Year-end Sale % OFF 
Abstract
BackgroundBrain metastases from non-small cell lung cancer (NSCLC) remain one of the most challenging malignancies. Afatinib (Afa) is an orally administered irreversible ErbB family blocker approved for epidermal growth factor receptor (EGFR)-mutated NSCLC. However, the incidence of brain metastases in patients with NSCLC and EGFR mutation is high. One of the major obstacles in the treatment of brain metastases is to transport drugs across the blood–brain barrier (BBB). A lipid polymeric nanoparticle (LPN) modified with a tight junction-modulating peptide is a potential formulation to deliver therapeutics across the BBB. FD7 and CCD are short peptides that perturb the tight junctions (TJs) of the BBB. In this study, the use of LPN modified with FD7 or CCD as a delivery platform was explored to enhance Afa delivery across the BBB model of mouse brain-derived endothelial bEnd.3 cells.ResultsOur findings revealed that Afa/LPN-FD7 and Afa/LPN-CCD exhibited a homogeneous shape, a uniform nano-scaled particle size, and a sustained-release profile. FD7, CCD, Afa/LPN-FD7, and Afa/LPN-CCD did not cause a significant cytotoxic effect on bEnd.3 cells. Afa/LPN-FD7 and Afa/LPN-CCD across the bEnd.3 cells enhanced the cytotoxicity of Afa on human lung adenocarcinoma PC9 cells. FD7 and CCD-modulated TJ proteins, such as claudin 5 and ZO-1, reduced transendothelial electrical resistance, and increased the permeability of paracellular markers across the bEnd.3 cells. Afa/LPN-FD7 and Afa/LPN-CCD were also partially transported through clathrin- and caveolae-mediated transcytosis, revealing the effective activation of paracellular and transcellular pathways to facilitate Afa delivery across the BBB and cytotoxicity of Afa on PC9 cells.ConclusionTJ-modulating peptide-modified LPN could be a prospective platform for the delivery of chemotherapeutics across the BBB to the brain for the potential treatment of the BM of NSCLC.
Highlights
Brain metastases from non-small cell lung cancer (NSCLC) remain one of the most challenging malignancies
The images of transmission electron microscopy (TEM) showed that the nanoparticles were spherical with an FD7 or Cyclic peptide (CCD) peptide-coating shell layer around the polylacticco-glycolic acid (PLGA) core in which Afa was incorporated (Fig. 2D–F)
A recent investigation has indicated that three first-line epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), such as gefitinib, erlotinib, and Afa, demonstrate a comparable treatment efficacy based on the results of progression-free survival and overall survival in patients with EGFRmutated NSCLC and brain metastases (Rijcken et al 2005)
Summary
Brain metastases from non-small cell lung cancer (NSCLC) remain one of the most challenging malignancies. FD7 and CCD are short peptides that perturb the tight junctions (TJs) of the BBB. About 30% of patients with NSCLC develop metastasis in the central nervous system (CNS), such as brain metastases (BM) and leptomeningeal metastases (LM), within the first 2 years after the diagnosis of primary tumors, those harboring EGFR mutation (Dempke et al 2015; Wei et al 2019). The poor penetration of gefitinib and erlotinib, two first-generation EGFR-TKIs, across the blood–brain barrier (BBB) remains a primary hindrance for this therapeutic regimen (Zeng et al 2015). The neuroprotective BBB is a dynamic barrier with tight junctions (TJs) to prevent organisms and potential neurotoxins from attacking the CNS (Chen and Liu 2012). The BBB possesses special features, including low paracellular permeability, because of TJs and efflux pump proteins such as P-glycoprotein (On and Miller 2014)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
