Immunoliposomal delivery of 213Bi for alpha-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, (213)Bi (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 (213)Bi 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 muCi) of liposome-CHX-A''-DTPA-(213)Bi, (b) 19.2 MBq of liposome-CHX-A''-DTPA-(213)Bi-7.16.4, (c) 4.44 MBq (120 muCi) of (213)Bi-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 (213)Bi radiolabeled immunoliposomes are effective in treating early-stage micrometastases, giving median survival times similar to those obtained with antibody-mediated delivery of (213)Bi in this animal model.
Lingappa
Mohanambe
M
Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD, USA.
Song
Hong
H
Thompson
Sarah
S
Bruchertseifer
Frank
F
Morgenstern
Alfred
A
Sgouros
George
G
D000512:Alpha Particles; D000818:Animals; D001729:Bismuth / Q000008:administration & dosage*; D005260:Female; D018796:Immunoconjugates / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D017879:Isothiocyanates / Q000008:administration & dosage / Q000737:chemistry; D008081:Liposomes / Q000008:administration & dosage / Q000737:chemistry; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000532:radiotherapy*; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D004369:Pentetic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000737:chemistry; D016499:Radioimmunotherapy / Q000379:methods*; D011868:Radioisotopes / Q000008:administration & dosage*; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000276:immunology
D001729:Bismuth; D018796:Immunoconjugates; D017879:Isothiocyanates; D008081:Liposomes; D004369:Pentetic Acid; D011868:Radioisotopes; D018719:Erb-b2 Receptor Tyrosine Kinases; C085678:N-(2-amino-3-(4-isothiocyanatophenyl)propyl)cyclohexane-1,2-diamine-N,N',N',N'',N''-pentaacetic acid