Electromotive drug administration accelerates intravesical tissue uptake of gemcitabine and docetaxel into porcine bladders: an ex vivo proof-of-concept study
Abstract
Background: Intravesical alternatives to bacillus Calmette-Guérin (BCG) are needed to treat patients with non-muscle-invasive bladder cancer (NMIBC) not responding to BCG or high-risk NMIBC. Electromotive drug administration (EMDA) enhances the penetration of mitomycin C into the bladder wall and could be used also with other drugs. We aimed to investigate whether EMDA accelerates intravesical delivery of gemcitabine and docetaxel as compared to passive diffusion (PD).
Methods: We instilled fifteen porcine bladders with gemcitabine and docetaxel using EMDA or PD. Drug concentrations in the mucosa, muscle, and adventitious layers of the bladder were quantified using reversed-phase high-performance liquid chromatography.
Results: Docetaxel mean total tissue penetration increased from 2.9% with PD to 6.4% with EMDA after pretreatment with gemcitabine. When no gemcitabine pretreatment was done, docetaxel absorption was statistically significantly higher with EMDA than with PD. Hyaluronic acid did not improve or worsen penetration and no statistically significant difference was observed between the treatment arm with saline (95% confidence intervals of the mean [95% CI] vs PD: 5.92-19.91) and hyaluronic acid/chondroitin sulphate solution (95% CI vs PD: 7.67-23.32). For gemcitabine, no statistically significant difference was observed among treatment arms. Total gemcitabine tissue penetration was similar in both treatment arms, but EMDA shortened the time needed to achieve similar tissue concentrations compared to passive diffusion, reducing the gemcitabine uptake time by 70 minutes and the docetaxel uptake time by 40 minutes.
Conclusions: EMDA accelerates gemcitabine and docetaxel uptake and enhances intravesical delivery of docetaxel.
Supporting Agencies
Uromed AG
Data Availability Statement
Data supporting the findings of this study are available from the corresponding author upon reasonable request.
References
- 1. Siegel RL, Kratzer TB, Giaquinto AN, et al. Cancer statistics, 2025. CA Cancer Stat. 2025; 75:10-45. DOI: https://doi.org/10.3322/caac.21871
- 2. Harvey M, Chislett B, Perera M, et al. Critical shortage in BCG immunotherapy: How did we get here and where will it take us? Urol Oncol: Seminars Orig Invest. 2022; 40:1-3. DOI: https://doi.org/10.1016/j.urolonc.2021.09.022
- 3. Crispen PL, Kusmartsev S. Mechanisms of immune evasion in bladder cancer. Cancer Immunol Immunother. 2020; 69:3-14. DOI: https://doi.org/10.1007/s00262-019-02443-4
- 4. Kamat AM, Lerner SP, O’Donnell M, et al. Evidence-based assessment of current and emerging bladder-sparing therapies for non-muscle- invasive bladder cancer after Bacillus Calmette-Guerin therapy: A systematic review and meta-analysis. Eur Urol Oncol. 2020; 3:318-40. DOI: https://doi.org/10.1016/j.euo.2020.02.006
- 5. EAU 2025. Combination therapy: systemic versus intravesical - the dynamic duo: gemcitabine and docetaxel - The bladder Is their domain! [Internet]. [cited 2025 Nov 12]. Available from: https://www.urotoday.com/conference-highlights/eau-2025/eau-2025-bladder-cancer/159204-eau-2025-combination-therapy-systemic-versus-intravesical-the-dynamic-duo-gemcitabine-and-docetaxel-thebladder-is-their-domain.html.
- 6. EAU. Oncology section perspective: Gemcitabine/docetaxel - a new option for European centres in the management of NMIBC - Uroweb [Internet]. [cited 2025 Nov 12]. Available from: https://uroweb.org/news/eau-oncology-section-perspective-gemcitabine-docetaxel-a-newoption-for-european-centres-in-the-management-of-nmibc.
- 7. Packiam VT, Werntz RP, Steinberg GD. Current clinical trials in non-muscle-invasive bladder cancer: Heightened need in an era of chronic BCG shortage. Curr Urol Rep. 2019; 20:84. DOI: https://doi.org/10.1007/s11934-019-0952-y
- 8. Lobo N, Bree KK, Hensley PJ, et al. Reduced-dose bacillus Calmette- Guérin (BCG) in an era of BCG shortage: real-world experience from a tertiary cancer centre. BJU International. 2022; 130:323-30. DOI: https://doi.org/10.1111/bju.15661
- 9. Chamie K, Chang SS, Kramolowsky E, et al. IL-15 superagonist NAI in BCG-unresponsive non-muscle-invasive bladder cancer. NEJM Evid. 2023; 2:EVIDoa2200167. DOI: https://doi.org/10.1056/EVIDoa2200167
- 10. Balar AV, Kamat AM, Kulkarni GS, et al. Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study. Lancet Oncol. 2021; 22:919-30. DOI: https://doi.org/10.1016/S1470-2045(21)00147-9
- 11. Pradere B, Schuit M, Guerrero-Ramos F, et al. Side effect management and procedural best practices with indwelling intravesical drug-releasing systems in the treatment of bladder cancer: recommendations from expert panels. Current Opinion in Urology. 2025;36:123-33. DOI: https://doi.org/10.1097/MOU.0000000000001350
- 12. Brisuda A, Hornák J, Žemlicková B, et al. Intravesical thermochemotherapy in the treatment of high-risk and very high-risk non-muscle-invasive urothelial bladder cancer: a single-arm study. Int Urol Nephrol. 2024; 56:2243-50. DOI: https://doi.org/10.1007/s11255-023-03924-3
- 13. Min JWS, Saeed N, Coene A, et al. Electromotive enhanced drug administration in oncology: Principles, evidence, current and emerging applications. Cancers (Basel). 2022; 14:4980. DOI: https://doi.org/10.3390/cancers14204980
- 14. Di Stasi SM, Giannantoni A, Massoud R, et al. Electromotive versus passive diffusion of mitomycin C into human bladder wall: concentration-depth profiles studies. Cancer Res. 1999; 59:4912-8.
