Sustained-release Formulation of Mitomycin C to the Upper Urinary Tract Using a Thermosensitive Polymer: A Preclinical Study

Urology. 2016 Oct 5. pii: S0090-4295(16)30689-6. doi: 0.1016/j.urology.2016.09.039. [Epub ahead of print]

Donin NM1, Duarte S2, Lenis AT3, Caliliw R3, Torres C2, Smithson A2, Strauss-Ayali D4, Agmon-Gerstein Y4, Malchi N4, Said J5, Raman SS6, Holden S3, Pantuck A7, Belldegrun AS7, Chamie K7

1Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.; 2Division of Laboratory and Animal Medicine, University of California, Los Angeles, Los Angeles, CA.; 3Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.; 4UroGen Pharma Ltd., Ra’anana, Israel.; 5Department of Pathology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.; 6Department of Radiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.; 7Department 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.

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.

MATERIALS AND 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.

CONCLUSION:

Antegrade MitoGel delivery to the pelvicalyceal system of Yorkshire swine is feasible and safe. Further evaluation of MitoGel in human clinical trials is warranted.

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