Enhanced Human Epidermal Growth Factor Receptor 2 Degradation in Breast Cancer Cells by Lysosome-Targeting Gold Nanoconstructs.
This paper describes how gold nanoparticle nanoconstructs can enhance anticancer effects of lysosomal targeting aptamers in breast cancer cells. Nanoconstructs consisting of anti-HER2 aptamer (human epidermal growth factor receptor 2, HApt) densely grafted on gold nanostars (AuNS) first targeted HER2 and then were internalized via HER2-mediated endocytosis. As incubation time increased, the nanoconstruct complexes were found in vesicular structures, starting from early endosomes to lysosomes as visualized by confocal fluorescence and differential interference contrast microscopy. Within the target organelle, lysosomes, HER2 was degraded by enzymes at low pH, which resulted in apoptosis. At specific time points related to the doubling time of the cancer cells, we found that accumulation of HER2-HApt-AuNS complexes in lysosomes, lysosomal activity, and lysosomal degradation of HER2 were positively correlated. Increased HER2 degradation by HApt-AuNS triggered cell death and cell cycle arrest in the G0/G1 phase inhibition of cell proliferation. This work shows how a perceived disadvantage of nanoparticle-based therapeutics-the inability of nanoconstructs to escape from vesicles and thus induce a biological response-can be overcome by both targeting lysosomes and exploiting lysosomal degradation of the biomarkers.
Hyojin
H
Lee
Department of Dermatology, Northwestern University , 676 N. St. Clair Street, Chicago, Illinois 60611, United States.
Duncan Hieu M
DH
Dam
Ji Won
JW
Ha
Jun
J
Yue
Teri W
TW
Odom
D052157:Aptamers, Nucleotide / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use*; D001483:Base Sequence; D001940:Breast / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems; D005260:Female; D006046:Gold / Q000737:chemistry*; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D049329:Nanostructures / Q000737:chemistry* / Q000648:ultrastructure; D059748:Proteolysis / Q000187:drug effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*
D052157:Aptamers, Nucleotide; D004337:Drug Carriers; D006046:Gold; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human
DNA aptamers; gold nanostars; lysosomes; nanoparticles; targeted drug delivery