Improving the anticancer effect of afatinib and microRNA by using lipid polymeric nanoparticles conjugated with dual pH-responsive and targeting peptides

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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.

Electronic supplementary material

The online version of this article (10.1186/s12951-019-0519-6) contains supplementary material, which is available to authorized users.

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Most cited references 41

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Endocytosis and exocytosis of nanoparticles in mammalian cells

Nuri Oh, Ji-Ho Park (2014)

Engineered nanoparticles that can be injected into the human body hold tremendous potential to detect and treat complex diseases. Understanding of the endocytosis and exocytosis mechanisms of nanoparticles is essential for safe and efficient therapeutic application. In particular, exocytosis is of significance in the removal of nanoparticles with drugs and contrast agents from the body, while endocytosis is of great importance for the targeting of nanoparticles in disease sites. Here, we review the recent research on the endocytosis and exocytosis of functionalized nanoparticles based on various sizes, shapes, and surface chemistries. We believe that this review contributes to the design of safe nanoparticles that can efficiently enter and leave human cells and tissues.

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Role of poly(ADP-ribose) polymerase (PARP) cleavage in apoptosis. Caspase 3-resistant PARP mutant increases rates of apoptosis in transfected cells.

A Boulares, A G Yakovlev, V Ivanova … (1999)

An early transient burst of poly(ADP-ribosyl)ation of nuclear proteins was recently shown to be required for apoptosis to proceed in various cell lines (Simbulan-Rosenthal, C., Rosenthal, D., Iyer, S., Boulares, H., and Smulson, M. (1998) J. Biol. Chem. 273, 13703-13712) followed by cleavage of poly(ADP-ribose) polymerase (PARP), catalyzed by caspase-3. This inactivation of PARP has been proposed to prevent depletion of NAD (a PARP substrate) and ATP, which are thought to be required for later events in apoptosis. The role of PARP cleavage in apoptosis has now been investigated in human osteosarcoma cells and PARP -/- fibroblasts stably transfected with a vector encoding a caspase-3-resistant PARP mutant. Expression of this mutant PARP increased the rate of staurosporine and tumor necrosis factor-alpha-induced apoptosis, at least in part by reducing the time interval required for the onset of caspase-3 activation and internucleosomal DNA fragmentation, as well as the generation of 50-kilobase pair DNA breaks, thought to be associated with early chromatin unfolding. Overexpression of wild-type PARP in osteosarcoma cells also accelerated the apoptotic process, although not to the same extent as that apparent in cells expressing the mutant PARP. These effects of the mutant and wild-type enzymes might be due to the early and transient poly(ADP-ribose) synthesis in response to DNA breaks, and the accompanying depletion of NAD apparent in the transfected cells. The accelerated NAD depletion did not seem to interfere with the later stages of apoptosis. These results indicate that PARP activation and subsequent cleavage have active and complex roles in apoptosis.

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Impact of EGFR expression on colorectal cancer patient prognosis and survival.

J-P Spano, C Lagorce, D Atlan … (2005)

Epidermal growth factor receptor (EGFR) is overexpressed in many types of cancers, especially colorectal cancer (CRC), and seems to reflect more aggressive histological and clinical behaviors. The aim of this study was to evaluate EGFR immunohistochemical reactivity in CRC biopsies, and to analyze its relationship with various histological and clinical characteristics and survival. A composite EGFR score, obtained by multiplying the grade (% positive cells) by the intensity of labeling (0-9) was used to define patients with low or high EGFR expression whose clinicopathological features were then compared. Univariate tests and multivariate Cox proportional hazards model were applied for data analysis. Tissue sections from 150 CRC patients with a median follow-up of 40 months were examined. Median patient age at diagnosis was 70 years (range 38-89 years). EGFR reactivity was positive for 143 patients (97%) and high for 118 (80%). According to multivariate analysis, EGFR overexpression was significantly associated with tumor stage, with a higher percentage of EGFR overexpression in T3 than T4 (P=0.003) and not with overall survival. EGFR was overexpressed in this CRC patient population and was significantly associated with TNM (tumor-node-metastasis) stage T3. In the context of a new therapeutic strategy using EGFR-targeted therapies, although EGFR remains a controversial prognostic factor, this expression-stage association may play a crucial role in a decision to initiate an adjuvant treatment.

