NanoFerrite particle based radioimmunonanoparticles: binding affinity and in vivo pharmacokinetics.
Dextran and PEG-coated iron oxide nanoparticles (NP), when suitably modified to enable conjugation with molecular targeting agents, provide opportunities to target cancer cells. Monoclonal antibodies, scFv, and peptides conjugated to 20 nm NP have been reported to target cancer for imaging and alternating magnetic field (AMF) therapy. The physical characteristics of NPs can affect their in vivo performance. Surface morphology, surface charge density, and particle size are considered important factors that determine pharmacokinetics, toxicity, and biodistribution. New NanoFerrite (NF) particles having improved specific AMF absorption rates and diameters of 30 and 100 nm were studied to evaluate the variation in their in vitro and in vivo characteristics in comparison to the previously studied 20 nm superparamagnetic iron oxide (SPIO) NP. SPIO NP 20 nm and NF NP 30 and 100 nm were conjugated to (111)In-DOTA-ChL6, a radioimmunoconjugate. Radioimmunoconjugates were conjugated to NPs using 25 microg of RIC/mg of NP by carbodiimide chemistry. The radioimmunonanoparticles (RINP) were purified and characterized by PAGE, cellulose acetate electrophoresis (CAE), live cell binding assays, and pharmacokinetics in athymic mice bearing human breast cancer (HBT 3477) xenografts. RINP (2.2 mg) were injected iv and whole body; blood and tissue data were collected at 4, 24, and 48 h. The preparations used for animal study were >90% monomeric by PAGE and CAE. The immunoreactivity of the RINP was 40-60% compared to (111)In-ChL6. Specific activities of the doses were 20-25 microCi/2.2 mg and 6-11 microg of mAb/2.2 mg of NP. Mean tumor uptakes (% ID/g +/- SD) of each SPIO 20 nm, NF 30 nm, and 100 nm RINP at 48 h were 9.00 +/- 0.8 (20 nm), 3.0 +/- 0.3 (30 nm), and 4.5 +/- 0.8 (100 nm), respectively; the ranges of tissue uptakes were liver (16-32 +/- 1-8), kidney (7.0-15 +/- 1), spleen (8-17 +/- 3-8), lymph nodes 5-6 +/- 1-2), and lung (2.0-4 +/- 0.1-2). In conclusion, this study demonstrated that 100 nm NF NP could be conjugated to (111)In-mAb so that the resulting RINP had characteristics suitable for AMF therapy. Although 100 nm RINP targeted tumor less than 20 nm SPIO RINP, their heating capacity is typically 6 times greater, suggesting the 100 nm NF RINP could still deliver better therapy with AMF.
School of Medicine, University of California Davis, Sacramento, California 95816, USA. arutselvan.natarajan@ucdmc.ucdavis.edu
A
A
Natarajan
C
C
Gruettner
R
R
Ivkov
G L
GL
DeNardo
G
G
Mirick
A
A
Yuan
A
A
Foreman
S J
SJ
DeNardo
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D005290:Ferric Compounds / Q000737:chemistry*; D006358:Hot Temperature / Q000627:therapeutic use; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*; D007205:Indium Radioisotopes; D008280:Magnetics; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D017785:Photons; D011092:Polyethylene Glycols / Q000737:chemistry; D011863:Radioimmunoassay; D013057:Spectrum Analysis; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D005290:Ferric Compounds; D018796:Immunoconjugates; D007205:Indium Radioisotopes; C001215:ferrite; C000499:ferric oxide; D011092:Polyethylene Glycols