- 15. Jones G, Cleves A, Wilt TJ, et al. Intravesical gemcitabine for non-muscle invasive bladder cancer. Cochrane Database Syst Rev. 2012; 1:CD009294. DOI: https://doi.org/10.1002/14651858.CD009294.pub2
- 16. Carando R, Zazzara M, Cotrufo S, Ludovico GM. Intravesical treatment with electro-mediated administration of mytomicin C as prophylaxis for intermediate and high-risk nonmuscle-Invasive Bladder cancer: A retrospective multicenter study. Urol Int. 2019;103:285-90. DOI: https://doi.org/10.1159/000502663
- 17. Zazzara M, Nazaraj A, Scarcia M, et al. Electromotive drug administration of mitomycin C (EMDA/MMC) versus intravesical immunotherapy with Bacillus Calmette-Guérin (BCG) in intermediate and high risk non muscle invasive bladder cancer. Urol Int. 2023; 107:64-71. DOI: https://doi.org/10.1159/000520630
- 18. Steinberg RL, Thomas LJ, Brooks N, et al. Multi-institution evaluation of sequential gemcitabine and docetaxel as rescue therapy for nonmuscle invasive bladder cancer. J Urol. 2020; 203:902-9. DOI: https://doi.org/10.1097/JU.0000000000000688
- 19. Carando R, Soldini E, Cotrufo S, et al. Electro-mediated drug administration of mitomycin C in preventing non-muscle-invasive bladder cancer recurrence and progression after transurethral resection of the bladder tumour in intermediate- and high-risk patients. Arab J Urol. 2020; 19:71-7. DOI: https://doi.org/10.1080/2090598X.2020.1816150
- 20. Steinberg RL, O’Donnell MA, Packiam VT. Nonrisk-adapted sequential intravesical gemcitabine and docetaxel for nonmuscleinvasive bladder cancer: The time is now. J Urol. 2023; 210:5-7. DOI: https://doi.org/10.1097/JU.0000000000003438
- 21. Scilipoti P, Longoni M, de Angelis M, et al. Gemcitabine and docetaxel for high-risk non-muscle-invasive bladder cancer: EuroGemDoce group results. BJU Int. 2025; 135:969-76. DOI: https://doi.org/10.1111/bju.16645
- 22. Bakula M, Hudolin T, Knezevic N, et al. Intravesical gemcitabine and docetaxel therapy for BCG-naïve patients: A promising approach to non-muscle invasive bladder cancer. Life. 2024; 14:789. DOI: https://doi.org/10.3390/life14070789
- 23. John J, Fieggen G, Kaestner L, Lazarus J. The porcine model for urological research and training: An endoscopic and CT-based study. Uro. 2026; 6:7. DOI: https://doi.org/10.3390/uro6010007
- 24. Shen JD, Chen SJ, Chen HY, et al. Review of animal models to study urinary bladder function. Biology (Basel). 2021; 10. DOI: https://doi.org/10.3390/biology10121316
- 25. Stoica R, Medina-Polo J, Manecksha RP, et al. A prospective, multicenter, real-world effectiveness and safety study of high molecular weight sodium hyaluronate for interstitial cystitis/bladder pain syndrome. Int Urol Nephrol. 2026. DOI: https://doi.org/10.21203/rs.3.rs-8336398/v1
- 26. Gülpınar Ö, Haliloglu AH, Gökce MI, Arıkan N. Instillation of Hyaluronic Acid via Electromotive Drug Administration Can Improve the Efficacy of Treatment in Patients With Interstitial Cystitis/Painful Bladder Syndrome: A Randomized Prospective Study. Korean J Urol. 2014; 55:354. DOI: https://doi.org/10.4111/kju.2014.55.5.354
- 27. Prasath H, Azhakesan A, manikandan G. Analytical methods for quantification of gemcitabine in pharmaceutical and biological samples: An overview of developments in the last decade. Asain J Green Chem. 2025; 9.
- 28. Kim DW, Yousaf AM, Li DX, et al. Development of RP-HPLC method for simultaneous determination of docetaxel and curcumin in rat plasma: Validation and stability. Asian J Pharm Sci. 2017;12:105-13. DOI: https://doi.org/10.1016/j.ajps.2016.08.002
- 29. International Conference On Harmonisation. ICH harmonised tripartite guideline validation of analytical procedures: Text and methodology Q2(R1), Current Step 4 version. November 2005.
- 30. Lu JL, Xia QD, Liu CQ, et al. Efficacy and toxicity in scheduled intravesical gemcitabine versus Bacille Calmette-Guérin for Ta and T1 bladder cancer: a systematic review and meta-analysis. Transl Cancer Res. 2021; 10:2849-58. DOI: https://doi.org/10.21037/tcr-21-291
Metrics
Citations and online attention from Dimensions, Altmetric and PlumX.
License
Copyright (c) 2026 the Author(s)

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
PAGEPress has chosen to apply the Creative Commons Attribution NonCommercial 4.0 International License (CC BY-NC 4.0) to all manuscripts to be published.