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

Targeted α-particle emitters hold great promise as therapeutics for micrometastatic disease. Because of their high energy deposition and short range, tumor targeted α-particles can result in high cancer-cell killing with minimal normal-tissue irradiation. Actinium-225 is a potential generator for α-particle therapy: it decays with a 10-day half-life and generates three α-particle-emitting daughters. Retention of ²²⁵Ac daughters at the target increases efficacy; escape and distribution throughout the body increases toxicity. During circulation, molecular carriers conjugated to ²²⁵Ac cannot retain any of the daughters. We previously proposed liposomal encapsulation of ²²⁵Ac 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 ²²⁵Ac 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 ²²⁵Ac. PEGylated MUVELs stably retained overtime 98% of encapsulated ²²⁵Ac. Retention of ²¹³Bi, 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 α-particles per targeted ²²⁵Ac compared to the relative fractions of α-particles delivered by ²²⁵Ac-labeled molecular carriers.