Radiolabeling Strategies for Tumor-Targeting  Proteinaceous Drugs

Sugiura, Grant; Kühn, Helen; Sauter, Max; Haberkorn, Uwe; Mier, Walter

doi:10.3390/molecules19022135

Cited by 53 publications

(56 citation statements)

References 120 publications

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“…7), conjugation of this chelator did not impair the binding of YY146 to CD146. This suggests that the lysine residues involved in the conjugation chemistry were not involved in the binding sites of YY146 [30-33]. Overall, PET imaging revealed that tumor uptake of 64 Cu-NOTA-YY146 was persistent, prominent, and highly specific.…”

Section: Discussionmentioning

confidence: 99%

ImmunoPET for assessing the differential uptake of a CD146-specific monoclonal antibody in lung cancer

Sun

England

Hernandez

et al. 2016

Eur J Nucl Med Mol Imaging

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Purpose Overexpression of CD146 in solid tumors has been linked to disease progression, invasion, and metastasis. In this study, we describe the generation of a 64Cu-labeled CD146-specific antibody for quantitative immunoPET imaging of CD146 expression in six lung cancer models. Methods The anti-CD146 antibody (YY146) was conjugated to 1,4,7-triazacyclononane-triacetic acid (NOTA) and radiolabeled with 64Cu. CD146 expression was evaluated in six human lung cancer cell lines (A549, NCI-H358, NCI-H522, HCC4006, H23, and NCI-H460) by flow cytometry and quantitative Western blot studies. The biodistribution and tumor uptake of 64Cu-NOTA-YY146 was assessed by sequential PET imaging in athymic nude mice bearing subcutaneous lung cancer xenografts. The correlation between CD146 expression and tumor uptake of 64Cu-NOTA-YY146 was evaluated by graphical software while ex vivo biodistribution and immunohistochemistry studies were performed to validate the accuracy of PET data and spatial expression of CD146. Results Flow cytometry and Western blot studies showed similar findings with H460 and H23 cells highly expressing CD146. Small differences in CD146 expression levels were found between A549, H4006, H522, and H358 cells. Tumor uptake of 64Cu-NOTA-YY146 was highest in CD146-expressing H460 and H23 tumors, peaking at 20.1 ± 2.86 and 11.6 ± 2.34 %ID/g at 48 h post-injection (n=4). Tumor uptake was lowest in the H522 model (4.1 ± 0.98 %ID/g at 48 h post-injection; n=4), while H4006, A549 and H358 exhibited similar uptake of 64Cu-NOTA-YY146. A positive correlation was found between tumor uptake of 64Cu-NOTA-YY146 (%ID/g) and relative CD146 expression (r2=0.98, p<0.01). Ex vivo biodistribution corroborated the accuracy of PET data. Conclusions The strong correlation between tumor uptake of 64Cu-NOTA-YY146 and CD146 expression demonstrates the potential use of this radiotracer for imaging tumors that elicit varying levels of CD146. In the future, this tool may promote enhanced monitoring of therapeutic response and improved patient stratification.

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Section: Discussionmentioning

confidence: 99%

ImmunoPET for assessing the differential uptake of a CD146-specific monoclonal antibody in lung cancer

Sun

England

Hernandez

et al. 2016

Eur J Nucl Med Mol Imaging

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“…ME-9F1 mAb was conjugated with 125 I, as previously described [28]. Tumor-bearing AlbTag and tumor-free animals were sacrificed.…”

Section: Methodsmentioning

confidence: 99%

Selective targeting of liver cancer with the endothelial marker CD146

et al. 2014

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Hepatocellular carcinomas are well-vascularized tumors; the endothelial cells in these tumors have a specific phenotype. Our aim was to develop a new approach for tumor-specific drug delivery with monoclonal antibody targeting of endothelial ligands. CD146, a molecule expressed on the endothelial surface of hepatocellular carcinoma, was identified as a promising candidate for targeting. In the present study, endothelial cells immediately captured circulating anti-CD146 (ME-9F1) antibody, while antibody binding in tumors was significantly higher than in hepatic endothelium. Macroscopically, after intravenous injection, there were no differences in the mean accumulation of anti-CD146 antibody in tumor compared to liver tissue, due to a compensating higher blood vessel density in the liver tissue. Additional blockade of nontumoral epitopes and intra-arterial administration, improved selective antibody capture in the tumor microvasculature and largely prevented antibody distribution in the lung and liver. The potential practical use of this approach was demonstrated by imaging of radionuclide-labeled ME-9F1 antibody, which showed excellent tumor-selective uptake. Our results provide a promising principle for the use of endothelial markers for intratumoral drug delivery. Tumor endothelium–based access might offer new opportunities for the imaging and therapy of hepatocellular carcinoma and other liver malignancies.

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“…Afterward, samples were dialyzed, lyophilized, and reconstituted as necessary as described previously. 3,24,42–44,50–52 …”

Section: Methodsmentioning

confidence: 99%

“…HA molecular weights of 7, 30, 67, 215, and 741 kDa were studied, and biodistribution was assessed by using fluorescent or radiolabeled HA. 3,42–44 …”

Section: Introductionmentioning

confidence: 99%

Hyaluronic Acid Molecular Weight Determines Lung Clearance and Biodistribution after Instillation

et al. 2016

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Hyaluronic acid (HA) has emerged as a versatile polymer for drug delivery. Multiple commercial products utilize HA, it can be obtained in a variety of molecular weights, and it offers chemical handles for cross-linkers, drugs, or imaging agents. Previous studies have investigated multiple administration routes, but the absorption, biodistribution, and pharmacokinetics of HA after delivery to the lung is relatively unknown. Here, pharmacokinetic parameters were investigated by delivering different molecular weights of HA (between 7 and 741 kDa) to the lungs of mice. HA was labeled with either a near-infrared dye or with iodine-125 conjugated to HA using a tyrosine linker. In initial studies, dye-labeled HA was instilled into the lungs and fluorescent images of organs were collected at 1, 8, and 24 h post administration. Data suggested longer lung persistence of higher molecular weight HA, but signal diminished for all molecular weights at 8 h. To better quantitate pharmacokinetic parameters, different molecular weights of iodine-125 labeled HA were instilled and organ radioactivity was determined after 1, 2, 4, 6, and 8 h. The data showed that, after instillation, the lungs contained the highest levels of HA, as expected, followed by the gastrointestinal tract. Smaller molecular weights of HA showed more rapid systemic distribution, while 67 and 215 kDa HA showed longer persistence in the lungs. Lung exposure appeared to be optimum in this size range due to the rapid absorption of <67 kDa HA and the poor lung penetration and mucociliary clearance of viscous solutions of HA > 215 kDa. The versatility of HA molecular weight and conjugation chemistries may, therefore, provide new opportunities to extend pulmonary drug exposure and potentially facilitate access to lymph nodes draining the pulmonary bed.

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Radiolabeling Strategies for Tumor-Targeting Proteinaceous Drugs

Cited by 53 publications

References 120 publications

ImmunoPET for assessing the differential uptake of a CD146-specific monoclonal antibody in lung cancer

ImmunoPET for assessing the differential uptake of a CD146-specific monoclonal antibody in lung cancer

Selective targeting of liver cancer with the endothelial marker CD146

Hyaluronic Acid Molecular Weight Determines Lung Clearance and Biodistribution after Instillation

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