Donin Nicholas M, Duarte Sandra, Lenis Andrew T, Caliliw Randy, Torres Cristobal, Smithson Anthony, Strauss-Ayali Dalit, Agmon-Gerstein Yael, Malchi Nadav, Said Jonathan, Raman Steven S, Holden Stuart, Pantuck Allan, Belldegrun Arie S, Chamie Karim
Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
Division of Laboratory and Animal Medicine, University of California, Los Angeles, Los Angeles, CA.
Urology. 2017 Jan;99:270-277. doi: 10.1016/j.urology.2016.09.039. Epub 2016 Oct 5.
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.
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.
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.
Antegrade MitoGel delivery to the pelvicalyceal system of Yorkshire swine is feasible and safe. Further evaluation of MitoGel in human clinical trials is warranted.
使用临床前猪动物模型评估单次和连续向上尿路灌注米托凝胶的安全性和可行性。米托凝胶是一种基于RTGel（一种专有的热敏水凝胶技术）的新型丝裂霉素C（MMC）缓释制剂。米托凝胶在低温下呈液态，在体温下凝固成凝胶状态。鉴于其能够在上尿路中持续释放MMC，它旨在用于治疗上尿路尿路上皮癌。
我们采用三相设计使用了23头猪。所有动物均接受双侧肾造瘘管置入。在第1阶段，3只动物在12小时内接受顺行RTGel灌注、成像并实施安乐死。在第2阶段，10头猪接受单次顺行灌注，灌注后3天进行单侧肾切除术，灌注后30天进行对侧肾切除术并实施安乐死。在第3阶段，10只动物在3周内接受6次灌注，灌注后30天进行双侧肾切除术和尸检。对米托凝胶（2mg/mL和4mg/mL）、水性MMC（2mg/mL和4mg/mL）以及单独的RTGel进行了评估。
在荧光镜和计算机断层扫描成像中，米托凝胶在肾盂肾盏系统内可观察到4 - 6小时。MMC血浆水平完全在可接受的安全阈值范围内。没有尿路梗阻、急性肾损伤、败血症或骨髓抑制的证据。泌尿系统的组织学变化轻微且短暂。
向约克郡猪的肾盂肾盏系统顺行递送米托凝胶是可行且安全的。有必要在人类临床试验中对米托凝胶进行进一步评估。
