Details
| Original language | English |
|---|---|
| Pages (from-to) | 20993-21006 |
| Number of pages | 14 |
| Journal | ONCOTARGET |
| Volume | 9 |
| Issue number | 30 |
| Publication status | Published - 20 Apr 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 membranelocalized multidrug resistance efflux pumps, thereby overcoming an important mechanism of cancer multidrug resistance.
Keywords
- Aptamers, Clathrin-mediated endocytosis, Lung cancer, Multidrug resistance, Targeted delivery
ASJC Scopus subject areas
- Medicine(all)
- Oncology
Sustainable Development Goals
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In: ONCOTARGET, Vol. 9, No. 30, 20.04.2018, p. 20993-21006.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Cancer cell-selective, clathrin-mediated endocytosis of aptamerdecorated nanoparticles
AU - Engelberg, Shira
AU - Modrejewski, Julia
AU - Walter, Johanna G.
AU - Livney, Yoav D.
AU - Assaraf, Yehuda G.
N1 - FUNDING: This work was supported by a grant from the Volkswagen Foundation, Niedersachsen-Israel collaboration fund (to JGW, YDL, and YGA).
PY - 2018/4/20
Y1 - 2018/4/20
N2 - 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 membranelocalized multidrug resistance efflux pumps, thereby overcoming an important mechanism of cancer multidrug resistance.
AB - 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 membranelocalized multidrug resistance efflux pumps, thereby overcoming an important mechanism of cancer multidrug resistance.
KW - Aptamers
KW - Clathrin-mediated endocytosis
KW - Lung cancer
KW - Multidrug resistance
KW - Targeted delivery
UR - http://www.scopus.com/inward/record.url?scp=85045834128&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.24772
DO - 10.18632/oncotarget.24772
M3 - Article
AN - SCOPUS:85045834128
VL - 9
SP - 20993
EP - 21006
JO - ONCOTARGET
JF - ONCOTARGET
SN - 1949-2553
IS - 30
ER -