Development of tumor targeting bioprobes ((111)In-chimeric L6 monoclonal antibody nanoparticles) for alternating magnetic field cancer therapy.
OBJECTIVE
(111)In-chimeric L6 (ChL6) monoclonal antibody (mAb)-linked iron oxide nanoparticle (bioprobes) pharmacokinetics, tumor uptake, and the therapeutic effect of inductively heating these bioprobes by externally applied alternating magnetic field (AMF) were studied in athymic mice bearing human breast cancer HBT 3477 xenografts. Tumor cell radioimmunotargeting of the bioprobes and therapeutic and toxic responses were determined.


METHODS
Using 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide HCl, (111)In-7,10-tetra-azacyclododecane-N, N',N'',N'''-tetraacetic acid-ChL6 was conjugated to the carboxylated polyethylene glycol on dextran-coated iron oxide 20 nm particles, one to two mAbs per nanoparticle. After magnetic purification and sterile filtration, pharmacokinetics, histopathology, and AMF/bioprobe therapy were done using (111)In-ChL6 bioprobe doses (20 ng/2.2 mg ChL6/ bioprobe), i.v. with 50 microg ChL6 in athymic mice bearing HBT 3477; a 153 kHz AMF was given 72 hours postinjection for therapy with amplitudes of 1,300, 1,000, or 700 Oe. Weights, blood counts, and tumor size were monitored and compared with control mice receiving nothing, or AMF or bioprobes alone.


RESULTS
(111)In-ChL6 bioprobe binding in vitro to HBT 3477 cells was 50% to 70% of that of (111)In-ChL6. At 48 hours, tumor, lung, kidney, and marrow uptakes of the (111)In-ChL6 bioprobes were not different from that observed in prior studies of (111)In-ChL6. Significant therapeutic responses from AMF/bioprobe therapy were shown with up to eight times longer mean time to quintuple tumor volume with therapy compared with no treatment (P = 0.0013). Toxicity was only seen in the 1,300 Oe AMF cohort, with 4 of 12 immediate deaths and skin erythema. Electron micrographs showed bioprobes on the surfaces of the HBT 3477 cells of excised tumors and tumor necrosis 24 hours after AMF/bioprobe therapy.


CONCLUSIONS
This study shows that mAb-conjugated nanoparticles (bioprobes), when given i.v., escape into the extravascular space and bind to cancer cell membrane antigen, so that bioprobes can be used in concert with externally applied AMF to deliver thermoablative cancer therapy.
DeNardo
Sally J
SJ
University of California, Davis, Sacramento, California, USA. sjdenardo@ucdavis.edu
DeNardo
Gerald L
GL
Miers
Laird A
LA
Natarajan
Arutselvan
A
Foreman
Alan R
AR
Gruettner
Cordula
C
Adamson
Grete N
GN
Ivkov
Robert
R
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D015374:Biosensing Techniques; D002614:Chelating Agents / Q000494:pharmacology; D015331:Cohort Studies; D004574:Electromagnetic Fields; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry; D018796:Immunoconjugates / Q000378:metabolism; D007205:Indium Radioisotopes / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D008854:Microscopy, Electron; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D011092:Polyethylene Glycols / Q000737:chemistry; D016499:Radioimmunotherapy / Q000379:methods*; D013997:Time Factors; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; C106337:ChL6 monoclonal antibody; D002614:Chelating Agents; D006573:Heterocyclic Compounds, 1-Ring; D018796:Immunoconjugates; D007205:Indium Radioisotopes; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D011092:Polyethylene Glycols