The Development of Hyaluronic Acid as a Targeted Transport Vehicle for Chemotherapeutic Drugs

Abstract

Introduction: The non-selective nature of systemic chemotherapeutic drugs necessitates the administration of high doses to achieve and maintain therapeutic levels within the tumor, which often results in severe side-effects. The efficacy of the drug could be maintained and the toxicity alleviated by direct targeting of anticancer agents to the tumor. The observation that the naturally occurring polysaccharide, hyaluronic acid (HA) has high affinity for tumors and that numerous tumors over-express HA receptors has lead to the development of a series of proprietary HA/cytotoxic drug formulations. The purpose of this study was to evaluate if such formulations could target and expedite the delivery of anticancer agents to solid tumors and enhance their function. Methodology: The mode of interaction between HA and the cytotoxic drugs was investigated using CD and NMR spectroscopy. The ability of HA to target anticancer agents to the HA receptor, CD44, was demonstrated by IV injection of radioactive anticancer agents ± 12.5mg/kg of HA (Mr 750 kDa) into nude mice bearing human breast cancer xenografts. The effect of HA on the therapeutic index of chemotherapeutic drugs was established by treatment of nude mice carrying human breast xenografts with methotrexate, 5-fluorouracil (5FU) and doxorubicin (DOX) + HA for six cycles of one week. The safety of HyFIVETM (HA/5-FU) and HyDOXTM (HA/DOX) drug formulations was established in Phase l clinical trials where 30 patients with metastatic cancer were administered 500mg/m2 HA in combination with escalating doses of DOX (30-60mg/m2) or 5FU (cumulative dose of 1350-2250mg/m2 per cycle). Results: Chemical interaction studies demonstrated that no ionic, hydrophobic or covalent interaction existed between the HA and drugs but instead, the small anti-cancer agents were entrained within the HA matrix through a viscosity related effect. It was demonstrated that HA could target anticancer drugs to tumors where, within 10min, HA directed up to 400% more anticancer agent to the tumor and lymph nodes whilst reducing the gastrointestinal (GI) and cardiac drug content by up to 660%. Efficacy studies in breast cancer xenograft models demonstrated a greater tumor response, elimination of secondary cancer and a significant reduction in both Gl and cardiac toxicities. The Phase l studies showed that the HA formulations were well tolerated; tumour responses were observed and the co-administration of HA did not alter the pharmacokinetics of clinically relevant doses of 5FU or DOX. Conclusions: These studies demonstrate that HA can act as a targeted transport vehicle for chemotherapeutic drugs thereby potentially increasing treatment efficacy while reducing treatment toxicity.