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Author and article information

Contributors

Yu-Li Lo:

ORCID: http://orcid.org/0000-0002-6548-3280

yulilo@ym.edu.tw

Journal

Journal ID (nlm-ta): J Nanobiotechnology

Journal ID (iso-abbrev): J Nanobiotechnology

Title: Journal of Nanobiotechnology

Publisher: BioMed Central (London )

ISSN (Electronic): 1477-3155

Publication date (Electronic): 19 August 2019

Publication date PMC-release: 19 August 2019

Publication date Collection: 2019

Volume: 17

Electronic Location Identifier: 89

Affiliations

[1 ]ISNI 0000 0001 0425 5914, GRID grid.260770.4, Institute of Pharmacology, , National Yang-Ming University, ; Taipei, 112 Taiwan

[2 ]ISNI 0000 0004 0572 7890, GRID grid.413846.c, Division of Colorectal Surgery, , Cheng Hsin General Hospital, ; Taipei, Taiwan

[3 ]ISNI 0000 0001 0425 5914, GRID grid.260770.4, Faculty of Pharmacy, , National Yang-Ming University, ; Taipei, 112 Taiwan

[4 ]ISNI 0000 0001 0425 5914, GRID grid.260770.4, Center for Advanced Pharmaceutics and Drug Delivery Research, , National Yang-Ming University, ; Taipei, 112 Taiwan

[5 ]ISNI 0000 0004 0604 5314, GRID grid.278247.c, Department of Medical Research, , Taipei Veterans General Hospital, ; Taipei, 112 Taiwan

[6 ]ISNI 0000 0004 0546 0241, GRID grid.19188.39, Institute of Oncology, , National Taiwan University, ; Taipei, 106 Taiwan

Author information

Yu-Li Lo http://orcid.org/0000-0002-6548-3280

Article

Publisher ID: 519

DOI: 10.1186/s12951-019-0519-6

PMC ID: 6699136

PubMed ID: 31426807

SO-VID: 501f0da6-6852-4ecb-86e2-0a24a5b70936

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 6 May 2019

Date accepted : 30 July 2019

Funding

Funded by: Ministry of Science and Technology of Taiwan

Award ID: MOST 106-2320-B-010-005

Award ID: MOST 107-2320-B-010-015-MY3

Award Recipient : Yu-Li Lo

Funded by: Veterans General Hospitals and University System of Taiwan

Award ID: VGHUST106-G7-7-3

Award ID: VGHUST108-G2-1-2

Award Recipient : Yu-Li Lo

Funded by: National Yang-Ming University and Cheng Hsin General Hospital

Award ID: CY10726

Award ID: CY10839

Award Recipient : Huaching Lin

Funded by: National Yang-Ming University

Award ID: Center for Advanced Pharmaceutics

Award ID: Drug Delivery Research

Award Recipient : Yu-Li Lo

Funded by: School of Medicine, National Yang-Ming University

Award ID: Development

Award ID: Construction Plan

Award Recipient : Yu-Li Lo

Funded by: Ministry of Education of Taiwan

Award ID: Aiming for the Top University Plan

Award Recipient : Yu-Li Lo

Custom metadata

ScienceOpen disciplines: Biotechnology

Keywords: afatinib,epidermal growth factor receptor (egfr),nanoparticles,cell-penetrating peptides,colorectal cancer,targeting delivery

Data availability:

ScienceOpen disciplines: Biotechnology

Keywords: afatinib, epidermal growth factor receptor (egfr), nanoparticles, cell-penetrating peptides, colorectal cancer, targeting delivery

Improving the anticancer effect of afatinib and microRNA by using lipid polymeric nanoparticles conjugated with dual pH-responsive and targeting peptides

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Conclusion

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Genome Engineering using CRISPR

Most cited references 41

Endocytosis and exocytosis of nanoparticles in mammalian cells

Role of poly(ADP-ribose) polymerase (PARP) cleavage in apoptosis. Caspase 3-resistant PARP mutant increases rates of apoptosis in transfected cells.

Impact of EGFR expression on colorectal cancer patient prognosis and survival.

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