Cited by 74Nanoparticle-Based Drug DeliveryRNA Interference and Gene DeliveryLung Cancer Treatments and Mutations

Chloroquine in combination with aptamer-modified nanocomplexes for tumor vessel normalization and efficient erlotinib/Survivin shRNA co-delivery to overcome drug resistance in EGFR-mutated non-small cell lung cancer

Lv, Tingting, Li, Ziying, Xu, Liang, Zhang, Yingying, Chen, Haijun, Gao, Yu·2018·Acta Biomaterialia

Abstract

Although novel molecular targeted drugs have been recognized as an effective therapy for non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) activating mutations, their efficacy fails to meet the expectation due to the acquired resistance in tumors. Up-regulation of the anti-apoptotic protein Survivin was shown to contribute to the resistance to EGFR tyrosine kinase inhibitors (TKI) in EGFR mutation-positive NSCLC. However, the unorganized tumor blood vessels impeded drug penetration into tumor tissue. The resulting insufficient intracellular drug/gene delivery in drug-resistant cancer cells remarkably weakened the drug efficacy in NSCLC. In this work, a multi-functional drug delivery system AP/ES was developed by using anti-EGFR aptamer (Apt)-modified polyamidoamine to co-deliver erlotinib and Survivin-shRNA. Chloroquine (CQ) was used in combination with AP/ES to normalize tumor vessels for sufficient drug/gene delivery to overcome drug resistance in NSCLC cells. The obtained AP/ES possessed desired physicochemical properties, good biostability, controlled drug release profiles, and strong selectivity to EGFR-mutated NSCLC mediated by Apt. CQ not only enhanced endosomal escape ability of AP/ES for efficient gene transfection to inhibit Survivin, but also showed strong vessel-normalization ability to improve tumor microcirculation, which further promoted drug delivery and enhanced drug efficacy in erlotinib-resistant NSCLC cells. Our innovative gene/drug co-delivery system in combination with CQ showed a promising outcome in fighting against erlotinib resistance both in vitro and in vivo. This work indicates that normalization of tumor vessels could help intracellular erlotinib/Survivin-shRNA delivery and the down-regulation of Survivin could act synergistically with erlotinib for reversal of erlotinib resistance in EGFR mutation-positive NSCLC.Statement of significance NSCLC patients who benefited from EGFR-TKIs inevitably developed acquired resistance. Previous research focused on synthesis of new generation of molecular targeted drugs that could irreversibly inhibit EGFR with a particular gene mutation to overcome drug resistance. However, they failed to inhibit EGFR with other gene mutations. Activation of bypass signaling pathway and the changes of tumor microenvironment are identified as two of the mechanisms of acquired resistance to EGFR-TKIs. We therefore constructed multifunctional gene/drug co-delivery nanocomplexes AP/ES co-formulated with chloroquine that could target the both two mechanisms. We found that chloroquine not only enhanced endosomal escape ability of AP/ES for efficient gene transfection to inhibit Survivin, but also showed strong vessel-normalization ability to improve tumor microcirculation, which further promoted drug delivery into tumor tissue and enhanced drug efficacy in erlotinib-resistant NSCLC.

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Crossref · 10.1016/j.actbio.2018.06.034

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  • Anti-EGFR aptamers have been successfully used to recognize EGFR-expressing cells.

    “The specific ligands used to modify the nanosystem targeting the EGFR targets, in addition to the antibodies and peptides described above, EGFR aptamers have been successfully used to recognize EGFR-expressing cells.257”

    From Smart nanoparticles for cancer therapy (2023) · cites this paper as [257]

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Authors
Lv, T., Li, Z., Xu, L., Zhang, Y., Chen, H., & Gao, Y.
Affiliations
Fuzhou University (CN)
Corresponding author
Gao, Yu
Venue
Acta Biomaterialia
Publisher
Elsevier BV
Published
2018-08
Volume
76
Pages
257-274
ISSN
1742-7061 (ISSN-L)
OpenAlex
W2811390231
Cited by
74
References
74
Citations by year
2026: 1 · 2025: 9 · 2024: 6 · 2023: 15 · 2022: 12 · 2021: 10 · 2020: 11 · 2019: 10
FWCI
2.51
Type
journal article
Language
en
Open access
closed
Locations
  • Acta Biomaterialia (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Natural Science Foundation of China (81571802)
  • Ministry of Science and Technology (2015CB931804)
  • Natural Science Foundation of Fujian Province (2016J06020)
Topics
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Keywords
chloroquine, tumor vasculature normalization, erlotinib, EGFR-mutant non-small cell lung cancer, EGFR tyrosine kinase inhibitor resistance, endosomal escape, tumor microcirculation, apoptosis, drug resistance reversal, targeted drug delivery
MeSH terms
Erlotinib Hydrochloride, Survivin, Animals, Carcinoma, Non-Small-Cell Lung, Chloroquine, Female, Humans, Lung Neoplasms, Mice, Inbred BALB C, Mice, Nude, Mutation, Neoplasm Proteins, Drug Resistance, Neoplasm, Xenograft Model Antitumor Assays, RNA, Small Interfering, Cell Line, Tumor, Mice, Aptamers, Nucleotide, Nanoparticles, ErbB Receptors

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