Block copolymer micelles for controlled delivery of glycolytic enzyme inhibitors

Purpose: To develop block copolymer micelles as an aqueous dosage form for a potent glycolytic enzyme inhibitor, 3-(3- pyridinyl)-1-(4-pyridinyl)-2-propen- 1-one (3PO). Methods: The micelles were prepared from poly(ethylene glycol)-poly(aspartate hydrazide) [PEG-p(HYD)] block copolymers to which 3PO was conjugated through an acid-labile hydrazone bond. The optimal micelle formulation was determined following the screening of block copolymer library modified with various aromatic and aliphatic pendant groups. Both physical drug entrapment and chemical drug conjugation methods were tested to maximize 3PO loading in the micelles during the screening. Results: Particulate characterization showed that the PEG-p (HYD) block copolymers conjugated with 3PO (2.08∼2.21 wt. %) appeared the optimal polymer micelles. Block copolymer compositions greatly affected the micelle size, which was 38 nm and 259 nm when 5 kDa and 12 kDa PEG chains were used, respectively. 3PO release from the micelles was accelerated at pH 5.0, potentiating effective drug release in acidic tumor environments. The micelles retained biological activity of 3PO, inhibiting various cancer cells (Jurkat, He-La and LLC) in concentration ranges similar to free 3PO. Conclusion: A novel micelle formulation for controlled delivery of 3PO was successfully prepared.