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Abstract：
Although a variety of drug delivery strategies have been designed for enhancing the treatment of Triple negative breast cancer (TNBC), combating with TNBCs is still dramatically challenged by the selection of appropriate therapeutic targets and insufficient tumor accumulation or inner penetration of chemotherapeutics. To address these issues, the classical EGFR-inhibitor, erlotinib (EB), was selected as the model drug here and PLA-based nano-platform (NP-EB) was prepared for tumor site drug delivery. Given the significant role of Notch-EGFR interplay in raising severe resistance to EGFR inhibition of EB, gamma secretase inhibitor (GSI)-DAPT was further entrapped into the core of nanoparticles to inhibit the activation of Notch signaling (NP-EB/DART). For achieving the goal of tumor targeting drug delivery, we developed a new peptide CF and decorating it on the surface of EB/DART-dual loaded nanoparticles (CF-NP-EB/DART). Such CF peptide was designed by conjugating two separated peptide CREKA, tumor-homing peptide, and F3, cell penetrating peptide, to together via a pH-sensitive hydrazone bond. By this way, the tumor unspecific property of F3 was sealed and significantly reduced the site effects. However, after the nanoparticles reach the tumor site, the pH-sensitive linkage can be broken down by the unique acidic environment of tumor, and subsequently discovered the F3 peptide to penetrate into tumor cells.
摘要：
尽管已经设计了多种药物递送策略来增强三阴性乳腺癌(TNBC)的治疗,通过选择合适的治疗靶标和化疗药物的不足的肿瘤积累或内部渗透,对抗TNBC仍然面临着巨大的挑战。为了解决这些问题,经典的EGFR抑制剂，厄洛替尼（EB），在此选择作为模型药物,并且制备基于PLA的纳米平台(NP-EB)用于肿瘤部位药物递送。鉴于Notch-EGFR相互作用在提高对EGFR抑制EB的严重耐药性中的重要作用，将γ分泌酶抑制剂(GSI)-DAPT进一步包埋在纳米颗粒的核心中以抑制Notch信号(NP-EB/DART)的活化。为了达到肿瘤靶向给药的目的,我们开发了一种新的肽CF，并将其装饰在EB/DART双负载纳米颗粒（CF-NP-EB/DART）的表面上。这种CF肽是通过缀合两个分离的肽CREKA设计的，肿瘤归巢肽，和F3，细胞穿透肽，通过pH敏感的腙键连接在一起。通过这种方式,F3的肿瘤非特异性特性被密封，并显着降低了部位效应。然而,纳米粒子到达肿瘤部位后，肿瘤独特的酸性环境可以破坏pH敏感的连接，随后发现F3肽可以渗透到肿瘤细胞中。
