Paclitaxel (PTX) is one of the most effective chemotherapeutic agents for a wide spectrum of cancers, but its therapeutic benefit is often limited by severe side effects.
We have developed a micelle-based PTX formulation based on a simple conjugate derived from polyethylene glycol 5000 (PEG5K) and embelin (EB). Embelin is a natural product and exhibits antitumor activity through blocking the activity of X-linked inhibitor of apoptosis protein (XIAP). PEG5K-EB₂ conjugate self-assembles to form stable micelles in aqueous solution and efficiently encapsulates hydrophobic drugs such as PTX. PEG5K-EB₂ micelles have a relatively low CMC of 0.002 mg/mL (0.35 μM) with sizes in the range of 20 ∼ 30 nm with or without loaded PTX. In vitro cell uptake study showed that the PEG5K-EB₂ micelles were efficiently taken up by tumor cells. In vitro release study showed that PTX formulated in PEG5K-EB₂ micelles was slowly released over 5 days with much slower release kinetics than that of Taxol formulation. PTX formulated in PEG5K-EB₂ micelles exhibited more potent cytotoxicity than Taxol in several cultured tumor cell lines. Total body near infrared fluorescence (NIRF) imaging showed that PEG5K-EB₂ micelles were selectively accumulated at tumor site with minimal uptake in major organs including liver and spleen. PTX-loaded PEG5K-EB₂ micelles demonstrated an excellent safety profile with a maximum tolerated dose (MTD) of 100-120 mg PTX/kg in mice, which was significantly higher than that for Taxol (15-20 mg PTX/kg). Finally, PTX formulated in PEG5K-EB₂ micelles showed superior antitumor activity compared to Taxol in murine models of breast and prostate cancers.
Written by:
Lu J, Huang Y, Zhao W, Marquez RT, Meng X, Li J, Gao X, Venkataramanan R, Wang Z, Li S. Are you the author?
Center for Pharmacogenetics, University of Pittsburgh School of Pharmacy, Pittsburgh, PA 15261, USA.
Reference: Biomaterials. 2013 Feb;34(5):1591-600.
doi: 10.1016/j.biomaterials.2012.10.073
PubMed Abstract
PMID: 23182923
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