Temperature-responsive silk-elastinlike protein polymer enhancement of intravesical drug delivery of a therapeutic glycosaminoglycan for treatment of interstitial cystitis/painful bladder syndrome.

Interstitial cystitis (IC), also known as painful bladder syndrome, is a debilitating chronic condition with many patients failing to respond to current treatment options. Rapid clearance, mucosal coating, and tight epithelium create strong natural barriers that reduce the effectiveness of many pharmacological interventions in the bladder. Intravesical drug delivery (IDD) is the administration of therapeutic compounds or devices to the urinary bladder via a urethral catheter. Previous work in improving IDD for IC has focused on the sustained delivery of analgesics within the bladder and other small molecule drugs which do not address underlying inflammation and bladder damage. Therapeutic glycosaminoglycans (GAG) function by restoring the mucosal barrier within the bladder, promoting healing responses, and preventing irritating solutes from reaching the bladder wall. There is an unmet medical need for a therapy that provides both acute relief of symptoms while alleviating underlying physiological sources of inflammation and promoting healing within the urothelium. Semi-synthetic glycosaminoglycan ethers (SAGE) are an emerging class of therapeutic GAG with intrinsic anti-inflammatory and analgesic properties. To reduce SAGE clearance and enhance its accumulation in the bladder, we developed a silk-elastinlike protein polymer (SELP) based system to enhance SAGE IDD. We evaluated in vitro release kinetics, rheological properties, impact on bladder function, pain response, and bladder inflammation and compared their effectiveness to other temperature-responsive polymers including Poloxamer 407 and poly(lactic-co-glycolic acid)-poly(ethylene glycol). SAGE delivered via SELP-enhanced intravesical delivery substantially improved SAGE accumulation in the urothelium, provided a sustained analgesic effect 24 h after administration, and reduced inflammation.

Biomaterials. 2019 Jun 20 [Epub ahead of print]

M Martin Jensen, Wanjian Jia, Austin J Schults, Kyle J Isaacson, Douglas Steinhauff, Bryant Green, B Zachary, Joseph Cappello, Hamidreza Ghandehari, Siam Oottamasathien

Department of Bioengineering, University of Utah, Salt Lake City, UT, 84112, USA; (b)Utah Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT, 84112, USA., Division of Urology, Section of Pediatric Urology, University of Utah, Salt Lake City, UT, 84113, USA., Department of Bioengineering, University of Utah, Salt Lake City, UT, 84112, USA., Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, 84112, USA., Department of Bioengineering, University of Utah, Salt Lake City, UT, 84112, USA; (b)Utah Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT, 84112, USA; Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, 84112, USA. Electronic address: ., Division of Urology, Section of Pediatric Urology, University of Utah, Salt Lake City, UT, 84113, USA; Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, 84112, USA; Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT, 84112, USA; Department of Surgery and Division of Pediatric Urology, Primary Children's Hospital, Salt Lake City, UT, 84113, USA; Department of Pediatric Surgery, Division of Pediatric Urology, Massachusetts General Hospital for Children, Harvard Medical School, Boston, MA, 02114, USA. Electronic address: .

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