||2-Methoxyestradiol (2-ME2) is an endogenous metabolite of estradiol. Previous studies demonstrated that 2-ME2 is a potent antiproliferative, pro-apoptotic, antiangiogenic drug and exogenous 2-ME2 is effective against different types of tumors. Unfortunately, only low systemic concentrations of 2-ME2 can be achieved following oral administration, even after very high doses are administered to patients. The major barriers to high systemic levels of 2-ME2 include, but are not limited to, formulation, solubility, permeability, transporter effects, and first-pass metabolism. In an effort to solve this problem we have now synthesized and tested a new prodrug of 2-ME2 that is water soluble due to a bio-reversible hydrophilic group added at the 3-position and more effectively resists metabolic inactivation due to an ester moiety added to mask the 17-position alcohol. The 3-position modification is designed to be cleave by phosphatases at the brush-border of the intestinal epithelium to generate high local concentrations of the prodrug intermediate for intestinal absorption, and on the first-pass through the intestinal epithelium and liver, the masked 17-position will be de-esterified to produce active drug. We are reporting here for the first time that this double prodrug of 2-ME2 is effective as an antiproliferative and anti-cancer agent for both in vitro and in vivo studies against Barrett's esophageal adenocarcinoma (BEAC), and provided greater potency than 2-ME2 in inhibiting the growth of BEAC xenografts. Finally, studies indicate that, like 2-ME2, the 2-ME2-PD1 exhibits anticancer effect through disruption of microtubule-network.