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Thermal Dosimetry Predictive of Efficacy of 111In-ChL6 Nanoparticle AMF–Induced Thermoablative Therapy for Human Breast Cancer in Mice

Sally J. DeNardo1, Gerald L. DeNardo1, Arutselvan Natarajan1, Laird A. Miers1, Allan R. Foreman2, Cordula Gruettner3, Grete N. Adamson1 and Robert Ivkov2

1 School of Medicine, University of California Davis, Sacramento, California; 2 Triton BioSystems, Inc., Chelmsford, Massachusetts; and 3 Micromod Partikeltechnologie, GmbH, Rostock-Warnemuende, Germany


Figure 1
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FIGURE 1.  Schematic of a bioprobe: 111In-ChL6 conjugated to PEG on iron oxide–impregnated dextran 20-nm nanoparticles.

 

Figure 2
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FIGURE 2.  AMF delivery coil used to treat mice bearing human xenograft tumors. AMF is focused in a 1-cm band in which subcutaneous tumor located on abdomen of each mouse was positioned. Major components of the system are (a) induction coil, (b) capacitance network, and (c) power supply (17).

 

Figure 3
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FIGURE 3.  Pharmacokinetics of 111In-ChL6 bioprobes in mice with HBT3477 human breast cancer xenografts. (A) Blood clearance of 111In-ChL6 bioprobes (•) was more rapid than that of 111In-ChL6 mAb alone ({circ}). Whole-body clearances ({blacksquare}, {square}) were similar. (B) Concentrations (%ID/g) of 111In-ChL6 bioprobes in blood, tumor, liver, lung, kidneys, spleen, and marrow at 1 d (Figure 3), 2 d (Figure 3), 3 d (Figure 3), and 4 d (Figure 3) after injection. Maximum concentrations in liver and spleen were almost twice and tumor concentration was about 75% of that previously observed for 111In-ChL6 mAb (16). Concentrations of 111In in other normal tissues were similar to those of 111In-ChL6 mAb.

 

Figure 4
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FIGURE 4.  Relationship of tumor response to bioprobe AMF Rx. Therapeutic response is reflected by increased time to double, triple, and quadruple tumor volume in mice receiving higher THDs (J). A statistical relationship between response and THD was demonstrated for tumors receiving 13–19 and 21 J/g compared with that of controls (Table 3). Tumor growths of AMF alone, bioprobes alone, and untreated control groups of mice were statistically indistinguishable, so they were grouped as controls.

 

Figure 5
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FIGURE 5.  Electron micrographs of ultrathin osmium tetroxide–fixed epoxy-embedded HBT3477 xenografts that had been excised from mice at time of sacrifice: (A) 48 h after bioprobes, no AMF; (B) 24 h after AMF Rx (18 J/g); and (C) 48 h after AMF Rx (18 J/g). Healthy cells (A) contrast with evidence for cell necrosis at 24 h after AMF Rx (B) and further evidence for necrosis 48 h after AMF Rx (C).

 





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