Micelle-forming macromolecular conjugates of methotrexate and paclitaxel: Structural effects on micellar properties and drug release

Block copolymer micelles have been used for the solubilization of hydrophobic drugs. However, the application of polymeric micelles in drug delivery has been limited by suboptimal drug loading capacity and unpredictable drug release, which is largely related to the physicochemical properties of polymeric micelles. The current study aimed to develop amphiphilic block copolymers containing covalently conjugated drugs. A hydrolyzable ester linkage was incorporated into the structure of the micelle-forming polymer-drug conjugates, and therefore, release of drug was potentially achievable through hydrolysis. Two anticancer drugs, methotrexate (MTX) and paclitaxel, were conjugated to a block copolymer, poly(ethylene oxide)-block-poly(aspartic acid), using an alkyl group as a linker. The resultant conjugates self-assembled into micelles in aqueous environments. Under physiological pH values, MTX and paclitaxel, were released slowly from the conjugates.; Poly(ethylene oxide)-block-poly(β-benzyl- L-aspartate) (PEO-b-PBLA) was used as the starting material for the synthesis of drug-polymer conjugates. For the synthesis of methotrexate esters, the benzyl groups on the PBLA block were replaced by a C₂ or C₆ alkyl spacer group introduced by the aminolysis of PEO-b-PBLA with 2-aminoethanol or 6-aminohexanol, yielding poly(ethylene oxide)-block-poly(hydroxyalkylaspartamide) (PEO-b-PHAA). Methotrexate was coupled to PEO-b-PHAA through an ester bond.; The conjugation of MTX to PEO-b-PHAA greatly enhanced the hydrophobicity of the block copolymer. The resultant conjugates underwent self-assembly in an aqueous environment, and the drug moieties were incorporated into the core of the micelles. The hydrophobicity of the conjugates influenced the physicochemical properties of the polymeric micelles and drug release. Eight micelle-forming MTX esters with varied hydrophobicity were synthesized. The critical micelle concentration, micelle stability, and MTX release were correlated with the hydrophobicity of the polymeric conjugates. A highly hydrophobic polymer conjugate displayed a low CMC. The conjugates that form stable micelles released MTX slowly.; MTX esters exhibited decreased inhibitory activity toward dihydrofolate reductase (DHFR) compared with free drug and decreased anticancer activity against murine leukemia L1210 cells. The presence of folate lowered the cell inhibitory activity of MTX esters toward L1210 cells, implying the altered cellular uptake pathway of MTX, as a result of conjugation to polymeric carriers.