):8740-8748. doi: 10.1021/acsami.8b16363. Epub 2019 Feb 20.
Amphiphilic polymeric prodrugs show improved therapeutic indices with respect to traditional hydrophobic anticancer drugs because these prodrugs can self-assemble into nanoparticles, prolong the circulation of drugs in the blood, improve the accumulation of drugs in the disease site, reduce the side effects of drugs, and achieve therapeutic effect. Here, we describe a novel pH/reduction dual-responsive polymeric prodrug, abbreviated as CPT- ss-poly(BYP- co-EEP), with simultaneous conjugating camptothecin (CPT) and doxorubicin (DOX), wherein BYP and EEP represent two cyclic phosphate monomers, respectively, that is, 2-(but-3-yn-1-yloxy)-2-oxo-1,3,2-dioxaphospholane and 2-ethoxy-2-oxo-1,3,2-dioxaphospholane. This prodrug was prepared through a polyphosphoester-DOX conjugate using a CPT derivative (CPT- ss-OH) as the initiator. CPT is linked to the terminal of polyphosphoester via disulfide carbonate, which is easy to break up under intracellular reductive environment and release the parent CPT, whereas DOX was efficiently incorporated onto the pendants of polyphosphoester through a hydrazone bond (- hyd-), which would be cleaved in the intracellular acidic medium. We show that the stable prodrug nanoparticles formed by self-assembly could release CPT and DOX simultaneously in the tumor microenvironment. The results of MTT assay demonstrate that the prodrug, which binds two antitumor drugs simultaneouly, has the properties of dual pH/reduction sensitiveness, biocompatibility, biodegradability, and effective tumor therapy.
两亲性聚合物前药相对于传统的疏水性抗癌药物具有改善的治疗指数，因为这些前药可以自组装成纳米粒子，延长药物在血液中的循环时间，提高药物在疾病部位的积累，降低药物的副作用，并实现治疗效果。在这里，我们描述了一种新型的 pH/还原双重响应聚合物前药，缩写为 CPT-ss-聚（BYP-co-EEP），同时缀合了喜树碱（CPT）和阿霉素（DOX），其中 BYP 和 EEP 分别代表两种环状磷酸酯单体，即 2-（丁-3-炔-1-氧基）-2-氧代-1,3,2-二氧杂磷杂环戊烷和 2-乙氧基-2-氧代-1,3,2-二氧杂磷杂环戊烷。该前药是通过聚磷酸酯-DOX 缀合物使用 CPT 衍生物（CPT-ss-OH）作为引发剂制备的。CPT 通过二硫碳酸酯连接到聚磷酸酯的末端，该末端在细胞内还原环境下易于断裂并释放出母体 CPT，而 DOX 通过腙键（-hyd-）有效地结合到聚磷酸酯的侧链上，该键在细胞内酸性介质中会被切断。我们表明，自组装形成的稳定前药纳米粒子可以在肿瘤微环境中同时释放 CPT 和 DOX。MTT 测定结果表明，同时结合两种抗癌药物的前药具有双重 pH/还原敏感性、生物相容性、可生物降解性和有效的肿瘤治疗作用。
