The fate of MAb-targeted Cd(125m)Te/ZnS nanoparticles in vivo.
BACKGROUND
Nanoparticles (NP) have potential as carriers for drugs and radioisotopes. Quantitative measures of NP biodistribution in vivo are needed to determine the effectiveness of these carriers. We have used a model system of radiolabeled quantum dots to document the competition between efficient vascular targeting and interaction of the NP with the reticuloendothelial (RE) system.


METHODS
We have prepared (125m)Te-labeled CdTe NP that are capped with ZnS. Te-125m has a half-life and decay characteristics very similar to those for (125)I. The synthesized particles are stable in aqueous solution and are derivatized with mercaptoacetic acid and then conjugated with specific antibody. To evaluate specific targeting, we used the monoclonal antibody MAb 201B that binds to murine thrombomodulin expressed in the lumen of lung blood vessels. The MAb-targeted NP were tested for targeting performance in vivo using single-photon emission computed tomography (SPECT)/computed tomography (CT) imaging, tissue autoradiography and standard organ biodistribution techniques. Biodistribution was also determined in mice that had been depleted of phagocytic cells by use of clodronate-loaded liposomes.


RESULTS
Cd(125m)Te/ZnS NP coupled with MAb 201B retained radioisotope and antibody activity and accumulated in lung (>400% injected dose [ID]/g) within 1 h of intravenous injection. Control antibody-coupled NP did not accumulate in lung (<10% ID/g) but accumulated in liver and spleen. Images from microSPECT/CT and autoradiography studies of the targeted NP document this specific uptake and demonstrate uniform distribution in lung with minor accumulation in liver and spleen. Within a few hours, a large fraction of lung-targeted NP redistributed to spleen and liver or was excreted. We hypothesized that NP attract phagocytic cells that engulfed and removed them from circulation. This was confirmed by comparing biodistribution of targeted NP in normal mice versus those depleted of phagocytic cells. In mice treated with clodronate liposomes, accumulation of NP in liver was reduced by fivefold, while accumulation in lung at 1 h was enhanced by approximately 50%. By 24 h, loss of the targeted NP from lung was inhibited by several-fold, while accumulation in liver and spleen remained constant. Thus, the treated mice had a much larger accumulation and retention of the NP at the target site and a decrease in dose to other organs except spleen.


CONCLUSIONS
Nanoparticles composed of CdTe, labeled with (125m)Te and capped with ZnS, can be targeted with MAb to sites in the lumen of lung vasculature. In clodronate-treated mice, which have a temporary depletion of phagocytic cells, accumulation in liver was reduced dramatically, whereas that in spleen was not. The targeting to lung was several-fold more efficient in clodronate-treated mice due to larger initial accumulation and better retention of the MAb-targeted NP at that site. This model system indicates that targeting of NP preparations is a competition between the effectiveness of the targeting agent and the natural tendency for RE uptake of the particles. Temporary inhibition of the RE system may enhance the usefulness of NP for drug and radioisotope delivery.
Kennel
Stephen J
SJ
Graduate School of Medicine, University of TN, Knoxville, TN 37920, USA. skennel@utmck.edu
Woodward
Jonathan D
JD
Rondinone
Adam J
AJ
Wall
Jonathan
J
Huang
Ying
Y
Mirzadeh
Saed
S
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000493:pharmacokinetics*; D001345:Autoradiography; D001808:Blood Vessels / Q000276:immunology*; D019187:Cadmium Compounds / Q000138:chemical synthesis / Q000493:pharmacokinetics; D004002:Clodronic Acid / Q000494:pharmacology; D004339:Drug Compounding; D004355:Drug Stability; D005260:Female; D008168:Lung / Q000098:blood supply / Q000000981:diagnostic imaging*; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D010586:Phagocytes / Q000187:drug effects / Q000378:metabolism; D016719:Radioimmunodetection; D011868:Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics; D011875:Radionuclide Angiography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D013691:Tellurium / Q000737:chemistry / Q000493:pharmacokinetics*; D018180:Thrombomodulin / Q000032:analysis / Q000276:immunology; D015899:Tomography, Emission-Computed, Single-Photon; D014057:Tomography, X-Ray Computed; D019287:Zinc Sulfate / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D019187:Cadmium Compounds; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D018180:Thrombomodulin; D004002:Clodronic Acid; D019287:Zinc Sulfate; D013691:Tellurium