Development of antibody directed nanoparticles for cancer therapy

The pharmacokinetics, tumor uptake, and biologic effects of inductively heating ¹¹¹In-chimeric L6 (ChL6) monoclonal antibody (mAb)-linked iron oxide nanoparticle (bioprobes) by externally applied alternating magnetic fields (AMF) were studied in athymic mice bearing human breast cancer HBT 3477 xenografts. In addition, response was correlated with calculated total deposited heat dose. Methods: Using l-ethyl-3-(3-dimethylaminopropyl)-carbodiimideHCl, ¹¹¹In-7,10-tetraazacyclododecane-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 ¹¹¹In-ChL6 bioprobe doses (20 mcg/2.2 mg ChL6/ bioprobe), i.v. with 50 mcg 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: ¹¹¹In-ChL6 bioprobe binding in vitro to HBT 3477 cells was 50% to 70% of that of ¹¹¹In-ChLo. At 48 hours, tumor, lung, kidney, and marrow uptakes of the ¹¹¹In-ChL6 bioprobes were not different from that observed in prior studies of ¹¹¹In-ChL6. Significant therapeutic responses from AMF/bioprobe therapy were shown compared with no treatment. In addition, greatest therapeutic benefit was observed for the 700 Oe treatment cohort. Toxicity was only seen in the 1,300 Oe AMF cohort, with 4 of 12 immediate deaths associated with skin erythema and petechiae. Conclusion: This study shows that mAb-conjugated nanoparticles (bioprobes), when given i.v., escape into the extravascular space and bind to cancer cell membrane antigen.Thus, bioprobes can be used in concert with externally applied AMF to deliver thermoablative cancer therapy. Therapeutic benefit was observed with increasing calculated heat dose deposited in tumors.