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

Purpose. To study the effects of hydrophobicity of the micelle-funning block copolymeric drug conjugate, methotrexate /MTX) esters of poly(ethylene oxide)-block-poly(2-hydroxyethyl-L-aspartamide) (MTX esters of PEO-b-PHEA), on 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 light scattering (DLS). The critical micelle concentration (CMC) was determined by a light scattering study. Size exclusion high performance liquid chromatography (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 54% were prepared. The conjugates formed micelles based on DLS. The stability of the micelles correlated with the level of MTX conjugation. The conjugate 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 significantly slower for the conjugate with 54% MTX than that with 22% and 7.4% MTX. Slower release of MTX: from the micelles was also observed for the conjugate with the higher MTX attachment. Conclusions. MTX esters of PEO-b-PHEA can be structurally modulated by varying the degree of MTX substitution, which in turn changes the hydrophobicity of the conjugate, thereby modifying micelle stability and controlling drug release.