title: Urodynamic and immunohistochemical evaluation of intravesical botulinum toxin A delivery using liposomes.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Department of Urology, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan, Republic of China. chuang82@ms26.hinet.net
authors.forename: Yao-Chi
authors.initials: YC
authors.lastname: Chuang
authors.forename: Pradeep
authors.initials: P
authors.lastname: Tyagi
authors.forename: Chao-Cheng
authors.initials: CC
authors.lastname: Huang
authors.forename: Naoki
authors.initials: N
authors.lastname: Yoshimura
authors.forename: Moya
authors.initials: M
authors.lastname: Wu
authors.forename: Jonathan
authors.initials: J
authors.lastname: Kaufman
authors.forename: Michael B
authors.initials: MB
authors.lastname: Chancellor
mesh_terms: D000283:Administration, Intravesical; D000818:Animals; D019274:Botulinum Toxins, Type A / Q000008:administration & dosage* / Q000494:pharmacology; D005260:Female; D007150:Immunohistochemistry; D008081:Liposomes; D009465:Neuromuscular Agents / Q000008:administration & dosage* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D001743:Urinary Bladder / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D014563:Urodynamics / Q000187:drug effects*
chemical_list: D008081:Liposomes; D009465:Neuromuscular Agents; D019274:Botulinum Toxins, Type A