Targeted Chemotherapy of Tumors and Metastases With Hyaluronic Acid-Anti-Tumor Bioconjugates
Abstract
Metastatic cancer cells over-express characteristic variants of the hyaluronic acid (HA) receptors CD% and RHAMM that mediate cell adhesion, cell motility, and cell proliferation. Rapid uptake and catabolism of HA is common in several breast cancer cell-lines. We have developed a targeted delivery system for controlled release of chemotherapeutic drugs, and we prepared HA-Taxol to test our hypothesis that HA-anti-tumor prodrugs will be more effective therapeutic agents than the unconjugated drugs. Fluorescently-labeled HA shows selective uptake, and HA-Taxol shows selective cytotoxicity to breast, colon, and ovarian cancer cells in culture; it also shows release of free drug from the HA-prodrug form that is consistent with improved selectivity. Studies are in progress to (i) prepare an HA-brefeldin A prodrug, and (ii) evaluate the HA-Taxol in nude mice bearing xenografted human tumors. Chondroitin sulfate will saturate HA uptake by non-target tissues. Animal data are being obtained to support use of radiolabeled HA and HA-Taxol in Phase I clinical trials in terminal diagnosis patients. A second line of research revealed the molecular basis of the RHAMM-HA interaction, and has provided unexpected molecular leads that disrupt the oncogenic transformation of RHAMM-overexpressing cells.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2000
- Accession Number
- ADA383945
Entities
People
- Glenn Prestwich
Organizations
- University of Utah