Cancer cell-selective, clathrin-mediated endocytosis of aptamerdecorated nanoparticles

verfasst von

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

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 (K_d = 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 membranelocalized multidrug resistance efflux pumps, thereby overcoming an important mechanism of cancer multidrug resistance.

Organisationseinheit(en)

Institut für Technische Chemie

Externe Organisation(en)

Technion-Israel Institute of Technology

Typ

Artikel

Journal

ONCOTARGET

Band

9

Seiten

20993-21006

Anzahl der Seiten

14

ISSN

1949-2553

Publikationsdatum

20.04.2018

Publikationsstatus

Veröffentlicht

Peer-reviewed

Ja

ASJC Scopus Sachgebiete

Onkologie

Ziele für nachhaltige Entwicklung

SDG 3 – Gute Gesundheit und Wohlergehen

Elektronische Version(en)

https://doi.org/10.18632/oncotarget.24772 (Zugang: Offen)
https://doi.org/10.15488/3435 (Zugang: Offen)