Pharmaceutical Science, The University of British Columbia, Vancouver, BC, Canada.
Centre for Drug Research and Development, The University of British Columbia, Vancouver, BC, Canada.
BJU Int. 2018 Nov;122(5):898-908. doi: 10.1111/bju.14423. Epub 2018 Jul 27.
To investigate the effect of three anticancer drugs (mitomycin c (MMC), doxorubicin or gemcitabine) on bladder wall morphology and the uptake of paclitaxel or docetaxel following coadministration. The primary objective of this study was to measure the uptake of MMC, doxorubicin or gemcitabine with or without exposure of the tissue to amine terminated cationic nanoparticles (CNPs) and to investigate any possible exfoliation effects of the three drugs on intact bladder tissue. The secondary objective was to investigate the uptake of taxane drugs (docetaxel, DTX) and paclitaxel, (PTX) from surfactant micelle formulations in the presence of MMC, doxorubicin or gemcitabine.
Sections of fresh pig bladder tissue were incubated in Franz diffusion cells with the urothelial side exposed to solutions of doxorubicin, MMC and gemcitabine containing radioactive drug for 90 min. Some tissue samples were simultaneously exposed to each of the three drugs in combination with the surfactant micelle formulations of PTX (Taxol) or DTX (Taxotere). Tissue sections were then cryostat sectioned for drug quantitation by liquid scintillation counting or fixed for scanning electron microscopy and haematoxylin and eosin staining.
All three drugs caused exfoliation of the urothelial layer of bladder tissues. Drug uptake studies showed that all three drugs effectively penetrated the lamina propria through to the muscular layer over a 2-h incubation and these levels were unaffected by pre-treatment with CNPs. The uptake levels of the taxane drugs PTX and DTX were significantly enhanced following simultaneous treatment of bladders with MMC, doxorubicin or gemcitabine.
The exfoliation effects of MMC, doxorubicin and gemcitabine allow for good tissue penetration of these drugs with no additional effect from CNP treatment of bladders. The observed exfoliation effect of these amine-containing drugs probably arises from a cationic interaction with the mucus and urothelium cell layer in a manner similar to that previously reported for CNPs. These studies suggest that the lack of long-term clinical efficacy of these drugs may not arise from poor intravesical drug penetration but may result from a rapid diffusion of the drugs into the deeper vascularised muscular region with rapid drug clearance. The enhanced uptake of PTX or DTX following co-administration with MMC, doxorubicin or gemcitabine probably arises from the removal of the urothelial barrier by exfoliation allowing for improved taxane partitioning into superficial layers. These effects may allow for dual drug intravesical strategies offering greatly improved taxane uptake and potential additive drug effects for improved efficacy.
研究三种抗癌药物（丝裂霉素 C（MMC）、多柔比星或吉西他滨）联合给药后对膀胱壁形态和紫杉醇或多西他赛摄取的影响。本研究的主要目的是测量 MMC、多柔比星或吉西他滨的摄取情况，无论组织是否暴露于胺封端阳离子纳米颗粒（CNP）以及研究这三种药物对完整膀胱组织是否有任何可能的剥落作用。次要目的是研究在 MMC、多柔比星或吉西他滨存在的情况下，紫杉醇（多烯紫杉醇）和多西他赛（多西紫杉醇）从表面活性剂胶束制剂中的摄取情况。
新鲜猪膀胱组织切片在 Franz 扩散细胞中孵育，尿路上皮侧暴露于含有放射性药物的多柔比星、MMC 和吉西他滨溶液中 90 分钟。一些组织样本同时暴露于三种药物联合紫杉醇（Taxol）或多西他赛（Taxotere）的表面活性剂胶束制剂中。然后将组织切片进行冷冻切片，通过液体闪烁计数进行药物定量，或固定进行扫描电子显微镜和苏木精-伊红染色。
三种药物均导致膀胱组织尿路上皮层剥落。药物摄取研究表明，所有三种药物在 2 小时孵育期间均有效地穿透固有层到达肌肉层，并且这些水平不受 CNP 预处理的影响。在同时用 MMC、多柔比星或吉西他滨处理膀胱后，紫杉醇和多西他赛的摄取水平显著增加。
MMC、多柔比星和吉西他滨的剥落作用允许这些药物很好地穿透组织，而 CNP 处理膀胱没有额外的作用。这些含胺药物的观察到的剥落作用可能是由于与粘液和尿路上皮细胞层的阳离子相互作用引起的，类似于先前报道的 CNP 情况。这些研究表明，这些药物缺乏长期临床疗效可能不是由于膀胱内药物渗透不良引起的，而是由于药物迅速扩散到更深的血管化肌肉区域并迅速清除药物引起的。多柔比星或吉西他滨联合给药后紫杉醇或多西他赛摄取增加可能是由于剥落作用去除了尿路上皮屏障，从而改善了-taxane 分配到浅层。这些作用可能允许双重药物膀胱内策略，提供大大改善的-taxane 摄取和潜在的附加药物作用，以提高疗效。
