pH-Sensitive siRNA nanovector for targeted gene silencing and cytotoxic effect in cancer cells.
A small interfering RNA (siRNA) nanovector with dual targeting specificity and dual therapeutic effect is developed for targeted cancer imaging and therapy. The nanovector is composed of an iron oxide magnetic nanoparticle core coated with three different functional molecules: polyethyleneimine (PEI), siRNA, and chlorotoxin (CTX). The primary amine group of PEI is blocked with citraconic anhydride that is removable at acidic conditions, not only to increase its biocompatibility at physiological conditions but also to elicit a pH-sensitive cytotoxic effect in the acidic tumor microenvironment. The PEI is covalently immobilized on the nanovector via a disulfide linkage that is cleavable after cellular internalization of the nanovector. CTX as a tumor-specific targeting ligand and siRNA as a therapeutic payload are conjugated on the nanovector via a flexible and hydrophilic PEG linker for targeted gene silencing in cancer cells. With a size of ∼60 nm, the nanovector exhibits long-term stability and good magnetic property for magnetic resonance imaging. The multifunctional nanovector exhibits both significant cytotoxic and gene silencing effects at acidic pH conditions for C6 glioma cells, but not at physiological pH conditions. Our results suggest that this nanovector system could be safely used as a potential therapeutic agent for targeted treatment of glioma as well as other cancers.
Mok
Hyejung
H
Center for Molecular Imaging, Departments of Radiation Oncology and, and Radiology, University of Michigan, Ann Arbor, Michigan 48109, United States 98195, USA.
Veiseh
Omid
O
Fang
Chen
C
Kievit
Forrest M
FM
Wang
Freddy Y
FY
Park
James O
JO
Zhang
Miqin
M
D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003287:Contrast Media / Q000737:chemistry / Q000633:toxicity; D005290:Ferric Compounds / Q000737:chemistry / Q000633:toxicity; D020868:Gene Silencing / Q000187:drug effects*; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D006863:Hydrogen-Ion Concentration; D008279:Magnetic Resonance Imaging; D008280:Magnetics; D015394:Molecular Structure; D053758:Nanoparticles / Q000737:chemistry / Q000633:toxicity*; D010316:Particle Size; D011094:Polyethyleneimine / Q000737:chemistry / Q000633:toxicity; D034741:RNA, Small Interfering / Q000737:chemistry / Q000633:toxicity*; D012604:Scorpion Venoms / Q000737:chemistry / Q000633:toxicity
D003287:Contrast Media; D005290:Ferric Compounds; D034741:RNA, Small Interfering; D012604:Scorpion Venoms; C091539:Chlorotoxin; C000499:ferric oxide; D011094:Polyethyleneimine