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.