Nanoformulations of Carfilzomib for Improved Metabolic Stability and Anti‐Cancer Efficacy

Abstract

Carfilzomib (Cfz) is a second‐generation proteasome inhibitor drug approved for the treatment of multiple myeloma. In contrast to its promising anti‐myeloma activity, Cfz has shown limited efficacy in solid cancer patients, which may be in part due to its poor metabolic stability and short half‐life in vivo. Additionally, preclinical data suggest that prolonged administration of Cfz may be more effective than the current bolus dosing strategy. Thus, we hypothesized that Cfz nanoformulations with improved metabolic stability and sustained drug release profiles may enhance anti‐cancer efficacy. To test our hypothesis, we first prepared tethered nanoassembly (TNA) and micelle‐based formulations of Cfz and compared the rates of in vitro NADPH‐dependent Cfz metabolism in liver microsomes. Our results indicated that micelle‐based formulations were superior in improving metabolic stability to TNA formulations. Based on these results, we next prepared six micelle‐based formulations of varying polymer weight ratios and excipient modifications. All six micelle‐based formulations displayed improved Cfz metabolic stability and prolonged Cfz release profiles in vitro. Results from cell viability assays indicated that some of these nanoformulations can induce cancer cell death more effectively than free Cfz. In summary, we report that micelle‐based formulations of Cfz can achieve sustained drug release and improved metabolic stability. Taken together, these nanoformulations may have potential in expanding the therapeutic utility of Cfz.