Abstract 4453: Development of a crosslinked, daunorubicin-loaded micelle with superior pharmacokinetics compared to free daunorubicin and with tunable stability

Abstract

Abstract Chemotherapeutic drugs are widely used for the treatment of cancer; however, use of these drugs is often associated with patient toxicity and poor delivery to the tumor. Poor delivery to the tumor can be attributed, in part, to rapid elimination of the drug by the reticuloendothelial system (RES), resulting in short circulation times. Nanoscopic drug carriers offer a promising approach to achieving improved delivery of chemotherapeutic drugs to tumors due to their size and ability to avoid RES uptake, but conventional nanoparticles are not stable in complex biological environments. This instability has resulted in little clinical success of conventional nanoparticles to date. Intezyne's IVECTTM Method, which utilizes triblock copolymers to form micelles that are stabilized to dilution in complex media, was used to encapsulate daunorubicin. The resulting daunorubicin loaded micelle's size was determined to be 60 nm by dynamic light scattering analysis. To generate stable micelles, iron (II) chloride was used to form pH-reversible iron-acetate crosslinking bonds in the outer core of the micelle. Release of daunorubicin from stabilized micelles was shown to be pH-dependent through the use of drug-release dialysis assays. Cytotoxicity studies in cancer cell lines revealed that the IC50 values of daunorubicin micelles were similar to free daunorubicin. In vivo, the AUC of daunorubicin released from stabilized daunorubicin micelles was up to 60-fold higher compared to free daunorubicin. Furthermore, the pharmacokinetic parameters were proportional to the iron (II) concentrations used for crosslinking. Repeated injections of daunorubicin micelles in rats showed little to no change in the pharmacokinetic parameters and did not exhibit accelerated blood clearance based on rat IgM ELISA measurements. These data report the development of a stabilized daunorubicin micelle that exhibits pH-dependent release and superior pharmacokinetics based on tunable crosslinking chemistry. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4453. doi:10.1158/1538-7445.AM2011-4453