The disclosure relates generally to gamma polyglutamated lometrexol compositions, including delivery vehicles such as liposomes containing the gamma polyglutamated lometrexol, and methods of making and using the gamma polyglutamated lometrexol compositions to treat hyperproliferative disorders (e.g., cancer) and disorders of the immune system (e.g., inflammation and autoimmune diseases such as rheumatoid arthritis).