Chemically modified short interfering hybrids (siHYBRIDS): nanoimmunoliposome delivery in vitro and in vivo for RNAi of HER-2.
A blunt-ended 19-mer short interfering hybrid (siHybrid) (H) comprised of sense-DNA/antisense-RNA targeting HER-2 mRNA was encapsulated in a liposomal nanoplex with anti-transferrin receptor single-chain antibody fragment (TfRscFv) as the targeting moiety for clinically relevant tumor-specific delivery. In vitro delivery to a human pancreatic cell line (PANC-1) was shown to exhibit sequence-specific inhibition of 48-h cell growth with an IC50 value of 37 nM. The inhibitory potency of this siHybrid was increased (IC50 value of 7.8 nM) using a homologous chemically modified siHybrid (mH) in which the 19-mer sense strand had the following pattern of 2 '-deoxyinosine (dI) and 2 '-O-methylribonucleotide (2 '-OMe) residues: 5'-d(TITIT)-2'OMe(GCGGUGGUU)-d(GICIT). These modifications were intended to favor antisense strand-mediated RNAi while mitigating possible sense strand-mediated off-target effects and RNase H-mediated cleavage of the antisense RNA strand. The presently reported immunoliposomal delivery system was successfully used in vivo to inhibit HER-2 expression, and thus induce apoptosis in human breast carcinoma tumors (MDA-MB-435) in mice upon repeated i.v. treatment at a dose of 3 mg/kg of H or mH. The in vivo potency of modified siHybrid mH appeared to be qualitatively greater than that of H, as was the case in vitro.
Hogrefe
Richard I
RI
Trilink Biotechnologies Inc., San Diego, California 92121, USA.
Lebedev
Alexandre V
AV
Zon
Gerald
G
Pirollo
Kathleen F
KF
Rait
Antonina
A
Zhou
Qi
Q
Yu
Wei
W
Chang
Esther H
EH
D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy*; D002277:Carcinoma / Q000188:drug therapy*; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000276:immunology; D008081:Liposomes; D051379:Mice; D049329:Nanostructures; D010179:Pancreas / Q000166:cytology / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D011990:Receptors, Transferrin / Q000276:immunology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D007135:Immunoglobulin Variable Region; D008081:Liposomes; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D011990:Receptors, Transferrin