Targeted Therapies for Myeloma and Metastatic Bone Cancers

摘要

The goal of this project was to determine, in preclinical studies, the potential of skeletally targeted polymeric nanoparticles as carriers of the proteasome inhibitor Bortezomib (Velcade), to be used as a selective and efficacious treatment of Multiple Myeloma. In clinical oncology practice, Velcade is a chemotherapeutic agent currently approved for the treatment of myeloma in the relapsed setting post transplant or as a second line treatment in patients unsuitable for transplantation. In a clinical trial, Velcade patients had a significantly higher rate of overall survival (80 per cent) versus patients who received dexamethasone alone. However, Velcade causes significant problems including systemic toxicity, which limits the actual therapeutic window and efficacy of the treatment. Our hypothesis is that bone- targeting nanocarriers can preferentially accumulate in the skeleton and locally release Velcade to impair the capacity of myeloma cells to survive and grow in vivo, thereby reducing the formation and growth of tumor-induced lytic bone lesions. Otherwise, Velcade is not selective to bone. The major tasks of this research were: (1) Formulate and characterize drug-containing, bone- targeting nanoparticles; (2) Determine the in vivo biodistribution of bone- targeting nanoparticles; (3) Evaluate the efficacy of bone-targeted delivery of proteasome inhibitors on myeloma tumor progression using the well-characterized 5TGM1 GFP label murine model of myeloma.