Therapeutic Efficacy of onabotulinumtoxinA Delivered Using Various Approaches in Sensory Bladder Disorder

Abstract

Cystoscopic onabotulinumtoxinA (onaBoNTA) intradetrusor injection is an efficient and durable modality for treating sensory bladder disorders. However, the inconvenience of using the cystoscopic technique and anesthesia, and the adverse effects of direct needle injection (e.g., haematuria, pain, and infections) have motivated researchers and clinicians to develop diverse injection-free procedures to improve accessibility and prevent adverse effects. However, determining suitable approaches to transfer onaBoNTA, a large molecular and hydrophilic protein, through the impermeable urothelium to reach therapeutic efficacy remains an unmet medical need. Researchers have provided potential solutions in three categories: To disrupt the barrier of the urothelium (e.g., protamine sulfate), to increase the permeability of the urothelium (e.g., electromotive drug delivery and low-energy shock wave), and to create a carrier for transportation (e.g., liposomes, thermosensitive hydrogel, and hyaluronan-phosphatidylethanolamine). Thus far, most of these novel administration techniques have not been well established in their long-term efficacy; therefore, additional clinical trials are warranted to validate the therapeutic efficacy and durability of these techniques. Finally, researchers may make progress with new combinations or biomaterials to change clinical practices in the future.

Low-Energy Shock Wave Plus Intravesical Instillation of Botulinum Toxin A for Interstitial Cystitis/Bladder Pain Syndrome: Pathophysiology and Preliminary Result of a Novel Minimally Invasive Treatment

“…Therapeutic approaches have been devoted to searching for a method that can deliver BoNT-A molecules across the barrier boundary of the bladder mucosa without the need for needle injections, such as using protamine sulfate to disrupt the barrier of the urothelium; electromotive drug delivery and LESW to increase the permeability of the urothelium; and liposomes, thermosensitive hydrogel, and hyaluronan–phosphatidylethanolamine to create a carrier for BoNT-A transportation [ 85 ]. In a rat model of bladder cancer, LESW applied on the bladder plus intravesical instillation of epirubicin was used to enhance the delivery of a chemotherapeutic agent into the mucosa.…”

Nano-BTA: A New Strategy for Intravesical Delivery of Botulinum Toxin A

“…Some factors prevent BoNT-A from penetrating the mucosa: First, the passive diffusion of BoNT-A is limited by tight junctions due to its large molecular weight (150 KDa). Second, the intact BPB blocks the adherence and permeation of BoNT-A, and third, the dilution and flushing effect of urine prevents BoNT-A from remaining localized in the bladder [ 40 ]. As previously mentioned, BoNT-A injections are associated with AEs in patients.…”

“…Liposomes can load both lipophilic drugs (e.g., capsaicin) and hydrophilic drugs (e.g., botulinum toxin) [ 43 , 44 ]. Subsequently, liposomes penetrate the urothelium via endocytosis for IDD [ 45 ]. Empty liposomes have been shown to partially reverse high micturition frequency in a rat model of bladder hyperactivity induced by potassium chloride irritation after protamine sulfate intravesical instillation [ 46 ].…”

Botulinum Toxin Paves the Way for the Treatment of Functional Lower Urinary Tract Dysfunction

“…such as protamine sulfate pretreatment and low energy shock wave to increase urothelial permeability, and liposomes to create a carrier for the transportation of BoNT-A [5]. Because BoNT-A has dual motor and sensory effects, the reduction of the expression of TRPV1 and P2X3 on suburothelial sensory afferents can be achieved in patients treated with detrusor BoNT-A injections.…”

“…Wang et al [ 3 ], and Liao et al [ 4 ] carried out comprehensive reviews and clinical reports of the treatment outcome in these patient cohorts. Chen et al review the therapeutic efficacy of BoNT-A delivered using various approaches such as protamine sulfate pretreatment and low energy shock wave to increase urothelial permeability, and liposomes to create a carrier for the transportation of BoNT-A [ 5 ]. Because BoNT-A has dual motor and sensory effects, the reduction of the expression of TRPV1 and P2X3 on suburothelial sensory afferents can be achieved in patients treated with detrusor BoNT-A injections.…”