Intravesical Therapy of Interstitial Cystitis

[摘要] Leaf Huang Ph.D.INTRAVESICAL THERAPY OF INTERSTITIAL CYSTITISPradeep Tyagi, Ph.D.University of Pittsburgh, April 4th, 2005Interstitial cystitis (IC) is an inflammatory disorder of bladder which affects middle-aged Caucasian women. Intravesical administration of drugs is a mainstay in its treatment either as adjunct to oral therapy or as second-line therapy. The vehicles currently used for this route of administration are ideally suited for hydrophobic drugs and typically maintain drug exposure in the bladder for very short duration of time. The present dissertation project was aimed at investigating the use of alternative vehicles for improving intravesical drug delivery of hydrophobic small molecular weight drugs such as capsaicin misoprostol in addition to the delivery of large molecular weight peptide nucleic acid (PNA) for antisense based therapy. The hydrophobic drugs selected for this study were delivered by intravesical route using liposomes, thermosensitive hydrogel and TAT peptide. The efficiency of drug delivery was assessed by measuring the physiological response of normal and diseased rat bladder by metabolic cages and the method of cystometrogram (CMG). Histology and immunohistochemistry of bladder and spinal cord sections was done to corroborate the response measured in the physiological measurement. Liposomes were demonstrated to be a superior vehicle for capsaicin and thermosensitive hydrogel was able to sustain the exposure of a hydrophobic drug in the bladder for prolonged time and increase the efficacy of misoprostol in rat model of cystitis induced by cyclophosphamide. An interesting observation made during the study was that liposomes in absence of drug were able to modulate physiological response of bladder and this observation was further investigated to define the charge on the lipid headgroup and the structural requirements of hydrophobic backbone in the lipids for reducing bladder hyperactivity induced by sequential infusion of protamine sulfate and high concentration of KCl. Overexpression of NGF in cyclophosphamide induced cystitis was downregulated in the urothelium of rat bladder using antisense based therapy with PNA, which was delivered with the aid of TAT peptide. Overall, the study concluded that liposomes cannot only be a treatment option but can also be used for delivery of hydrophobic drugs. The potential of hydrogels and cell penetrating peptides for intravesical drug delivery needs further investigation.

[发布机构] the University of Pittsburgh

[效力级别] Liposomes