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Sequentially Triggered Nanoparticles with Tumor Penetration and Intelligent Drug Release for Pancreatic Cancer Therapy
Advanced Science ( IF 14.3 ) Pub Date : 2018-02-26 , DOI: 10.1002/advs.201701070 Xi He 1 , Xinli Chen 1 , Lisha Liu 1 , Yu Zhang 1 , Yifei Lu 1 , Yujie Zhang 1 , Qinjun Chen 1 , Chunhui Ruan 1 , Qin Guo 1 , Chao Li 1 , Tao Sun 1 , Chen Jiang 1
Advanced Science ( IF 14.3 ) Pub Date : 2018-02-26 , DOI: 10.1002/advs.201701070 Xi He 1 , Xinli Chen 1 , Lisha Liu 1 , Yu Zhang 1 , Yifei Lu 1 , Yujie Zhang 1 , Qinjun Chen 1 , Chunhui Ruan 1 , Qin Guo 1 , Chao Li 1 , Tao Sun 1 , Chen Jiang 1
Affiliation
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Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive malignancy with a five year survival rate of <5%. The aberrant expression of extracellular matrix (ECM) in the tumor stroma forms a compact physical barrier, which that leads to insufficient extravasation and penetration of nanosized therapies. To overcome the severe resistance of PDAC to conventional therapies, a sequentially triggered nanoparticle (aptamer/cell‐penetrating peptide‐camptothecin prodrug, i.e., Apt/CPP‐CPTD NPs) with tumor penetration and intelligent drug release profile is designed. An ECM component (tenescin‐C) targeting aptamer (GBI‐10) is modified onto stroma‐permeable cell‐penetrating peptide (CPP) for the in vivo CPP camouflage and PDAC‐homing. In PDAC stroma, tenascin‐C can detach GBI‐10 from CPP and exposed CPP can facilitate further PDAC penetration and tumor cell endocytosis. After being endocytosed into PDAC cells, intracellular high redox potential can further trigger controlled chemodrug release. Apt/CPP‐CPTD NPs show both deep penetration in vitro 3D PDAC spheroids and in vivo tumor sections. The relatively mild in vitro cytotoxicity and excellent in vivo antitumor efficacy proves the improved PDAC targeting drug delivery and decreased systemic toxicity. The design of ECM‐redox sequentially triggered stroma permeable NPs may provide a practical approach for deep penetration of PDAC and enhanced drug delivery efficacy.
中文翻译：
用于胰腺癌治疗的具有肿瘤穿透和智能药物释放的顺序触发纳米颗粒
胰腺导管腺癌（PDAC）是最具侵袭性的恶性肿瘤，五年生存率<5%。肿瘤基质中细胞外基质（ECM）的异常表达形成了致密的物理屏障，导致纳米疗法的外渗和渗透不足。为了克服 PDAC 对常规疗法的严重耐药性，设计了一种具有肿瘤渗透性和智能药物释放特性的顺序触发纳米颗粒（适体/细胞穿透肽喜树碱前药，即 Apt/CPP-CPTD NP）。将靶向适体 (GBI-10) 的 ECM 成分 (腱生蛋白-C) 修饰到基质渗透性细胞穿透肽 (CPP) 上，用于体内 CPP 伪装和 PDAC 归巢。在 PDAC 基质中，生腱蛋白-C 可以将 GBI-10 从 CPP 上分离，暴露的 CPP 可以促进 PDAC 进一步渗透和肿瘤细胞内吞。被PDAC细胞内吞后，细胞内的高氧化还原电位可以进一步触发受控的化学药物释放。Apt/CPP-CPTD NPs 在体外 3D PDAC 球体和体内肿瘤切片中均显示出深度渗透。相对温和的体外细胞毒性和优异的体内抗肿瘤功效证明了PDAC靶向药物递送的改善和全身毒性的降低。ECM-氧化还原顺序触发基质渗透性纳米粒子的设计可能为 PDAC 的深度渗透和增强药物递送功效提供实用方法。
更新日期：2018-02-26
中文翻译：
用于胰腺癌治疗的具有肿瘤穿透和智能药物释放的顺序触发纳米颗粒
胰腺导管腺癌（PDAC）是最具侵袭性的恶性肿瘤，五年生存率<5%。肿瘤基质中细胞外基质（ECM）的异常表达形成了致密的物理屏障，导致纳米疗法的外渗和渗透不足。为了克服 PDAC 对常规疗法的严重耐药性，设计了一种具有肿瘤渗透性和智能药物释放特性的顺序触发纳米颗粒（适体/细胞穿透肽喜树碱前药，即 Apt/CPP-CPTD NP）。将靶向适体 (GBI-10) 的 ECM 成分 (腱生蛋白-C) 修饰到基质渗透性细胞穿透肽 (CPP) 上，用于体内 CPP 伪装和 PDAC 归巢。在 PDAC 基质中，生腱蛋白-C 可以将 GBI-10 从 CPP 上分离，暴露的 CPP 可以促进 PDAC 进一步渗透和肿瘤细胞内吞。被PDAC细胞内吞后，细胞内的高氧化还原电位可以进一步触发受控的化学药物释放。Apt/CPP-CPTD NPs 在体外 3D PDAC 球体和体内肿瘤切片中均显示出深度渗透。相对温和的体外细胞毒性和优异的体内抗肿瘤功效证明了PDAC靶向药物递送的改善和全身毒性的降低。ECM-氧化还原顺序触发基质渗透性纳米粒子的设计可能为 PDAC 的深度渗透和增强药物递送功效提供实用方法。
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