Lectin Mediated Biorecognition as a Novel Strategy for Targeted Delivery to Bladder Cancer

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Abstract
Inadequate urothelial delivery of drugs is considered a primary cause of current shortcomings in adjuvant intravesical chemotherapy for bladder cancer. We report what is to our knowledge a novel biorecognitive approach to achieve more regionally selective targeting of malignant tissue and improve urothelial uptake based on specific interaction between lectins and bladder cell glycocalyces. We assessed the cytoadhesive and cytoinvasive potential of selected plant lectins in 3 human urothelial cell lines, corresponding to healthy tissue, and low and high grade carcinoma, respectively. Flow cytometry and fluorimetry were used to determine binding capacity and specificity in single cells and confluent monolayers. Monensin quenching experiments, microscopic analysis and enzyme treatment allowed further characterization of internalization, the uptake pathway and the potential cause of tumor selectivity. Wheat germ agglutinin had the highest bioadhesive potential while peanut agglutinin was the most potent discriminator between healthy and cancerous tissue (p <0.01). In each case cell interaction was highly specific (greater than 80%) and proved decisive for efficient uptake. Within 60 minutes after exposure greater than 50% of membrane bound lectins were internalized in acidic compartments. Cancer associated aberrant glycosylation likely represents the determining cause of peanut agglutinin selectivity. Given careful choice of the targeting ligand, the development of carbohydrate based delivery strategies for bladder cancer therapy seems feasible. Lectin bioadhesion may not only mediate preferential accumulation in malignant tissue but also promote cellular internalization via increased recruitment of membrane bound material to physiological uptake routes.

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