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.
OBJECTIVE
To study the effects of hydrophobicity of the micelle-forming 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.
Li
Y
Y
School of Pharmacy, University of Wisconsin-Madison, 53706-1515, USA.
Kwon
G S
GS
D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry*; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000737:chemistry; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002851:Chromatography, High Pressure Liquid; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D008727:Methotrexate / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000737:chemistry; D008823:Micelles; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry*; D012995:Solubility
D000964:Antimetabolites, Antineoplastic; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D008823:Micelles; C416385:poly(ethylene oxide)-block-poly(2-hydroxyethylaspartamide); D001224:Aspartic Acid; D011092:Polyethylene Glycols; D008727:Methotrexate