Assessment of the efficacy of repeated instillations of mitomycin C mixed with a thermosensitive hydrogel in an orthotopic rat bladder cancer model.

BACKGROUND: We investigated a thermoreversible hydrogel that is highly viscous at body temperature, while fluid-like at a low temperature, thus aiming for a slow and prolonged intravesical drug release. Our study purposed to assess antitumor efficacy of mitomycin C (MMC) mixed with hydrogel in an orthotopic rat bladder cancer model. METHODS: Bladders of female Fischer F344 rats were grafted with 1.5 × 106 AY-27 urothelial carcinoma cells. On day 5, tumor presence was assessed by cystoscopy and rats were divided into six groups (five treatment, one control, n = 10/group). Intravesical treatments (0.5 mg or 1 mg MMC-H2O or MMC-hydrogel, or 2 mg MMC-hydrogel) were administered on days 5, 8 and 11. Rats were sacrificed at day 14 and bladders were evaluated. RESULTS: Rats with tumor at cystoscopy (47/60) were evaluated for efficacy. At necropsy, all control animals (8/8) had tumors. No microscopic tumors were present in the 0.5 mg and 1 mg MMC-hydrogel groups compared with 2/8 and 1/8 rats in the 0.5 mg and 1 mg MMC-H2O groups (p = 0.47 and p = 1.00, respectively).Greater toxicity was seen in animals treated with MMC-hydrogel compared with MMC-H2O, as demonstrated by lower body weights at necropsy (p = 0.000) and a tendency for more severe clinical signs in the 1 and 2 mg MMC-hydrogel groups. Rats that died prematurely received 1 mg (4/10) or 2 mg (9/10) of MMC-hydrogel. CONCLUSIONS: Under the current model conditions it is unclear whether instillation of MMC-hydrogel is more effective than MMC-H2O. Nonetheless, the observed difference in toxicity, acting as a surrogate marker for systemic MMC exposure in the MMC-hydrogel-treated rats, supports the prolonged drug release mechanism of the hydrogel.

Serial retrograde instillations of sustained release formulation of mitomycin C to the upper urinary tract of the Yorkshire swine using a thermosensitive polymer: Safety and feasibility.

BACKGROUND: MitoGel is a novel drug formulation intended for the treatment of upper tract urothelial cancer with proven feasibility and safety in an animal model. OBJECTIVE: To evaluate the feasibility, safety, toxicokinetics, and histologic changes associated with serial retrograde MitoGel instillations to the upper urinary tract in a swine model. DESIGN, SETTING, AND PARTICIPANTS: Overall, 27 Yorkshire swine underwent 6 once-weekly unilateral retrograde instillations of MitoGel. Doses of 14, 28, or 56-mg mitomycin C (respective concentrations of 2, 4, and 8mg/ml with 9 animals per group) were evaluated. Additionally, 6 animals received sterile water as a procedure control, and 9 received gel alone (without mitomycin C), as a vehicle control. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Blood and urine samples were collected for determination of MMC toxicokinetics and for hematology, biochemistry, coagulation, and urinalysis throughout the study. Two-thirds of the cohort were euthanized 24 hours after final instillation, and one-third was euthanized 1 month after final instillation. Necropsy was performed to evaluate the histologic effects of treatments. RESULTS AND LIMITATIONS: All animals received all 6 doses of agents per protocol. No mortality, clinical adverse events, or meaningful changes in hematology, chemistry, coagulation, or urinalysis were attributable to MitoGel, RTGel alone, or water instillations. Peak plasma levels of MMC were 2 orders of magnitude less than known toxicity thresholds. MitoGel-related dose-dependent microscopic findings were seen in the treated kidneys and ureters, but were of limited severity, lacked associated clinical adverse findings, and decreased over time. CONCLUSIONS: Serial retrograde instillations of MitoGel to the pyelocaliceal system were technically feasible, and produced no observable adverse clinical, laboratory, or histologic effects.

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

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.