Targeted Chemotherapy of Tumors and Metastases With Hyaluronic Acid- Anti-Tumor Bioconjugates

摘要

Metastatic cancer cells over-express characteristic variants of the hyaluronic acid (HA) receptors CD44 and RHAMM, which mediate cell adhesion, cell motility, and cell proliferation. Rapid uptake and catabolism of HA is common in several breast cancer cell-lines. We 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. FITC-labeled HA and FITC-HA-Taxol showed selective uptake, and both FITC-HA-Taxol and HA-Taxol showed selective cytotoxicity to breast, colon, and ovarian cancer cells in culture. Release of free drug from the HA-prodrug form was demonstrated by HPLC. Evaluation of the HA-Taxol in nude mice bearing xenografted human tumors, with or without co- treatment with chondroitin sulfate to saturate HA uptake by non-target tissues, demonstrated in vivo efficacy. A macromolecular prodrug, HMPA-DOX-HA, in which a biocompatible polymer serves as the carrier and HA serves as a targeting moiety, was impressive in improving efficacy and targeting of HMPA-DOX. A second line of research revealed the molecular basis of the RHAMM-HA interaction, and has provided peptide leads for disrupting the oncogenic transformation of RHAMM overexpressing cells.