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.
Highlights
Triple negative breast cancer (TNBC), belonging to the subtype of epithelial breast tumors, are famous for their negative expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) (Bauer et al, 2007)
Given the significant role of Notch-Epidermal growth factor receptor (EGFR) interplay in raising severe resistance to EGFR inhibition of EB (Arasada et al, 2014), a gamma secretase inhibitor (GSI)-DAPT was further introduced to inhibit the activation of Notch signaling
The transmission emission microscopy (TEM) images (Figure 1(B)) of the nanoparticles demonstrated that both the prepared NP-EB/DAPT and CF-NP-EB/ DAPT were of vesicle-like shape with averaged diameters of 100 nm around, which is in good accordance with DLS results (96.37 ± 4.48 nm for NP-EB/DAPT and 104.65 ± 5.14 nm for the peptide modified ones)
Summary
TNBCs, belonging to the subtype of epithelial breast tumors, are famous for their negative expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) (Bauer et al, 2007). Epidermal growth factor receptor (EGFR), known as HER1, is the membrane glycoprotein that belongs to the receptor tyrosine kinases and is encoded by proto-oncogene CerbB-1 (Li et al, 2016; Yan et al, 2017). It has been welldefined that the aberrant tyrosine kinase activity by EGFR has a close relation with tumorigenesis in a variety of cancer types such as lung, colon, and breast cancers (Corkery et al, 2009; Efferth, 2012; Quan et al, 2018)
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