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

Abstract

Current treatment for late-stage metastatic breast cancer is largely palliative. α-Particles are highly potent, short-range radiation emissions capable of sterilizing individual cells with one to three traversals of the cell nucleus. The α-emitter, ²¹³Bi (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 ²¹³Bi 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 10⁵ 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 μCi) of liposome-CHX-A″-DTPA-²¹³Bi, (b) 19.2 MBq of liposome-CHX-A″-DTPA-²¹³Bi-7.16.4, (c) 4.44 MBq (120 μCi) of ²¹³Bi-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 ²¹³Bi radiolabeled immunoliposomes are effective in treating early-stage micrometastases, giving median survival times similar to those obtained with antibody-mediated delivery of ²¹³Bi in this animal model. Cancer Res; 70(17); 6815–23. ©2010 AACR.