Pharmaceutical Research

, Volume 17, Issue 5, pp 607-611

First online:

Methotrexate Esters of Poly(Ethylene Oxide)-Block-Poly(2-Hydroxyethyl-L-Aspartamide). Part I: Effects of the Level of Methotrexate Conjugation on the Stability of Micelles and on Drug Release

  • Yu LiAffiliated withSchool of Pharmacy, University of Wisconsin-Madison
  • , Glen S. KwonAffiliated withSchool of Pharmacy, University of Wisconsin-Madison

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Purpose. To study the effects of hydrophobicity of the micelle-formingblock copolymeric drug conjugate, methotrexate (MTX) esters ofpoly-(ethylene oxide)-block-poly(2-hydroxyethyl-L-aspartamide) (MTXesters of PEO-b-PHEA), on the stability of micelles and on drug release.

Methods. MTX esters of PEO-b-PHEA with three levels of MTXconjugation were synthesized. Size distribution of the micelles wasmeasured by dynamic light scattering (DLS). The critical micelleconcentration (CMC) was determined by a light scattering study. Sizeexclusion high performance liquid chromatography (SEC-HPLC) wasused to study the equilibrium between unimers and micelles, and releaseof MTX at pH 7.4.

Results. MTX esters of PEO-b-PHEA with MTX substitution of 7.4%,22%, and 54% were prepared. The conjugates formed micelles basedon DLS. The stability of the micelles correlated with the level of MTXconjugation. The conjugate with 54% MTX had a lower CMC (0.019mg/mL) than the conjugates with 22% MTX (0.081 mg/mL) or 7.4%MTX (0.14 mg/mL). Micelle dissociation was significantly slower forthe conjugate with 54% MTX than that with 22% and 7.4% MTX.Slower release of MTX from the micelles was also observed for theconjugate with the higher MTX attachment.

Conclusions. MTX esters of PEO-b-PHEA can be structurallymodulated by varying the degree of MTX substitution, which in turn changesthe hydrophobicity of the conjugate, thereby modifying micelle stabilityand controlling drug release.

methotrexate block copolymer polymeric conjugate micelles unimers drug delivery