Targeted Chemotherapy of Tumors and Metastases With Hyaluronic Acid-Anti-Tumor Bioconjugates
Annual rept. 15 Jul 1998-14 Jul 1999
UTAH UNIV SALT LAKE CITY
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Metastatic cancer cells over-express characteristic variants of the hyaluronic acid HA receptors CD44 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. Fluorescent HA shows selective uptake, and HA-Taxol shows selective cytooxicity 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 1 prepare an HA-brefeldin A prodrug, and 2 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.
- Medicine and Medical Research