文献类型：期刊文献

英文题名：Multiple targeting strategies achieve novel protein drug delivery into proapoptosis lung cancer cells by precisely inhibiting survivin

作者：Hu, Fabiao[1];Yan, Ting[1];Guo, Wei[1];Liu, Qiuli[2];Han, Myong Hun[1,3];Liu, Chang[1];Liu, Yuping[2];Zheng, Wenyun[2];You, Fang[4,5];Yang, Yi[5];Zhang, Wenliang[6];Ma, Xingyuan[1]

机构：[1]East China Univ Sci & Technol, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China;[2]East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China;[3]KIM IL SUNG Univ, Fac Life Sci, Dept Genet, Pyongyang 999093, North Korea;[4]Natl Univ Singapore, Dept Chem & Biomol Engn, Singapore 117585, Singapore;[5]SinGENE Biotech Pte Ltd, Singapore Sci Pk, Singapore 118258, Singapore;[6]Univ North Carolina Greensboro, Ctr Translat Biomed Res, Greensboro, NC 27310 USA

年份：2020

卷号：12

期号：19

起止页码：10623

外文期刊名：NANOSCALE

收录：;EI(收录号：20202408817376);WOS:【SCI-EXPANDED(收录号:WOS:000537113200017)】；

基金：This study was supported by the National Key Research and Development Project of China (2018YFA0902804), the National Natural Science Foundation (31670944, 81673345), and the Science and Technology Innovation Action Plan of Shanghai (17431904600).

语种：英文

外文关键词：Cancer cells - Tumors - Cell death - Mammals - Diseases - Targeted drug delivery - Biocompatibility - Controlled drug delivery - Recombinant proteins

摘要：Therapeutic recombinant proteins have numerous advantages and benefits over chemical drugs, particularly high specificity and good biocompatibility. However, the therapeutic potential and clinical application of current anticancer protein drugs are limited as most biomarkers are located within cells, and multiple physiological barriers exist between the point of administration and the intracellular biomarker. Herein, we report a novel strategy to accurately deliver a cell-permeable dominant-negative TATm-Survivin (TmSm) protein (T34A) to intracellular survivin in cancer cells by overcoming multiple barriers in vivo. A poly(d,l-lactide-co-glycolide) (PLGA) inner core, a polyethylene glycol (PEG) modification, and a TATm peptide were simultaneously introduced to mediate tumor tissue targeting and response to pH-triggered TmSm release. Compared to free TmSm, the PEGylated-PLGA nanoparticle platform achieved a significantly higher cellular uptake efficiency (1.79-fold for A549 and 1.77-fold for Capan-2), effectively decreased IC50 (1.22-fold for A549 and 1.17-fold for Capan-2), and largely elevated apoptosis in different cancer cells (1.17-fold for A549 and 1.15-fold for Capan-2). Besides, this newly developed nanoplatform showed increased protein drug accumulation in the tumor site in A549-bearing nude mice and reached a tumor inhibition rate of 55.81% (1.35-fold versus free TmSm) by reducing the expression of intracellular survivin. All these results confirmed that our newly developed delivery strategy is a very promising tool, which helps protein drugs to cross multiple barriers in vivo and achieves precise targeting to intracellular biomarkers. This strategy could also be applied to other types of protein drugs to further improve their clinical anticancer therapeutic efficacy.