Department of Oncology, Yancheng First People's Hospital, Yancheng, 224005, China.
Department of Oncology, Shuyang Hospital Affiliated to Xuzhou Medical University, Shuyang People's Hospital, Suqian, 223600, China.
J Nanobiotechnology. 2019 Aug 26;17(1):91. doi: 10.1186/s12951-019-0521-z.
The selectively accumulate in tumor site and completely release drug within cancer cells great limit the therapeutic effect of nano-drug delivery system. Moreover, absence of appropriate biomarker is one of the major challenges for prostate specific membrane antigen negative (PSMA (-)) prostate cancer therapy.
Herein, a PSMA (-) prostate cancer specific targeted and intracellular reactive oxygen species (ROS) amplification for ROS-responsive self-accelerating drug release nanoplatform (ATD-NPs) was developed. ATD-NPs was formed by three parts, including PSMA (-) prostate cancer specifically targeted part (DUP-PEG-DSPE), ROS-sensitive doxorubicin (DOX) polymeric prodrug (P(L-TK-DOX)), and the ROS generation agent (α-tocopheryl succinate, α-TOS); and this delivery system is expected to enhance PSMA (-) prostate cancer therapeutic effect, increase selective accumulation at tumor site and overcome intracellular incomplete drug release. After administration i.v injection, ATD-NPs could specifically accumulate in tumor site and markedly be internalized by cancer cells based on the DUP-1 (a PSMA (-) cancer cells specific target peptide). Subsequently, ATD-NPs could be dissociated under the high concentration reactive oxygen species (ROS) condition, resulting in DOX and α-TOS release. Then, the released α-TOS could be reacted with mitochondria to produce ROS, which in turn accelerating the release of drugs. Finally achieved the purpose of enhancing therapeutic efficacy and reducing side effect. Both in vitro and in vivo experiments demonstrated that the combination of tumor actively-targeted and self-amplifying ROS-responsive drug release showed more significant antitumor activity in the human PSMA (-) prostate cancer.
The described technology unifies the tumor actively targets, self-amplified drug release, and excellent biocompatibility into one formulation, are promising for cancer treatment.
肿瘤部位的选择性积累和癌细胞内完全释放药物极大地限制了纳米药物传递系统的治疗效果。此外，缺乏适当的生物标志物是前列腺特异性膜抗原阴性（PSMA（-））前列腺癌治疗的主要挑战之一。
本文开发了一种 PSMA（-）前列腺癌特异性靶向和细胞内活性氧物种（ROS）放大用于 ROS 响应自加速药物释放纳米平台（ATD-NPs）。ATD-NPs 由三部分组成，包括 PSMA（-）前列腺癌特异性靶向部分（DUP-PEG-DSPE）、ROS 敏感阿霉素（DOX）聚合物前药（P（L-TK-DOX））和 ROS 生成剂（α-生育酚琥珀酸酯，α-TOS）；该递药系统有望增强 PSMA（-）前列腺癌的治疗效果，增加肿瘤部位的选择性积累，并克服细胞内不完全的药物释放。静脉注射给药后，ATD-NPs 可基于 DUP-1（PSMA（-）癌细胞特异性靶肽）特异性积聚在肿瘤部位，并被癌细胞大量内化。随后，在高浓度活性氧（ROS）条件下，ATD-NPs 可解离，导致 DOX 和 α-TOS 释放。然后，释放的 α-TOS 可与线粒体反应生成 ROS，从而加速药物释放。最终达到增强治疗效果和降低副作用的目的。体外和体内实验均表明，肿瘤主动靶向和自放大 ROS 响应药物释放的组合在人 PSMA（-）前列腺癌中表现出更显著的抗肿瘤活性。
所描述的技术将肿瘤主动靶向、自放大药物释放和优异的生物相容性统一到一个制剂中，有望用于癌症治疗。
