Abstract
BackgroundTo evaluate the effects of intravesical administration of paclitaxel (PTX-30W), which was prepared by solubilization with a water-soluble amphiphilic polymer composed of PMB30W, a copolymer of 2-methacryloyloxyethyl phosphorylcholine and n-butyl methacrylate, in an orthotopic bladder cancer model.MethodsThe cytotoxicities of PMB30W were examined in MBT-2 cell cultures and the results were compared with those of the conventional paclitaxel solubilizer Cremophor. In an orthotopic MBT-2 bladder cancer model, the effect of intravesical administration of PTX-30W was compared with that of paclitaxel solubilized with Cremophor (PTX-CrEL). The paclitaxel concentration in bladder tumors after the intravesical treatment was also evaluated using liquid chromatography tandem mass spectrometry (LC-MS/MS) system.ResultsIn vitro, Cremophor exhibited dose-dependent cytotoxicity towards MBT-2 cells, whereas no cytotoxicity was observed with PMB30W. In the orthotopic bladder cancer model, intravesical administration of PTX-30W resulted in a significant reduction of bladder wet weight compared with that of PTX-CrEL. The paclitaxel concentration in bladder tumors after the intravesical treatment was significantly higher in PTX-30W treated mice than in PTX-CrEL treated mice.ConclusionsIntravesically administered PTX-30W can elicit stronger antitumor effects on bladder tumors than conventional paclitaxel formulated in Cremophor, presumably because of its better penetration into tumor cells. PTX-30W might be a promising antitumor agent for intravesical treatment of non-muscle invasive bladder cancer.
Highlights
To evaluate the effects of intravesical administration of paclitaxel (PTX-30W), which was prepared by solubilization with a water-soluble amphiphilic polymer composed of PMB30W, a copolymer of 2-methacryloyloxyethyl phosphorylcholine and n-butyl methacrylate, in an orthotopic bladder cancer model
The incidence of side effects is lower compared to by adjuvant intravesicalBacillus Calmette-Guérin (BCG) therapy, the recurrence rate is still high in intravesical chemotherapy [8]
We previously demonstrated successful implantation of bladder tumors after instillation of MBT-2 cells into C3H/ HeN mice with an incidence of almost 100% [21], and we have been using this novel MBT-2 orthotopic bladder cancer model to investigate the therapeutic effects of various intravesical agents [22,23,24]
Summary
To evaluate the effects of intravesical administration of paclitaxel (PTX-30W), which was prepared by solubilization with a water-soluble amphiphilic polymer composed of PMB30W, a copolymer of 2-methacryloyloxyethyl phosphorylcholine and n-butyl methacrylate, in an orthotopic bladder cancer model. Bacillus Calmette-Guérin (BCG) is currently the most successful agent for adjuvant intravesical treatment [3,4,5,6]. Intravesical BCG therapy sometimes causes local or systemic side effects [7]. The incidence of side effects is lower compared to BCG therapy, the recurrence rate is still high in intravesical chemotherapy [8]. A poor response to intravesical chemotherapy is thought to be in part due to the poor drug uptake into the bladder tissue within short indwelling times [9,10]. In a clinical setting, in some patients, a drug can be held in the bladder for only a short time because of bladder irritability, and intravesical treatment can be expected to be only slightly effective in such patients. New agents which can be delivered more efficiently to the cancer tissue in the bladder are urgently needed
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