Improving the anticancer effect of afatinib and microRNA by using lipid polymeric nanoparticles conjugated with dual pH-responsive and targeting peptides
Journal
Journal of Nanobiotechnology
Journal Volume
17
Journal Issue
1
Date Issued
2019
Author(s)
Abstract
Background: The emergence of resistance to chemotherapy or target therapy, tumor metastasis, and systemic toxicity caused by available anticancer drugs hamper the successful colorectal cancer (CRC) treatment. The rise in epidermal growth factor receptor (EGFR; human epidermal growth factor receptor 1; HER1) expression and enhanced phosphorylation of HER2 and HER3 are associated with tumor resistance, metastasis and invasion, thus resulting in poor outcome of anti-CRC therapy. The use of afatinib, a pan-HER inhibitor, is a potential therapeutic approach for resistant CRC. Additionally, miR-139 has been reported to be negatively correlated with chemoresistance, metastasis, and epithelial-mesenchymal transition (EMT) of CRC. Hence, we develop a nanoparticle formulation consisting of a polymer core to carry afatinib or miR-139, which is surrounded by lipids modified with a targeting ligand and a pH-sensitive penetrating peptide to improve the anticancer effect of cargos against CRC cells. Results: Our findings show that this formulation displays a spherical shape with core/shell structure, homogeneous particle size distribution and negative zeta potential. The prepared formulations demonstrate a pH-sensitive release profile and an enhanced uptake of cargos into human colorectal adenocarcinoma Caco-2 cells in response to the acidic pH. This nanoparticle formulation incorporating afatinib and miR-139 exhibits low toxicity to normal cells but shows a better inhibitory effect on Caco-2 cells than other formulations. Moreover, the encapsulation of afatinib and miR-139 in peptide-modified nanoparticles remarkably induces apoptosis and inhibits migration and resistance of Caco-2 cells via suppression of pan-HER tyrosine kinase/multidrug resistance/metastasis pathways. Conclusion: This study proposes a multifunctional nanoparticle formulation for targeted modulation of apoptosis/EGFR/HER/EMT/resistance/progression pathways to increase the sensitivity of colon cancer cells to afatinib. ? 2019 The Author(s).
Subjects
Afatinib; Cell-penetrating peptides; Colorectal cancer; Epidermal growth factor receptor (EGFR); Nanoparticles; Targeting delivery
SDGs
Other Subjects
Amino acids; Cell death; Chemotherapy; Controlled drug delivery; Diseases; Nanoparticles; Particle size; Particle size analysis; Pathology; Peptides; pH effects; pH sensors; RNA; Toxicity; Tumors; Afatinib; Cell-penetrating peptide; Colorectal cancer; Epidermal growth factor receptors; Targeting deliveries; Targeted drug delivery; afatinib; cell penetrating peptide; drug carrier; epidermal growth factor receptor; microRNA; nanoparticle; nanoshell; polymer; protein miR 139; unclassified drug; afatinib; antineoplastic agent; epidermal growth factor receptor; lipid; microRNA; nanoparticle; peptide; polymer; protein kinase inhibitor; animal cell; antineoplastic activity; apoptosis; Article; Caco-2 cell line; cancer inhibition; cell pH; colorectal carcinoma; drug conjugation; drug formulation; drug release; drug targeting; drug uptake; human; human cell; metastasis inhibition; migration inhibition; multidrug resistance; nanoencapsulation; nonhuman; particle size; protein synthesis inhibition; rat; zeta potential; animal; chemistry; colorectal tumor; drug effect; drug resistance; medicinal chemistry; metabolism; pH; procedures; Sprague Dawley rat; tumor cell line; Afatinib; Animals; Antineoplastic Agents; Apoptosis; Caco-2 Cells; Cell Line, Tumor; Chemistry, Pharmaceutical; Colorectal Neoplasms; Drug Resistance, Neoplasm; ErbB Receptors; Humans; Hydrogen-Ion Concentration; Lipids; MicroRNAs; Nanoparticles; Peptides; Polymers; Protein Kinase Inhibitors; Rats; Rats, Sprague-Dawley
Publisher
BioMed Central Ltd.
Type
journal article