Protein-encapsulated nanoparticles for oral delivery of anti-mitotic agents in prostate cancer
Mentor: Omid C. Farokhzad, MD (Brigham and Women's Hospital)
Taxanes are mitotic inhibitors often used in the treatment of solid tumors. These drugs include the common chemotherapeutic agents’ paclitaxel and docetaxel which exhibit hydrophobic properties requiring the use of harmful organic solvents for intravenous administration. The oral administration of these medications are usually unexplored due to issues of irregular absorption, uncertain bioavailability, and patient compliance. If uniquely designed, oral chemotherapy can display higher antitumor activity and lower systemic toxicity than similar intravenous regimens. Human serum albumin (HSA), with diverse biological properties, can act as a carrier for hydrophobic molecules. The heart shaped protein has a hydrophobic pocket in subdomain IIA which exhibits a natural affinity for these drugs. FDA approved Abraxane (nab-paclitaxel) utilizes this property for improved treatment of metastatic breast cancer, metastatic pancreatic cancer and non-small cell lung cancer. HSA bound taxanes accumulate in the rapid angiogenic microenvironment of tumors and exploits the overexpressed albumin receptor gp60 leading to specific uptake and distribution. For safe digestion, the HSA-paclitaxel complex can further be modified with transferrin through high pressure homogenization. This final protein complex can then be evaluated for oral use. This novel approach could provide important results for further work into the development of oral chemotherapy.
Digestion Diagram: Adapted from Lodish, H., Berk, A., Kaiser, C. A., Krieger, M., Scott, M. P., Bretscher, A., Ploegh, H., & Matsudaira, P. (2008). Molecular cell biology (6th ed.) W.H. Freeman. Cellular entry diagram: Nanoparticle albumin-bound (nab™)-paclitaxel: improving efficacy and tolerability by targeted drug delivery in metastatic breast cancer. Cortes, Javier et al. EJC Supplements , Volume 8 , Issue 1 , 1 – 10 Source: