Reduction-responsive Dehydroepiandrosterone Prodrug Nanoparticles Loaded with Camptothecin for Cancer Therapy by Enhancing Oxidation Therapy and Cell Replication Inhibition.
Reduction-responsive Dehydroepiandrosterone Prodrug Nanoparticles Loaded with Camptothecin for Cancer Therapy by Enhancing Oxidation Therapy and Cell Replication Inhibition.
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DOI：
10.1016/j.ijpharm.2021.120671
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发表时间：
2021-05
影响因子：
5.8
通讯作者：
Congjun Xu;Haolan Yang;Zhanghong Xiao;Tao Zhang;Zilin Guan;Jie Chen;Hualu Lai;Xiaoyu Xu;Yanjuan Huang;Zeqian Huang;Chunshun Zhao
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文献类型：
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作者：
Congjun Xu;Haolan Yang;Zhanghong Xiao;Tao Zhang;Zilin Guan;Jie Chen;Hualu Lai;Xiaoyu Xu;Yanjuan Huang;Zeqian Huang;Chunshun Zhao
戊糖磷酸途径（PPP）通过分别为核苷酸合成和还原提供核酮糖-5-磷酸（Ru 5 P）和NADPH而起关键作用。因此，阻断PPP过程可能是增强氧化治疗和抑制细胞复制的有效策略。在这里，我们设计了一种新的还原响应性聚乙二醇化的前药，并构建了纳米颗粒PsD@CPT，以同时提供PPP阻滞剂，脱氢表雄酮（DHEA）和化疗喜树碱（CPT），以整合放大氧化治疗和增强细胞复制抑制。细胞摄取后，在高谷胱甘肽（GSH）水平存在下，DHEA和CPT从PsD@CPT中释放。正如预期的那样，DHEA介导的还原水平降低，CPT诱导的氧化水平协同增加，破坏氧化还原平衡，加重癌症氧化应激。此外，DHEA通过还原Ru 5 P抑制核苷酸合成和CPT阻断DNA复制进一步激发了对肿瘤细胞增殖的协同抑制作用。结果表明，PsD@CPT具有多模式治疗的特点，在体外和体内均具有良好的抗肿瘤活性。本研究提供了一种新的肿瘤治疗策略，该策略结合了氧化应激的放大和基于PPP过程抑制的细胞增殖抑制的增强。
The pentose phosphate pathway (PPP) plays a critical role by providing ribulose-5-phosphate (Ru5P) and NADPH for nucleotide synthesis and reduction energy, respectively. Accordingly, blocking the PPP process may be an effective strategy for enhancing oxidation therapy and inhibiting cell replication. Here, we designed a novel reduction-responsive PEGylated prodrug and constructed nanoparticles PsD@CPT to simultaneously deliver a PPP blocker, dehydroepiandrosterone (DHEA), and chemotherapeutic camptothecin (CPT) to integrate amplification of oxidation therapy and enhance cell replication inhibition. Following cellular uptake, DHEA and CPT were released from PsD@CPT in the presence of high glutathione (GSH) levels. As expected, DHEA-mediated reduction level decreases and CPT-induced oxidation level increases synergistically, breaking the redox balance to aggravate cancer oxidative stress. In addition, suppressing nucleotide synthesis by DHEA through the reduction of Ru5P and blocking DNA replication by CPT further motivates a synergistic inhibition effect on tumor cell proliferation. The results showed that PsD@CPT featuring multimodal treatment has satisfactory antitumor activity bothin vitroandin vivo. This study provides a new tumor treatment strategy, which combines the amplification of oxidative stress and enhancement of inhibition of cell proliferation based on inhibition of the PPP process.