Immunoliposomal Delivery of 213Bi for α-Emitter Targeting of Metastatic Breast Cancer

Current treatment for late-stage metastatic breast cancer is largely palliative. alpha-Particles are highly potent, short-range radiation emissions capable of sterilizing individual cells with one to three traversals of the cell nucleus. The alpha-emitter, Bi-213 (T-1/2 = 45.6 min), was conjugated to a 100-nm diameter liposomal-CHX-A ''-DTPA construct, upon which the rat HER2/neu reactive antibody, 7.16.4, was grafted. A conjugation time of 10 minutes was achieved giving a specific activity corresponding to 0.1 Bi-213 atom per liposome; stability in vitro and in vivo was confirmed. Efficacy in a rat/neu transgenic mouse model of metastatic mammary carcinoma was investigated. Three days after left cardiac ventricular injection of 10(5) rat HER-2/neu-expressing syngeneic tumor cells, macrophage-depleted Neu-N mice were treated by i.v. injection with (a) 19.2 MBq (520 mu Ci) of liposome-CHX-A ''-DTPA-Bi-213, (b) 19.2 MBq of liposome-CHX-A ''-DTPA-Bi-213-7.16.4, (c) 4.44 MBq (120 mu Ci) of Bi-213-7.16.4, and (d) cold (nonradioactive) liposome-CHX-A ''-DTPA-7.16.4 as control. Treatment with (a) increased median survival time to 34 days compared with 29 days for the untreated controls (P = 0.013) and 27 days for treated cold controls. Treatment with the radiolabeled antibody-conjugated liposome (b) increased median survival time to 38 days (P = 0.0002 relative to untreated controls). The radiolabeled antibody-treated group (c) gave a median survival of 39 days, which was similar to that for the radiolabeled antibody-conjugated liposome-treated group (P = 0.5). We have shown that the Bi-213 radiolabeled immunoliposomes are effective in treating early-stage micrometastases, giving median survival times similar to those obtained with antibody-mediated delivery of Bi-213 in this animal model. Cancer Res; 70(17); 6815-23. (C)2010 AACR.