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Acidity-triggered TAT-presenting nanocarriers augment tumor retention and nuclear translocation of drugs

Nano Research 2018年第10期11卷 5716-5734页

作者： Wei Jiang Jilong Wang Jinbin Yang Zhiwei He Zhenhui Hou Yingli Luo Li Wang Jing Liu Houbing Zhang Yangyang Zhao Guoqing Zhang Fang Huang Xuechang Zhou Lifeng Yan Xianzhu Yang Yucai Wang Jun Wang Hefei National Laboratory for Physical Sciences at the Microscale University of Science and Technology of China Hefei230027 China The CAS Key Laboratory of Innate Immunity and Chronic Disease School of Life Sciences and Medical Center University of Science and Technology of China Hefei 23002 7 China School of Chemistry and Environmental Engineering Shenzhen University Shenzhen 518060 China School of Earth and Space Sciences University of Science and Technology of China Hefei230027 China Institutes for Life Sciences School of Medicine and National Engineering Research Center for Tissue Restoration and Reconstruction South China University of Technology Guangzhou 510006 China

Hierarchical targeting strategy can combat the sequential drug delivery barriers by changing their properties with response to tumor stimuli. Among these strategies, much less attention has been paid to address the issues of rapid tumor clearance and insufficient cellular translocation. In this work, we demonstrate that a transactivator of transcription （TAT）-presenting nanomedicine （DATAT-NP/Pt）, apart from improving tumor accumulation and cellular uptake, can simultaneously enhance tumor retention and promote nuclear translocation of encapsulated platinum prodrugs, and thus improve therapeutic efficacy. Specifically, a protecting 2,3-dimethylmaleic anhydride （DA） corona on the nanomedicine prevented the TAT peptide from serum. DATAT-NP/Pt efficiently accumulated at the tumor site through the enhanced permeability and retention （EPR） effect, followed by acid-triggered TAT presenting within the tumor acidic microenvironment （pH ~ 6.8）. The exposed TAT peptide augmented tumor retention and nuclear translocation of DATAT-NP/Pt. We used a tumor-on-a-chip microfluidic system to real-time mimic and analyze tumor accumulation and retention at physiological flow conditions and revealed that surface absorption of nanomedicines on tumors was critical in determining their tumor retention and clearance. Furthermore, the TAT peptide rapidly translocated the DATAT-NP/Pt into the perinuclear region, allowing for higher nuclear platinum concentrations and increased Pt-DNA adduct formation in nuclei, which consequently reversed cisplatin resistance. Our work presents a new strategy to overcome path- ophysiological barriers of tumor clearance and insufficient cellular translocation and provides new insights for the design of cancer nanomedicines.

关键词： acidic tumor microenvironment cancer therapy cellular nucleus translocation ligand presenting nanomedicines tumor retention acidic tumormicroenvironment cancer therapy cellular nucleustranslocation ligand presentingnanomedicines tumor retention

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