Block copolymer micelles for controlled delivery of glycolytic enzyme inhibitors.
OBJECTIVE
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.


CONCLUSIONS
A novel micelle formulation for controlled delivery of 3PO was successfully prepared.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone, Lexington, Kentucky, 40536-0596, USA.
Shanjida
S
Akter
Brian F
BF
Clem
Hyun Jin
HJ
Lee
Jason
J
Chesney
Younsoo
Y
Bae
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003692:Delayed-Action Preparations / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D051379:Mice; D008823:Micelles; D058726:Nanoconjugates / Q000737:chemistry; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D025481:Phosphofructokinase-2 / Q000037:antagonists & inhibitors*; D011092:Polyethylene Glycols / Q000737:chemistry*; D011506:Proteins / Q000737:chemistry*; D011725:Pyridines / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology
C527590:3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one; D000970:Antineoplastic Agents; D003692:Delayed-Action Preparations; D004791:Enzyme Inhibitors; D008823:Micelles; D058726:Nanoconjugates; D011506:Proteins; D011725:Pyridines; C523990:poly(ethylene glycol)-poly(aspartate hydrazide); D011092:Polyethylene Glycols; D025481:Phosphofructokinase-2