title: Sustained-release Formulation of Mitomycin C to the Upper Urinary Tract Using a Thermosensitive Polymer: A Preclinical Study.
abstract: OBJECTIVE
  To evaluate the safety and feasibility of single and serial instillations of MitoGel into the upper urinary tract using a preclinical swine animal model. MitoGel is a novel sustained release formulation of mitomycin C (MMC) based on RTGel, a proprietary thermosensitive hydrogel technology. MitoGel is liquid at cold temperatures and solidifies to gel state at body temperature. It is intended as a treatment for upper tract urothelial carcinoma, given its ability to provide sustained release of MMC in the upper urinary tract.
  
  
  METHODS
  We utilized 23 pigs in a 3-phase design. All animals underwent bilateral nephrostomy tube placement. During phase 1, 3 animals underwent antegrade RTGel instillation, imaging, and euthanasia within 12 hours. In phase 2, 10 pigs underwent single antegrade instillation, unilateral nephrectomy 3 days following instillation, and contralateral nephrectomy and euthanasia 30 days following instillation. During phase 3, 10 animals underwent 6 instillations over 3 weeks, followed by bilateral nephrectomy and necropsy 30 days postinstillation. MitoGel (2 mg/mL and 4 mg/mL), aqueous MMC (2 mg/mL and 4 mg/mL), and RTGel alone were evaluated.
  
  
  RESULTS
  MitoGel remained visible within the pelvicalyceal system on fluoroscopic and computed tomography imaging for 4-6 hours. MMC plasma levels were well within acceptable safety thresholds. There was no evidence of urinary obstruction, acute kidney injury, sepsis, or myelosuppression. Histologic changes in the urinary system were mild and transient.
  
  
  CONCLUSIONS
  Antegrade MitoGel delivery to the pelvicalyceal system of Yorkshire swine is feasible and safe. Further evaluation of MitoGel in human clinical trials is warranted.
authors.affiliation: Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA. Electronic address: NDonin@mednet.ucla.edu.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Donin
authors.affiliation: Division of Laboratory and Animal Medicine, University of California, Los Angeles, Los Angeles, CA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Duarte
authors.affiliation: Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Lenis
authors.affiliation: Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
authors.forename: Randy
authors.initials: R
authors.lastname: Caliliw
authors.affiliation: Division of Laboratory and Animal Medicine, University of California, Los Angeles, Los Angeles, CA.
authors.forename: Cristobal
authors.initials: C
authors.lastname: Torres
authors.affiliation: Division of Laboratory and Animal Medicine, University of California, Los Angeles, Los Angeles, CA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Smithson
authors.affiliation: UroGen Pharma Ltd., Ra'anana, Israel.
authors.forename: Dalit
authors.initials: D
authors.lastname: Strauss-Ayali
authors.affiliation: UroGen Pharma Ltd., Ra'anana, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Agmon-Gerstein
authors.affiliation: UroGen Pharma Ltd., Ra'anana, Israel.
authors.forename: Nadav
authors.initials: N
authors.lastname: Malchi
authors.affiliation: Department of Pathology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Said
authors.affiliation: Department of Radiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
authors.forename: Steven S
authors.initials: SS
authors.lastname: Raman
authors.affiliation: Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
authors.forename: Stuart
authors.initials: S
authors.lastname: Holden
authors.affiliation: Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA.
authors.forename: Allan
authors.initials: A
authors.lastname: Pantuck
authors.affiliation: Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA.
authors.forename: Arie S
authors.initials: AS
authors.lastname: Belldegrun
authors.affiliation: Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA.
authors.forename: Karim
authors.initials: K
authors.lastname: Chamie
mesh_terms: D000283:Administration, Intravesical; D000818:Animals; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy*; D003432:Cross-Linking Reagents / Q000008:administration & dosage; D003692:Delayed-Action Preparations; D004353:Drug Evaluation, Preclinical; D005240:Feasibility Studies; D005260:Female; D007322:Instillation, Drug; D016685:Mitomycin / Q000008:administration & dosage*; D009374:Neoplasms, Experimental; D011108:Polymers / Q000008:administration & dosage*; D013552:Swine; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy*
chemical_list: D003432:Cross-Linking Reagents; D003692:Delayed-Action Preparations; D011108:Polymers; D016685:Mitomycin