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Synthesis of cyclic graft polymeric prodrugs with heterogeneous grafts of hydrophilic OEG and reducibly conjugated CPT for controlled release.
Biomaterials Science ( IF 5.8 ) Pub Date : 2020-06-03 , DOI: 10.1039/d0bm00656d Chao Meng 1 , Yufei Cao 2 , Lu Sun 2 , Yuping Liu 2 , Guiying Kang 2 , Wei Ma 2 , Jinlei Peng 2 , Kaicheng Deng 2 , Liwei Ma 2 , Hua Wei 1
Biomaterials Science ( IF 5.8 ) Pub Date : 2020-06-03 , DOI: 10.1039/d0bm00656d Chao Meng 1 , Yufei Cao 2 , Lu Sun 2 , Yuping Liu 2 , Guiying Kang 2 , Wei Ma 2 , Jinlei Peng 2 , Kaicheng Deng 2 , Liwei Ma 2 , Hua Wei 1
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Fabrication of cyclic graft (cg) copolymer-based polymeric prodrugs by conjugation of drug molecules to cg copolymers via a dynamic covalent bond capable of responding to biorelevant signals integrates simultaneously the merits of cg copolymers and polymeric prodrugs for enhanced stability of nanocarriers and precise modulation of drug release kinetics. To completely eliminate the compromised drug conjugation efficiency due to the steric hindrance of hydrophilic grafts, it will be useful to develop cg polymeric prodrugs with heterogeneous grafts composed of hydrophilic polymers and drug species, respectively. For this purpose, we reported in this study the synthesis of cyclic graft polymeric prodrugs with heterogeneous grafts of hydrophilic oligo (ethylene glycol) (OEG) and reducibly conjugated camptothecin (CPT), cg-poly(oligo(ethylene glycol) monomethyl ether methacrylate)-b-poly((2-hydroxyethyl methacrylate)-disulfide link-camptothecin) (cg-P(OEGMA)-b-P(HEMA-SS-CPT), cg-prodrugs), via an integrated strategy of a previously reported diblock copolymer-based template and post-polymerization intermolecular click conjugation of a reducible CPT prodrug. The micelles self-assembled from cg-prodrugs on one hand had sufficient salt stability due to the branched cg structure, and on the other hand showed a reduction-triggered cleavage of the disulfide link for a promoted CPT release. Most importantly, we uncovered two interesting phenomena of the cg-based polymeric prodrugs as delivery vehicles: (i) the dimensions of both self-assemblies formed by the cg and bottlegraft (bg) polymers depend substantially on the molecular size of the cg and bg polymers likely due to the steric hindrance of the grafted structures of the cg and bg molecules and relatively low aggregation number of the self-assembled structures, and (ii) cg-prodrug-based micelles exhibited greater in vitro cytotoxicity against cancer cells despite the lower drug loading content (DLC) than the bg-based analogues, which results primarily from the faster reduction-triggered degradation and drug release as well as the greater cellular uptake efficiency of the former micelle prodrugs. Taken together, the developed cg-prodrugs provide great potential for chemotherapy, and the aforementioned interesting results will definitely inspire more upcoming studies on the future design and development of novel cg polymers for biomedical applications.
中文翻译：
用亲水性OEG和可还原共轭CPT的异质接枝合成环状接枝聚合物前药以进行控释。
通过能够响应生物相关信号的动态共价键将药物分子偶联到cg共聚物上来制备基于环状接枝（cg）共聚物的聚合物前药，同时整合了cg共聚物和聚合物前药的优点，从而增强了纳米载体的稳定性并精确调节了药物释放动力学。为了完全消除由于亲水性移植物的空间位阻而损害的药物结合效率，开发cg具有分别由亲水聚合物和药物种类组成的异质接枝的聚合物前药。为此目的，我们在这项研究中报道了用亲水性低聚（乙二醇）（OEG）和可还原性共轭喜树碱（CPT），cg-聚（低聚（乙二醇）单甲基醚甲基丙烯酸甲酯）异质接枝的环状接枝聚合物前药的合成- b -聚（（2-羟乙基甲基丙烯酸酯） -二硫化物链路喜树碱）（CG -P（OEGMA） - b -P（HEMA-SS-CPT），CG -prodrugs），经由以前报道的基于二嵌段共聚物的模板和可还原CPT前药的聚合后分子间点击偶联的综合策略。胶束自组装从CG -prodrugs一方面具有足够的盐稳定性归因于支链CG结构，并且在另一方面表明二硫化物链路用于促进CPT释放的还原-触发的裂解。最重要的是，我们发现了基于cg的聚合物前药作为传递媒介的两个有趣现象：（i）cg和瓶接枝（bg）聚合物形成的自组装体的尺寸基本上取决于cg和bg的分子大小由于的接枝结构的空间位阻可能聚合物CG和BG分子和自组装结构的相对低的聚集数，和（ii）CG -prodrug基于胶束显示出更大的在体外针对癌细胞的细胞毒性，尽管下与基于bg的类似物相比，药物负载量（DLC）主要是由降低的触发降解和药物释放引起的，以及前胶束前药具有更高的细胞吸收效率所致。综合起来，发达的CG-前药为化学疗法提供了巨大的潜力，上述有趣的结果必将激发更多有关生物医学应用新型cg聚合物的未来设计和开发的研究。
更新日期：2020-07-28
中文翻译：
用亲水性OEG和可还原共轭CPT的异质接枝合成环状接枝聚合物前药以进行控释。
通过能够响应生物相关信号的动态共价键将药物分子偶联到cg共聚物上来制备基于环状接枝（cg）共聚物的聚合物前药，同时整合了cg共聚物和聚合物前药的优点，从而增强了纳米载体的稳定性并精确调节了药物释放动力学。为了完全消除由于亲水性移植物的空间位阻而损害的药物结合效率，开发cg具有分别由亲水聚合物和药物种类组成的异质接枝的聚合物前药。为此目的，我们在这项研究中报道了用亲水性低聚（乙二醇）（OEG）和可还原性共轭喜树碱（CPT），cg-聚（低聚（乙二醇）单甲基醚甲基丙烯酸甲酯）异质接枝的环状接枝聚合物前药的合成- b -聚（（2-羟乙基甲基丙烯酸酯） -二硫化物链路喜树碱）（CG -P（OEGMA） - b -P（HEMA-SS-CPT），CG -prodrugs），经由以前报道的基于二嵌段共聚物的模板和可还原CPT前药的聚合后分子间点击偶联的综合策略。胶束自组装从CG -prodrugs一方面具有足够的盐稳定性归因于支链CG结构，并且在另一方面表明二硫化物链路用于促进CPT释放的还原-触发的裂解。最重要的是，我们发现了基于cg的聚合物前药作为传递媒介的两个有趣现象：（i）cg和瓶接枝（bg）聚合物形成的自组装体的尺寸基本上取决于cg和bg的分子大小由于的接枝结构的空间位阻可能聚合物CG和BG分子和自组装结构的相对低的聚集数，和（ii）CG -prodrug基于胶束显示出更大的在体外针对癌细胞的细胞毒性，尽管下与基于bg的类似物相比，药物负载量（DLC）主要是由降低的触发降解和药物释放引起的，以及前胶束前药具有更高的细胞吸收效率所致。综合起来，发达的CG-前药为化学疗法提供了巨大的潜力，上述有趣的结果必将激发更多有关生物医学应用新型cg聚合物的未来设计和开发的研究。
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