Methotrexate esters of poly(ethylene oxide)-block-poly(2-hydroxyethyl-L-aspartamide). Part I: Effects of the level of methotrexate conjugation on thestability of micelles and on drug release

Purpose. To study the effects of hydrophobicity of the micelle-funning bloc k copolymeric drug conjugate, methotrexate /MTX) esters of poly(ethylene ox ide)-block-poly(2-hydroxyethyl-L-aspartamide) (MTX esters of PEO-b-PHEA), o n the stability of micelles and on drug release. Methods. MTX esters of PEO-b-PHEA with three levels of MTX conjugation were synthesized. Size distribution of the micelles was measured by dynamic lig ht scattering (DLS). The critical micelle concentration (CMC) was determine d by a light scattering study. Size exclusion high performance liquid chrom atography (SEC-HPLC) was used to study the equilibrium between unimers and micelles, and release of MTX at pH 7.4. Results. MTX esters of PEO-b-PHEA with MTX substitution of 7.4%, 22%, and 5 4% were prepared. The conjugates formed micelles based on DLS. The stabilit y of the micelles correlated with the level of MTX conjugation. The conjuga te with 54% MTX had a lower CMC (0.019 mg/mL) than the conjugates with 22% MTX (0.081 mg/mL) or 7.4% MTX (0.14 mg/mL). Micelle dissociation was signif icantly slower for the conjugate with 54% MTX than that with 22% and 7.4% M TX. Slower release of MTX: from the micelles was also observed for the conj ugate with the higher MTX attachment. Conclusions. MTX esters of PEO-b-PHEA can be structurally modulated by vary ing the degree of MTX substitution, which in turn changes the hydrophobicit y of the conjugate, thereby modifying micelle stability and controlling dru g release.