前药
医学
药物输送
化疗
原发性中枢神经系统淋巴瘤
甲氨蝶呤
淋巴瘤
药理学
癌症研究
病理
化学
内科学
有机化学
作者
Hengyu Liu,Tianqi Nie,Xiao Duan,Xinyu Zhang,Yilu Zheng,Wenhao Zhong,Haolin Chen,Congxiu Miao,Jun Wu,Dongjun Lin
标识
DOI:10.1016/j.jconrel.2023.05.040
摘要
Primary central nervous system lymphoma (PCNSL) is an extremely malignant CNS tumor with high incidence and mortality rates. Its chemotherapy in the clinic has been restricted owing to unsatisfactory drug distribution in the cerebral tissues. In this study, a redox-responsive prodrug of disulfide-lenalidomide-methoxy polyethylene glycol (LND-DSDA-mPEG) was successfully developed for the cerebral delivery of lenalidomide (LND), and methotrexate (MTX) via subcutaneous (s.c.) administration at the neck for combined anti-angiogenesis and chemotherapy on PCNSL. Both the subcutaneous xenograft tumor model and orthotopic intracranial tumor model demonstrated that the co-delivery of LND and MTX nanoparticles ([email protected] NPs) may significantly inhibit the growth of lymphoma and effectively prevent liver metastasis by downregulating CD31 and VEGF expression. Moreover, an orthotopic intracranial tumor model further verified that through s.c. administration at the neck, redox-responsive [email protected] NPs could bypass the blood-brain barrier (BBB), efficiently distribute into brain tissues, and effectively inhibit lymphoma growth in the brain, as detected by magnetic resonance imaging (MRI). Taken together, this biodegradable, biocompatible, and redox-responsive nano-prodrug with highly effective targeted delivery of LND and MTX in the brain through the lymphatic vasculature may provide a facile and feasible treatment strategy for PCNSL in the clinic.
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