Enhanced retention of the α-particle-emitting daughters of actinium-225 by liposome carriers

Targeted a-particle emitters hold great promise as therapeutics for micrometastatic disease. Because of their high energy deposition and short range, tumor targeted a-particles can result in high cancer-cell killing with minimal normal-tissue irradiation. Actinium-225 is a potential generator for a-particle therapy: it decays with a 10-day half-life and generates three alpha-particle-emitting daughters. Retention of Ac-225 daughters at the target increases efficacy; escape and distribution throughout the body increases toxicity. During circulation, molecular carriers conjugated to Ac-225 cannot retain any of the daughters. We previously proposed liposomal encapsulation of Ac-225 to retain the daughters, whose retention was shown to be liposome-size dependent. However, daughter retention was lower than expected: 22% of theoretical maximum decreasing to 14%, partially due to the binding of Ac-225 to the phospholipid membrane. In this study, Multivesicular liposomes (MUVELs) composed of different phospholipids were developed to increase daughter retention. MUVELs are large liposomes with entrapped smaller lipid-vesicles containing Ac-225. PEGylated MUVELs stably retained over time 98% of encapsulated Ac-225. Retention of Bi-213, the last daughter, was 31% of the theoretical maximum retention of 213Bi for the liposome sizes studied. MUVELs were conjugated to an anti-HER2/neu antibody (immunolabeled MUVELs) and were evaluated in vitro with SKOV3-NMP2 ovarian cancer cells, exhibiting significant cellular internalization (83%). This work demonstrates that immunolabeled MUVELs might be able to deliver higher fractions of generated a-particles per targeted Ac-225 compared to the relative fractions of a-particles delivered by Ac-225-labeled molecular carriers.