Indian Journal of Urology
UROSCAN
Year
: 2011  |  Volume : 27  |  Issue : 2  |  Page : 293--294

Paclitaxel gelatin nanoparticles for intravesical bladder cancer therapy: A novel approach of treatment


Rohit Kathpalia, Swarnendu Mandal, Apul Goel 
 Department of Urology, CSM Medical University (Upgraded King George's Medical College), Lucknow, Uttar Pradesh, India

Correspondence Address:
Rohit Kathpalia
Department of Urology, CSM Medical University (Upgraded King George«SQ»s Medical College), Lucknow, Uttar Pradesh
India




How to cite this article:
Kathpalia R, Mandal S, Goel A. Paclitaxel gelatin nanoparticles for intravesical bladder cancer therapy: A novel approach of treatment.Indian J Urol 2011;27:293-294


How to cite this URL:
Kathpalia R, Mandal S, Goel A. Paclitaxel gelatin nanoparticles for intravesical bladder cancer therapy: A novel approach of treatment. Indian J Urol [serial online] 2011 [cited 2021 Jan 22 ];27:293-294
Available from: https://www.indianjurol.com/text.asp?2011/27/2/293/82863


Full Text

 Summary



Patients presenting with non-muscle-invading bladder tumors are typically treated with transurethral tumor resection plus neoadjuvant or adjuvant intravesical immunotherapy or chemotherapy. [1] The commonly used agents being bacillus Calmette-Guιrin and Mitomycin C (MMC).

However, intravesical therapy is associated with variable and incomplete response because of inadequate drug delivery, chemoresistance, and drug exposure variability due to dilution of the instilled drug by residual and newly produced urine. [2] To overcome these problems, Ze Lu et al. used gelatin nanoparticles of paclitaxel for intravesical instillation. Paclitaxel was used as it has higher activity against human bladder cancer cells and produces a 42% response in cases of advanced and/or metastatic bladder cancer in a phase II trial. [3] Also, due to its lipophilicity, paclitaxel penetrates the urothelium more readily than MMC.

Additionally, paclitaxel tightly binds to intracellular macromolecules resulting in significant drug accumulation (70 to 1 500-fold) and retention in tumor cells. [4]

The paclitaxel formulation approved for intravenous administration is dissolved in Cremophor® and ethanol. During intravesical therapy, paclitaxel remains entrapped in Cremophor® micelles, which decreases the free drug fraction and consequently lowers drug penetration into bladder tissue. [5] Therefore, the authors developed a new formulation, paclitaxel gelatin nanoparticles (PNPs), that rapidly releases paclitaxel, had activity in vitro, and yielded a high paclitaxel concentration in bladder tissue in vivo.

The study was done in tumor-free dogs and in pet dogs with naturally occurring bladder tumors. All animals received weekly intravesical PNP (1 mg/20 ml physiological saline) for 3 weeks. Paclitaxel pharmacokinetics was determined in plasma, urine, and bladder tissue of tumor-free dogs and in bladder tumors of pet dogs. Samples were analyzed for free and total (sum of free plus PNP bound) drug concentrations. Serum bioavailability was 0.60 to 0.84% of the administered dose during 0 to 4 hours and 0.35 to 0.50% during 4 to 8 hours with a cumulative value of 0.95 to 1.35% during 0 to 8 hours. Analyzing the bladder tissues, total drug concentrations were the highest at the first time point of 4 hours. Concentrations then decreased with time and attained a relatively constant level, which was sustained between 24 to 168 hours. In bladder tumors, the mean drug concentrations at different time points remained about 40 μg/g and median concentrations were within 20 to 40% of mean concentrations indicating relatively constant drug exposure. Comparing results, it showed a 360-fold higher average total paclitaxel concentration in bladder tumors than in the urothelium of tumor-free dogs, indicating greater drug delivery/retention in tumor tissues.

Authors concluded that intravesical PNP showed the desired properties for intravesical therapy, i.e., favorable bladder tissue/tumor targeting, penetration, and retention properties and low systemic absorption (very low serum bioavailability). Looking at the promising results, intravesical PNP can be a major breakthrough in nanotechnology.

 Comments



A major cause of failed intravesical therapy for non-muscle-invading bladder cancer had been inadequate drug delivery to tumor cells, partly due to the dilution of drug concentration by urine production during treatment. To address this problem, authors developed gelatin nanoparticles of paclitaxel designed to yield constant drug concentrations. The hypothesis that a constant, therapeutic concentration in urine, bladder tissue, and tumors can be attained was evaluated in dogs. Drug release from PNPs was studied in culture medium in vitro. On the other hand, in vivo studies were performed in tumor-free dogs and in pet dogs with naturally occurring transitional cell carcinoma, in which the pharmacokinetics of PNPs were determined in plasma, urine, and tumors. Paclitaxel release from PNPs in vitro and in vivo was rate limited by the drug solubility in aqueous medium. This property yielded constant drug concentrations independent of changes in urine volume during the 2-hour treatment. Intravesical PNPs showed low systemic absorption and favorable bladder tissue/tumor targeting and retention properties with pharmacologically active concentrations retained in tumors for at least 1 week.

Constant drug release from PNPs may overcome the problem of drug dilution by newly produced urine and the sustained drug levels in tumors may decrease treatment frequency. Thus warranting clinical evaluation, this nanotechnology can revolutionize the management of non-muscle-invasive bladder cancer.

References

1Smith JA Jr, Labasky RF, Cockett AT,Fracchia JA, Montie JE, Rowland RG. Bladdercancer clinical guidelines panel summary reporton the management of nonmuscle invasivebladder cancer (stages Ta, T1 and TIS). TheAmerican Urological Association. J Urol1999;162:1697-701.
2Wientjes MG, Dalton JT, Badalament RA, Dasani BM, Drago JR, Au JL. Amethod to study drug concentration-depth profilesin tissues: Mitomycin C in dog bladder wall.Pharmacol Res 1991;8:168-73.
3Roth BJ. Preliminary experience with paclitaxel inadvanced bladder cancer. Semin Oncol 1995;22:1-5.
4Kuh HJ, Jang SH, Wientjes MG,Au JL. Computationalmodel of intracellular pharmacokinetics ofpaclitaxel. J Pharmacol Exp Ther 2000;293:761-70.
5Knemeyer I, Wientjes MG,Au JL.Cremophorreduces paclitaxel penetration into bladder wallduring intravesical treatment. Cancer ChemotherPharmacol 1999;44:241-8.