The urgent demand for more potent treatment schedules in bladder cancer (BCa) therapy calls for a refinement of the intravesical administration modalities.
However, progress on drug delivery systems tailored to the penetration-hostile urothelial barrier lags behind the advancements in comparable fields. This study reports on a multimodal, carrier-based delivery concept that combines biorecognitive targeting with modified release strategies for improved intravesical chemotherapy. The plant lectin wheat germ agglutinin (WGA) was immobilized on poly(lactide-co-glycolide) (PLGA) microparticles (MP) to induce stable cytoadhesion via cellular carbohydrate chains, similar to the specific attachment mechanism utilized by uropathogenic bacteria. A panel of DNA-selective chemotherapeutics with established track record in uro-oncology was screened for physicochemical compatibility with the polymeric carrier formulation. Critical limitations in encapsulation efficiency were found for mitomycin C (MMC), doxorubicin (DOX), and gemcitabine hydrochloride (GEM), despite multiparametric optimization of the preparation conditions. In contrast, the amphiphilic 4-(N)-stearoyl prodrug of gemcitabine (GEM-C18) exhibited excellent processability with PLGA. In vitro bioassays on 5637 human BCa cells showed that the enhanced cytoadhesion of WGA-GEM-C18-PGLA-MP traces back to the specific lectin/carbohydrate interaction, and is not easily disrupted by adverse environmental factors. Owing to several synergistic effects, the combined prodrug/targeting approach resulted in strong cytostatic response even when adjusting the exposure scheme to the confined temporal conditions of instillative treatment. Our results highlight the importance of fine-tuning both pharmacokinetic and pharmacologic parameters to gain adequate impact on urothelial cancer cells, and assign promising potential to glycan-targeted delivery concepts for the intravesical route.
Written by:
Neutsch L, Wambacher M, Wirth EM, Spijker S, Kählig H, Wirth M, Gabor F. Are you the author?
Department of Pharmaceutical Technology and Biopharmaceutics, University of Vienna, Althanstrasse 14, Vienna A 1090, Austria.
Reference: Int J Pharm. 2013 Jun 25;450(1-2):163-76.
doi: 10.1016/j.ijpharm.2013.04.058
PubMed Abstract
PMID: 23628404
UroToday.com Investigative Urology Section
