Provided are methods and compositions for reducing the toxicity of certain hydrophobic therapeutic agents, especially polyene antibiotics, in particular, Amphotericin B (AmB), and therapeutics such as paclitaxel, tamoxifen, an acylated prodrug or an acylated cis-platin, by incorporating these agents within micelles comprising an amphiphilic block-forming copolymer. Where the polyene is amphotericin B, desirably the spacer is an alkyl molecule of aabout 2 to about 8 carbon atoms, desirably 6 carbon atoms, and the core is an N-alkyl molecule of about 8 to about 28 carbon atoms, desirably 12 to 22 carbon atoms, advantageously, 12 to 18 carbon atoms, and as specifically embodied, 18 carbon atoms (stearate moiety). For the formulation of a larger polyene, the spacer and core are proportionately larger than those for amphotericin B. As specifically exemplified herein, the polymer backbone is a PEO of about 270 units with about 10-30 core-forming PLAA subunits, and advantageously about 14-24. Desirably the stearate moiety has a substitution level on the copolymer from about 35 percent to about 70 percent.