基于偶联药物的纳米前药体系能够显著提高载药效率和载药量,还能够避免药物在血液循环过程出现过早泄露的问题,从而降低药物的毒副作用。因此,我们设计并制备了还原响应性的偶联药物IR806-CB,即通过二硫键链接光敏剂IR806和化疗药物苯...基于偶联药物的纳米前药体系能够显著提高载药效率和载药量,还能够避免药物在血液循环过程出现过早泄露的问题,从而降低药物的毒副作用。因此,我们设计并制备了还原响应性的偶联药物IR806-CB,即通过二硫键链接光敏剂IR806和化疗药物苯丁酸氮介CB,该偶联药物IR806-CB与聚乙二醇–环糊精(PEG-CD)通过苯丁酸氮介与环糊精之间的主客体识别作用、π-π堆积作用和亲疏水作用力在水中自组装形成超分子纳米前药SN-IR806/CB。该超分子纳米前药可以通过高通透性和滞留效应有效地富集在肿瘤组织,而后再通过内吞作用进入到肿瘤细胞内,在细胞内的还原环境中,即在高浓度的谷甘光肽(GSH)作用下,二硫键发生断裂,释放出CB。同时,在808 nm的近红外光照射下,IR806不仅能够吸收近红外光转换成热能,使温度升高杀死肿瘤细胞,而且能够释放出活性氧,造成癌细胞的死亡。The nanoprodrug system based on drug-drug conjugation can significantly enhance drug loading efficiency and drug encapsulation, and prevent premature drug leakage in the bloodstream, which reduce the toxic side effects of drugs. Consequently, we designed and synthesized a reduction-re- sponsive drug conjugate IR806-CB by linking the photosensitizer IR806 with the chemotherapeutic agent N-phenylbutyrate CB through a disulfide bond. The conjugated compound IR806-CB self-assembles with polyethylene glycol-cyclodextrin (PEG-CD) in aqueous solution to form supramolecular nanoprodrug SN-IR806/CB via host-guest recognition between N-phenylbutyrate and cyclodextrin, π-π stacking interactions, and hydrophilic-hydrophobic interactions. This supramolecular nanoprodrug can be effectively accumulated in tumor tissues through enhanced permeability and retention effect, subsequently internalized into tumor cells via endocytosis. In the intracellular reducing environment, the disulfide bond could be cleaved under high glutathione (GSH) concentration, leading to the release of CB. Simultaneously, upon irradiation with 808 nm near-infrared light, IR806 not only absorbed near-infrared light for conversion into heat energy that elevated temperature to induce cancer cell death but also generated reactive oxygen species for further cancer cell killing.展开更多
为解决热休克蛋白90(Heat shock protein 90,HSP90)抑制剂的周身毒性问题,自主设计并合成了两个HSP90抑制剂的三肽前药P1和P2。以4-(2-羟乙基)哌啶-1-甲酸叔丁酯和1-(溴甲基)-4-硝基苯为起始原料,经羟胺缩合、硝基还原、关环等反应合成H...为解决热休克蛋白90(Heat shock protein 90,HSP90)抑制剂的周身毒性问题,自主设计并合成了两个HSP90抑制剂的三肽前药P1和P2。以4-(2-羟乙基)哌啶-1-甲酸叔丁酯和1-(溴甲基)-4-硝基苯为起始原料,经羟胺缩合、硝基还原、关环等反应合成HSP90抑制剂HSP90i-1和HSP90i-2;以L-脯氨酸和L-缬氨酸衍生物为原料,经缩合、脱保护、酰化等反应合成多肽连接子M1。将HSP90i-1、HSP90i-2分别和M1缩合,得到两个三肽前药P1和P2。1H NMR、LCMS、13C NMR分析表征结果表明两个前药分子被成功合成。该研究具有使用的原料廉价易得、反应都在常温下进行、条件温和可控、总产率较高等特点,为多肽前药的设计及合成提供了新的思路和方法。展开更多
文摘基于偶联药物的纳米前药体系能够显著提高载药效率和载药量,还能够避免药物在血液循环过程出现过早泄露的问题,从而降低药物的毒副作用。因此,我们设计并制备了还原响应性的偶联药物IR806-CB,即通过二硫键链接光敏剂IR806和化疗药物苯丁酸氮介CB,该偶联药物IR806-CB与聚乙二醇–环糊精(PEG-CD)通过苯丁酸氮介与环糊精之间的主客体识别作用、π-π堆积作用和亲疏水作用力在水中自组装形成超分子纳米前药SN-IR806/CB。该超分子纳米前药可以通过高通透性和滞留效应有效地富集在肿瘤组织,而后再通过内吞作用进入到肿瘤细胞内,在细胞内的还原环境中,即在高浓度的谷甘光肽(GSH)作用下,二硫键发生断裂,释放出CB。同时,在808 nm的近红外光照射下,IR806不仅能够吸收近红外光转换成热能,使温度升高杀死肿瘤细胞,而且能够释放出活性氧,造成癌细胞的死亡。The nanoprodrug system based on drug-drug conjugation can significantly enhance drug loading efficiency and drug encapsulation, and prevent premature drug leakage in the bloodstream, which reduce the toxic side effects of drugs. Consequently, we designed and synthesized a reduction-re- sponsive drug conjugate IR806-CB by linking the photosensitizer IR806 with the chemotherapeutic agent N-phenylbutyrate CB through a disulfide bond. The conjugated compound IR806-CB self-assembles with polyethylene glycol-cyclodextrin (PEG-CD) in aqueous solution to form supramolecular nanoprodrug SN-IR806/CB via host-guest recognition between N-phenylbutyrate and cyclodextrin, π-π stacking interactions, and hydrophilic-hydrophobic interactions. This supramolecular nanoprodrug can be effectively accumulated in tumor tissues through enhanced permeability and retention effect, subsequently internalized into tumor cells via endocytosis. In the intracellular reducing environment, the disulfide bond could be cleaved under high glutathione (GSH) concentration, leading to the release of CB. Simultaneously, upon irradiation with 808 nm near-infrared light, IR806 not only absorbed near-infrared light for conversion into heat energy that elevated temperature to induce cancer cell death but also generated reactive oxygen species for further cancer cell killing.
