Co-delivery of doxorubicin and siRNA using octreotide-conjugated gold nanorods for targeted neuroendocrine cancer therapy.
A multifunctional gold (Au) nanorod (NR)-based nanocarrier capable of co-delivering small interfering RNA (siRNA) against achaete-scute complex-like 1 (ASCL1) and an anticancer drug (doxorubicin (DOX)) specifically to neuroendocrine (NE) cancer cells was developed and characterized for combined chemotherapy and siRNA-mediated gene silencing. The Au NR was conjugated with (1) DOX, an anticancer drug, via a pH-labile hydrazone linkage to enable pH-controlled drug release, (2) polyarginine, a cationic polymer for complexing siRNA, and (3) octreotide (OCT), a tumor-targeting ligand, to specifically target NE cancer cells with overexpressed somatostatin receptors. The Au NR-based nanocarriers exhibited a uniform size distribution as well as pH-sensitive drug release. The OCT-conjugated Au NR-based nanocarriers (Au-DOX-OCT, targeted) exhibited a much higher cellular uptake in a human carcinoid cell line (BON cells) than non-targeted Au NR-based nanocarriers (Au-DOX) as measured by both flow cytometry and confocal laser scanning microscopy (CLSM). Moreover, Au-DOX-OCT-ASCL1 siRNA (Au-DOX-OCT complexed with ASCL1 siRNA) resulted in significantly higher gene silencing in NE cancer cells than Au-DOX-ASCL1 siRNA (non-targeted Au-DOX complexed with ASCL1 siRNA) as measured by an immunoblot analysis. Additionally, Au-DOX-OCT-ASCL1 siRNA was the most efficient nanocarrier at altering the NE phenotype of NE cancer cells and showed the strongest anti-proliferative effect. Thus, combined chemotherapy and RNA silencing using NE tumor-targeting Au NR-based nanocarriers could potentially enhance the therapeutic outcomes in treating NE cancers.
Department of Biomedical Engineering, Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53706, USA.
Yuling
Y
Xiao
Renata
R
Jaskula-Sztul
Alireza
A
Javadi
Wenjin
W
Xu
Jacob
J
Eide
Ajitha
A
Dammalapati
Muthusamy
M
Kunnimalaiyaan
Herbert
H
Chen
Shaoqin
S
Gong
D000903:Antibiotics, Antineoplastic / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D018278:Carcinoma, Neuroendocrine / Q000188:drug therapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D004337:Drug Carriers / Q000737:chemistry*; D006046:Gold / Q000737:chemistry*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008081:Liposomes / Q000737:chemistry; D043942:Nanotubes / Q000737:chemistry* / Q000648:ultrastructure; D015282:Octreotide / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use
D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D008081:Liposomes; D010455:Peptides; D034741:RNA, Small Interfering; C015462:polyarginine; D006046:Gold; D004317:Doxorubicin; D015282:Octreotide