Oncotarget

Research Papers:

Cancer cell-selective, clathrin-mediated endocytosis of aptamer decorated nanoparticles

Shira Engelberg, Julia Modrejewski, Johanna G. Walter, Yoav D. Livney and Yehuda G. Assaraf _

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Oncotarget. 2018; 9:20993-21006. https://doi.org/10.18632/oncotarget.24772

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Abstract

Shira Engelberg1, Julia Modrejewski2, Johanna G. Walter2, Yoav D. Livney1 and Yehuda G. Assaraf3

1The Laboratory of Food Physical Chemistry and Biopolymeric Delivery Systems, Department of Biotechnology and Food Engineering, Technion, Israel Institute of Technology, Haifa, Israel

2Institute for Technical Chemistry, Leibniz University Hannover, Lower Saxony, Germany

3The Fred Wyszkowski Cancer Research Laboratory, Department of Biology, Technion-Israel Institute of Technology, Haifa, Israel

Correspondence to:

Yehuda G. Assaraf, email: assaraf@technion.ac.il

Yoav D. Livney, email: livney@technion.ac.il

Keywords: lung cancer; targeted delivery; aptamers; clathrin-mediated endocytosis; multidrug resistance

Received: October 09, 2017     Accepted: February 26, 2018     Published: April 20, 2018

ABSTRACT

Lung cancer is the leading cause of cancer mortality worldwide, resulting in 88% deaths of all diagnosed patients. Hence, novel therapeutic modalities are urgently needed. Single-stranded oligonucleotide-based aptamers (APTs) are excellent ligands for tumor cell targeting. However, the molecular mechanisms underlying their internalization into living cells have been poorly studied. Towards the application of APTs for active drug targeting to cancer cells, we herein studied the mechanism underlying S15-APT internalization into human non-small cell lung cancer A549 cells. We thus delineated the mode of entry of a model nanomedical system based on quantum dots (QDs) decorated with S15-APTs as a selective targeting moiety for uptake by A549 cells. These APT-decorated QDs displayed selective binding to, and internalization by target A549 cells, but not by normal human bronchial epithelial BEAS2B, cervical carcinoma (HeLa) and colon adenocarcinoma CaCo-2 cells, hence demonstrating high specificity. Flow cytometric analysis revealed a remarkably low dissociation constant of S15-APTs-decorated QDs to A549 cells (Kd = 13.1 ± 1.6 nM). Through the systematic application of a series of established inhibitors of known mechanisms of endocytosis, we show that the uptake of S15-APTs proceeds via a classical clathrin-dependent receptor-mediated endocytosis. This cancer cell-selective mode of entry could possibly be used in the future to evade plasma membrane-localized multidrug resistance efflux pumps, thereby overcoming an important mechanism of cancer multidrug resistance.


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