Enhanced Retention of the α-Particle-Emitting Daughters of Actinium-225 by Liposome Carriers

Abstract

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 cancercell 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 225 Ac daughters at the target increases efficacy; escape and distribution throughout the body increases toxicity. During circulation, molecular carriers conjugated to 225 Ac cannot retain any of the daughters. We previously proposed liposomal encapsulation of 225 Ac 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 binding of 225 Ac 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 225 Ac. PEGylated MUVELs stably retained over time 98% of encapsulated 225 Ac. Retention of 213 Bi, the last daughter, was 31% of the theoretical maximum retention of 213 Bi 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 could be able to deliver higher fractions of generated α-particles per targeted 225 Ac compared to the relative fractions of α-particles delivered by 225 Ac-labeled molecular carriers.

Noninternalizing Monoclonal Antibodies Are Suitable Candidates for 125I Radioimmunotherapy of Small-Volume Peritoneal Carcinomatosis

“…However, the use of a-particles in radioimmunotherapy requires the development of cost-effective radionuclide production and proteinlabeling chemistry. Another drawback of a-emitters is the production of radioactive daughter isotopes that can hardly be withheld in a chelator and tend to escape from targeted cells and accumulate in bone (16).…”

Radioisotopes and Nanomedicine

“…Sofou et al designed a multivesicular liposomal carrier of Ac-225 to enhance retention of daughter radionuclides. Though retention was not as high as hoped, when the particles were targeted to an ovarian cell line in vitro using immunolabeling with anti-HER2/neu, they were internalized at an impressive rate (Sofou et al 2007). More recently, Woodward et aldeveloped a lanthum phosphate nanoparticle (LaPO 4 NP) for Ac-225 encapsulation.…”

Nanotargeted Radiopharmaceuticals for Nuclear Imaging and Radiotherapy

“…Enhanced loading of 225 Ac and retention of three α-particleemitting daughters of 225 Ac by passively targeted liposomes have been demonstrated. 75,[129][130][131] Boron neutron capture therapy (BNCT) is a binary approach to cancer therapy involving the nuclear reaction that occurs when 10 B is irradiated with thermal neutrons to yield high LET of α-particles and lithium nuclei (2.4 MeV). These particles have a short range (<10 µm) and deposit their energy within single cells.…”