Abstract (eng)
Purpose: The inadequate urothelial delivery of drugs is considered a primary cause for current shortcomings in the adjuvant intravesical chemotherapy of bladder cancer. We here report on a novel, biorecognitive approach to gain a more regio-selective targeting of malignant tissue and improve urothelial uptake, based on the specific interaction between lectins and the glycocalyx of bladder cells.
Materials and Methods: The cytoadhesive and cytoinvasive potential of selected plant lectins was assessed on three human urothelial cell lines, corresponding to healthy tissue and low grade or high grade carcinoma, respectively. Flow cytometry and fluorimetry were used to determine binding capacity and specificity on single cells and confluent monolayers. Monensin quenching experiments, microscopic analysis and enzyme treatment allowed for a further characterization of internalization, uptake pathway and potential cause for tumor selectivity.
Results: Wheat germ agglutinin had the highest bioadhesive potential, while peanut agglutinin emerged as the most potent discriminator between healthy and cancerous tissue (p <0.01). In both cases, cell interaction was highly specific (>80%) and proved decisive for efficient uptake. Within 60 minutes after
exposure, >50% of membrane-bound lectins were internalized in acidic compartments. Cancer-associated aberrant glycosylation is likely to represent the determining cause for PNA selectivity.
Conclusions: Given a careful choice of the targeting ligand, the development of carbohydrate-based delivery strategies for bladder cancer therapy seems feasible. Lectin bioadhesion may at this not only mediate preferential accumulation in malignant tissue but also promote cellular internalization via an increased recruitment of membrane-bound material to physiological uptake routes.