Urodynamic and Immunohistochemical Evaluation of Intravesical Botulinum Toxin A Delivery Using Liposomes

被引:90
作者
Chuang, Yao-Chi [1 ]
Tyagi, Pradeep [3 ]
Huang, Chao-Cheng [2 ]
Yoshimura, Naoki [4 ]
Wu, Moya [1 ]
Kaufman, Jonathan [5 ]
Chancellor, Michael B. [3 ]
机构
[1] Chang Gung Univ, Coll Med, Dept Urol, Kaohsiung, Taiwan
[2] Chang Gung Univ, Coll Med, Chang Gung Mem Hosp, Dept Pathol,Kaohsiung Med Ctr, Kaohsiung, Taiwan
[3] William Beaumont Hosp, Dept Urol, Royal Oak, MI 48072 USA
[4] Univ Pittsburgh, Sch Med, Dept Urol, Pittsburgh, PA USA
[5] Lipella Pharmaceut Inc, Pittsburgh, PA USA
关键词
urinary bladder; urinary incontinence; botulinum toxin type A; liposomes; drug delivery systems; DETRUSOR OVERACTIVITY; INDUCED CYSTITIS; BLADDER PAIN; INJECTION; CAPSAICIN; BARRIER; MODEL; RATS;
D O I
10.1016/j.juro.2009.03.083
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
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. Materials 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 generelated 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.
引用
收藏
页码:786 / 792
页数:7
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