The development of tumor-activated hyaluronic acid chemotherapeutic drugs

4721 Introduction: The non-selective nature of chemotherapeutic drugs necessitates the administration of high doses to achieve therapeutic levels within the tumor, often resulting in severe side-effects. An approach to increasing efficacy while alleviating treatment toxicity has been to design pro-drugs that are enzymically activated within the tumor. In many tumors β-glucuronidase (s-GLUC) is present at higher levels than in the surrounding normal tissue. In contrast to normal tissue, tumoral s-GLUC is in part localized extracellularly, primarily due to secretion by inflammatory cells and disintegrating tumor cells. Improved therapeutic responses have been observed with several anticancer drugs conjugated to glucuronic acid with the limitation of cellular uptake and penetration. Proprietary formulations containing the polysaccharide, hyaluronic acid (HA) utilise the unique physiochemical and biological properties of HA enabling it to function as an excipient imparting its own pharmacological activity through directing the entrained anticancer agent/s to over-expressed CD44 receptors. Once localized in the tumor, the HA/drug complex aggregates forming a drug depot, increasing drug retention at the site; subsequently efficacy is enhanced through increased co-internalisation of the drug and HA. Preliminary pre-clinical studies demonstrated that high molecular weight HA up-regulated intra-tumoral s-GLUC; which could potentially exert a beneficial effect on glucuronide pro-drugs. The purpose of this study was to determine the mechanism and potential therapeutic effect of HA-mediated intra-tumoral activation of glucuronide pro-drugs. Methodology: The effect of a HA formulation of irinotecan (HyCAMP) on the genetic and cellular activation of tumoral s-GLUC was established in eight colon cancer cell lines treated with varying concentrations of HyCAMP, HA or irinotecan. After treatment the s-GLUC gene was quantitated using real time PCR and protein activity using a colorimetric assay. In vivo, [3H]irinotecan formulated as Camptosar® or HyCAMP was intravenously administered to nude mice bearing human colon cancer xenografts. At 5min - 96hr after drug administration, all body organs and fluids were collected and quantitatively analysed for irinotecan, SN-38 and SN-38G. Results: The HA component of the HyCAMP formulation up-regulated both the transcription and translation of tumoral s-GLUC when compared to irinotecan only. In vivo, HyCAMPincreased the intra-tumoral conversion of SN-38G to SN-38 thereby increasing treatment efficacy. Conclusions: HA formulated drugs enhance the intra-tumoral expression and activity of s-GLUC where the further development of HA anti-cancer agents could result in a new generation of tumor-activated glucuronide pro-drugs which demonstrate superior therapeutic indices as the HA directs the drug to the malignant site while increasing drug activation within the tumor.