Department of Urology, Radboud University Medical Center, Nijmegen, the Netherlands.
Department of Medicine III, University Hospital LMU Munich, Munich, Germany.
Int J Nanomedicine. 2021 Jan 7;16:75-88. doi: 10.2147/IJN.S280034. eCollection 2021.
Current treatment options for muscle-invasive bladder cancer (MIBC) are associated with substantial morbidity. Local release of doxorubicin (DOX) from phosphatidyldiglycerol-based thermosensitive liposomes (DPPG-TSL-DOX) potentiated by hyperthermia (HT) in the bladder wall may result in bladder sparing without toxicity of systemic chemotherapy. We investigated whether this approach, compared to conventional DOX application, increases DOX concentrations in the bladder wall while limiting DOX in essential organs.
Twenty-one pigs were anaesthetized, and a urinary catheter equipped with a radiofrequency-emitting antenna for HT (60 minutes) was placed. Experimental groups consisted of iv low or full dose (20 or 60 mg/m) DPPG-TSL-DOX with/without HT, iv low dose (20 mg/m) free DOX with HT, and full dose (50 mg/50 mL) intravesical DOX with/without HT. After the procedure, animals were immediately sacrificed. HPLC was used to measure DOX levels in the bladder, essential organs and serum, and fluorescence microscopy to evaluate DOX distribution in the bladder wall.
Iv DPPG-TSL-DOX with HT resulted in a significantly higher bladder wall DOX concentration which was more homogeneous distributed, than iv and intravesical free DOX administration with HT. Specifically in the detrusor, DPPG-TSL-DOX with HT led to a >7- and 44-fold higher DOX concentration, compared to iv free DOX with HT and intravesical DOX, respectively. Organ DOX concentrations were significantly lower in heart and kidneys, and similar in liver, spleen and lungs, following iv DPPG-TSL-DOX with HT, compared to iv free DOX. Intravesical DOX led to the lowest organ DOX concentrations.
Iv DPPG-TSL-DOX combined with HT achieved higher DOX concentrations in the bladder wall including the detrusor, compared to conventional iv and intravesical DOX application. In combination with lower DOX accumulation in heart and kidneys, compared to iv free chemotherapy, DPPG-TSL-DOX with HT has great potential to attain a role as a bladder-sparing treatment for MIBC.
肌层浸润性膀胱癌（MIBC）的当前治疗选择与大量发病率相关。在膀胱壁中通过高热（HT）使基于磷脂酰二甘油的热敏脂质体（DPPG-TSL-DOX）局部释放阿霉素（DOX）可能导致无毒性的全身化疗的膀胱保留。我们研究了与常规 DOX 应用相比，这种方法是否会增加膀胱壁中的 DOX 浓度，同时限制重要器官中的 DOX。
21 头猪被麻醉，并放置配备用于 HT（60 分钟）的射频发射天线的导尿管。实验组包括 iv 低或全剂量（20 或 60mg/m）DPPG-TSL-DOX 联合/不联合 HT、iv 低剂量（20mg/m）游离 DOX 联合 HT 和全剂量（50mg/50mL）膀胱内 DOX 联合/不联合 HT。手术后，动物立即被处死。HPLC 用于测量膀胱、重要器官和血清中的 DOX 水平，荧光显微镜用于评估膀胱壁中的 DOX 分布。
iv DPPG-TSL-DOX 联合 HT 导致膀胱壁 DOX 浓度显著升高，且分布更加均匀，比 iv 和膀胱内游离 DOX 联合 HT 更均匀。具体在逼尿肌中，与 iv 游离 DOX 联合 HT 和膀胱内 DOX 相比，DPPG-TSL-DOX 联合 HT 导致 DOX 浓度分别升高了>7 倍和 44 倍。与 iv 游离 DOX 相比，iv DPPG-TSL-DOX 联合 HT 后，心脏和肾脏中的器官 DOX 浓度显著降低，而在肝脏、脾脏和肺中则相似。膀胱内 DOX 导致最低的器官 DOX 浓度。
与常规 iv 和膀胱内 DOX 应用相比，iv DPPG-TSL-DOX 联合 HT 可在膀胱壁（包括逼尿肌）中获得更高的 DOX 浓度。与 iv 游离化疗相比，DPPG-TSL-DOX 联合 HT 具有较低的心脏和肾脏 DOX 积累，具有作为 MIBC 的膀胱保留治疗的巨大潜力。
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