PEG-derivatized embelin as a nanomicellar carrier for delivery of paclitaxel to breast and prostate cancers.

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 (PEG(5K)) and embelin (EB). Embelin is a natural product and exhibits antitumor activity through blocking the activity of X-linked inhibitor of apoptosis protein (XIAP). PEG(5K)-EB₂ conjugate self-assembles to form stable micelles in aqueous solution and efficiently encapsulates hydrophobic drugs such as PTX. PEG(5K)-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 PEG(5K)-EB₂ micelles were efficiently taken up by tumor cells. In vitro release study showed that PTX formulated in PEG(5K)-EB₂ micelles was slowly released over 5 days with much slower release kinetics than that of Taxol formulation. PTX formulated in PEG(5K)-EB₂ micelles exhibited more potent cytotoxicity than Taxol in several cultured tumor cell lines. Total body near infrared fluorescence (NIRF) imaging showed that PEG(5K)-EB₂ micelles were selectively accumulated at tumor site with minimal uptake in major organs including liver and spleen. PTX-loaded PEG(5K)-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 PEG(5K)-EB₂ micelles showed superior antitumor activity compared to Taxol in murine models of breast and prostate cancers.