Microbubble-enhanced ultrasound to deliver an antisense oligodeoxynucleotide targeting the human androgen receptor into prostate tumours.
We have shown recently that downregulation of the androgen receptor (AR), one of the key players in prostate tumor cells, with short antisense oligodeoxynucleotides (ODNs) results in inhibition of prostate tumor growth. Particularly with regard to an application of these antisense drugs in vivo, we now investigated the usefulness of microbubble-enhanced ultrasound to deliver these ODNs into prostate cancer cells. Our short antisense AR ODNs were loaded onto the lipid surface of cationic gas-filled microbubbles by ion charge binding, and delivered into the cells by bursting the loaded microbubbles with ultrasound. In vitro experiments were initially performed to show that this kind of delivery system works in principle. In fact, transfection of prostate tumor cells with antisense AR ODNs using microbubble-enhanced ultrasound resulted in 49% transfected cells, associated with a decrease in AR expression compared to untreated controls. In vivo, uptake of a digoxigenin-labelled ODN was found in prostate tumour xenografts in nude mice following intratumoral or intravenous injection of loaded microbubbles and subsequent exposure of the tumour to ultrasound, respectively. Our results show that ultrasound seems to be the driving force of this delivery system. Uptake of the ODN was also observed in tumors after treatment with ultrasound alone, with only minor differences compared to the combined use of microbubbles and ultrasound.
Haag
Petra
P
Department of Urology, Innsbruck Medical University, A-6020 Innsbruck, Anichstrasse 35, Austria.
Frauscher
Ferdinand
F
Gradl
Johann
J
Seitz
Alexander
A
Schäfer
Georg
G
Lindner
Jonathan R
JR
Klibanov
Alexander L
AL
Bartsch
Georg
G
Klocker
Helmut
H
Eder
Iris E
IE
D059002:Androgen Receptor Antagonists; D000818:Animals; D015153:Blotting, Western; D015536:Down-Regulation; D016503:Drug Delivery Systems; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D045423:Microbubbles; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014465:Ultrasonics; D023041:Xenograft Model Antitumor Assays
C410798:AR protein, human; D059002:Androgen Receptor Antagonists; D020319:Oligodeoxyribonucleotides, Antisense; D012333:RNA, Messenger; D011944:Receptors, Androgen