UROLOGICAL SURVEY
Basic and Translational Urology
Urodynamic and immunohistochemical evaluation of intravesical botulinum toxin A delivery using liposomes
Chuang YC, Tyagi P, Huang CC, Yoshimura N, Wu M, Kaufman J, Chancellor MB
Department of Urology, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan, Republic of China
J Urol. 2009; 182: 786-92
PURPOSE: Botulinum toxin A (Allergan, Irvine, California) is a high molecular weight neurotoxin used to treat hypersensitive bladder by direct injection to pass the urothelial barrier. We investigated the feasibility of intravesical botulinum toxin A delivery using liposomes (Lipella Pharmaceuticals, Pittsburgh, Pennsylvania), which are phospholipid bilayered vesicles, and evaluated the urodynamic and immunohistochemical effect on acetic acid induced bladder hyperactivity in rats.
MATERIAL AND METHODS: Liposomes (1 ml), botulinum toxin A (20 U/1 ml saline) or botulinum toxin A encapsulated in liposomes (lipotoxin, that is 20 U botulinum toxin A plus 1 ml liposomes) was administered in the bladder and retained for 1 hour on day 1 after baseline cystometrogram. Continuous cystometrogram was performed on day 1 by filling the bladder with saline and on day 8 by filling the bladder with saline, followed by 0.3% acetic acid. The bladder was then harvested. Cystometrogram parameters, histology, SNAP25 and calcitonin gene-related peptide expression were measured by Western blotting or immunostaining.
RESULTS: The intercontraction interval was decreased 57.2% and 56.0% after intravesical acetic acid instillation in liposome and botulinum toxin A pretreated rats, respectively. However, rats that received lipotoxin showed a significantly decreased intercontraction interval response (21.1% decrease) to acetic acid instillation but without compromised voiding function. Also, lipotoxin pretreated rats had a better decrease in the inflammatory reaction and SNAP-25 expression, and increase in calcitonin gene-related peptide immunoreactivity than those in liposome or botulinum toxin A pretreated rats.
CONCLUSIONS: Intravesical lipotoxin administration cleaved SNAP-25, inhibited calcitonin gene-related peptide release from afferent nerve terminals and blocked the acetic acid induced hyperactive bladder. These results support liposomes as an efficient vehicle for delivering botulinum toxin A without injection.
Editorial Comment
It has been proved that Botulinum toxin A applied as cystoscopic guided injections into the bladder wall have a therapeutic effect on overactive bladder and interstitial cystitis / painful bladder syndrome. Nevertheless, we know well that bladder injection therapy has some limitations, including drug leakage outside the bladder, hematuria, pain at injection sites and uneven distribution. In this way, the authors have been searching for a simpler and lower risk method to deliver Botulinum toxin A without injection.
We know that it is difficult for Botulinum toxin A to access the submucosal nerve plexus in formal use with saline as a vehicle without direct injection to pass the urothelial barrier. Based on previous experience, the authors speculated that delivery using liposomes, which are phospholipid bilayered vesicles, and evaluated the urodynamic and immunohistochemical effect on acetic acid induced bladder hyperactivity in rats.
Their results show that Botulinum toxin A can be combined with liposomes to be administered as a liquid instillation without cystoscopic injection, with good therapeutic results in rats.
To our knowledge, this is the first report of the promise of liquid instillation of Botulinum toxin A. I strong recommend this paper to all physicians involved in research on neurourology.
Dr. Francisco J. B. Sampaio
Full-Professor and Chair, Urogenital Research Unit
State University of Rio de Janeiro
Rio de Janeiro, RJ, Brazil
E-mail: sampaio@urogenitalresearch.org
Publication Dates
-
Publication in this collection
07 Dec 2009 -
Date of issue
Oct 2009
