Urothelium-adherent, ion-triggered liposome-in-gel system as a platform for intravesical drug delivery

Abstract

Instillations of therapeutic agents into the urinary bladder have limited efficacy due to drug washout and inadequate attachment to and penetration into the bladder wall. Instilled nanoparticles alone have low stability and high susceptibility to washout, while gel-based systems are difficult to administer and retain. To overcome disadvantages of current technologies, a biodegradable, in situ-gelling liposome-in-gel (LP-Gel) system was developed for instillation into the bladder, composed of nano-sized, fluidizing liposomes incorporated into a "smart" biopolymeric, urine-triggered hydrogel. The liposomes are optimized for their fluidizing composition in order to enhance cellular penetration through the urothelial barrier, while the hydrogel co-delivers the suspended nanocarriers and enhances adhesion on the mucin layer of the urothelium. The composite system thus mimics both the lipid membranes and mucosal layer that comprise the urothelial barrier. LP-Gel showed appreciable cytotoxicity in rat and human bladder cancer cells, and instillation into rat bladder showed enhanced adhesion on the urothelium and increased penetration into the bladder wall. Instillation of paclitaxel-loaded LP-Gel showed drug retention for at least 7days, substantially higher than free drug (few hours), and with negligible systemic levels. The LP-Gel platform system thus facilitates prolonged drug localization in the bladder, showing potential use in intravesical applications.