<i>In-Vitro</i>Internalization and<i>In-Vivo</i>Tumor Uptake of Anti-EGFR Monoclonal Antibody LA22 in A549 Lung Cancer Cells and Animal Model

Liu, Zhaofei; Yu, Zilin; He, Weiwei; Ma, Shujun; Sun, Lingyi; Wang, Fan

doi:10.1089/cbr.2008.0537

Cited by 22 publications

(21 citation statements)

References 27 publications

(26 reference statements)

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“…The cell uptake and efflux studies were performed as we previously described (9,10,22). The cell uptake was expressed as the percentage added dose after decay correction.…”

Section: Cell Uptake and Efflux Studiesmentioning

confidence: 99%

Small-Animal PET of Tumors with ⁶⁴Cu-Labeled RGD-Bombesin Heterodimer

et al. 2009

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The overexpression of gastrin-releasing peptide receptor (GRPR) in various tumor types suggests that GRPR is an attractive target for cancer imaging and therapy with radiolabeled bombesin analogs. We recently reported the ability of 18 Flabeled RGD-bombesin heterodimer to be used for dual integrin a v b 3 -and GRPR-targeted imaging. To further investigate the synergistic effect of the dual-receptor targeting of peptide heterodimers, we evaluated 64 Cu-labeled RGD-bombesin for PET imaging of tumors. Methods: RGD-bombesin was coupled with 1,4,7,10-tetraazacyclododecane-N, N9, N99, N999-tetraacetic acid (DOTA) and 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), and the conjugates were labeled with 64 Cu. The in vitro and in vivo characteristics of 64 Cu-NOTA-RGD-bombesin were compared with those of 64 Cu-NOTA-RGD, 64 Cu-NOTA-bombesin, and 64 Cu-DOTA-RGD-bombesin. Results: 64 Cu-NOTA-RGDbombesin and 64 Cu-DOTA-RGD-bombesin had comparable dual integrin a v b 3 -and GRPR-binding affinities in vitro, both of which were slightly lower than RGD for integrin binding and bombesin for GRPR binding. 64 Cu-NOTA-RGD-bombesin possessed significantly higher tumor uptake than did 64 Cu-NOTA-RGD, 64 Cu-NOTA-bombesin, the mixture of 64 Cu-NOTA-RGD and 64 Cu-NOTA-bombesin, or 64 Cu-DOTA-RGD-bombesin in PC-3 prostate cancer. 64 Cu-NOTA-RGD-bombesin also showed improved in vivo kinetics such as lower liver and intestinal activity accumulation than did the bombesin tracers. 64 Cu-NOTA-RGD-bombesin also outperformed 64 Cu-NOTA-RGD in a 4T1 murine mammary carcinoma model that expresses integrin on tumor vasculature but no GRPR in tumor tissue, which had no uptake of 64 Cu-NOTA-bombesin. Conclusion: Compared with other tracers, 64 Cu-NOTA-RGD-bombesin showed favorable in vivo kinetics and enhanced tumor uptake, which warrants its further investigation for targeting tumors that express integrin or GRPR or that coexpress integrin and GRPR for imaging and therapeutic applications. The synergistic effect of RGD-bombesin heterodimers observed in this study also encourages further investigations of novel heterodimers recognizing other cell surface receptors for tumor targeting.

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“…The cell uptake and efflux studies were performed as we previously described (9,10,22). The cell uptake was expressed as the percentage added dose after decay correction.…”

Section: Cell Uptake and Efflux Studiesmentioning

confidence: 99%

Small-Animal PET of Tumors with ⁶⁴Cu-Labeled RGD-Bombesin Heterodimer

et al. 2009

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“…The binding affinity of mAb Abegrin™ for integrin α v β 3 and the available binding sites per U87MG cell were measured by saturation binding assay [27]. Briefly, 125 I-Abegrin™ was generated by incubating Abegrin™ (50 µg) with Na 125 I (37 MBq) in a vial coated with Iodogen (Sigma-Aldrich, St. Louis, MO) and then purified by a PD-10 column using a previously described method [28].…”

Section: Methodsmentioning

confidence: 99%

Specific Targeting of Human Integrin αvβ3 with 111In-Labeled Abegrin™ in Nude Mouse Models

et al. 2010

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Purpose The cell adhesion molecule integrin αvβ3 is an important player in the process of tumor angiogenesis and metastasis. Abegrin™, a fully humanized anti-integrin αvβ3 monoclonal antibody, was currently in clinical trials for cancer therapy. Herein, we labeled Abegrin™ with 111In, evaluated the in vitro and in vivo characteristics, and investigated whether the expression of integrin αvβ3 in tumors could be imaged with 111In-labeled Abegrin™. Methods The binding affinity and specificity of Abegrin™ was analyzed using U87MG glioblastoma cells. Abegrin™ was coupled with 1,4,7,10-tetraazadodecane-N,N,N’,N”-tetraacetic acid (DOTA) for 111In radiolabeling. γ Imaging of 111In-DOTA–Abegrin™ was carried out in nude mice bearing both integrin αvβ3-positive U87MG and integrin αvβ3-negative HT-29 tumors. Biodistribution and blocking studies of 111In-DOTA–Abegrin™ were investigated in U87MG tumor-bearing nude mice. Results Abegrin™ exhibited high-binding affinity to human integrin αvβ3 expressed on U87MG cells (Kd of 0.35±0.06 nM). The antibody retained antigen-binding affinity/specificity after DOTA conjugation. γ Imaging showed that the tumor uptake of 111In-DOTA–Abegrin™ in integrin αvβ3-positive U87MG tumors was much higher than that in integrin αvβ3-negative HT-29 tumors. In the HT-29 tumors, Abegrin™ was mainly nonspecifically accumulated around the blood vessels, while in the U87MG tumors, besides the nonspecific tumor retention, Abegrin™ also specifically bound the human integrin αvβ3 expressed on the tumor cells. Biodistribution and blocking studies exhibited that the U87MG tumor uptake of 111In-DOTA–Abegrin™ decreased from 14.12±0.44 to 6.93±0.94 percentage of injected dose per gram of tissue after coinjection of excess dose of cold Abegrin™, which confirmed the in vivo integrin αvβ3 binding specificity of 111In-DOTA–Abegrin™. Conclusions Abegrin™ showed specific binding to human integrin αvβ3 expressed on the tumor cells. 111In-DOTA–Abegrin™ can specifically target the human integrin αvβ3 expression in the nude mouse model. 111In-DOTA–Abegrin™ has a potential for clinical translation as an agent for integrin αvβ3-positive tumor imaging, evaluating tumor angiogenic status and monitoring the therapeutic efficacy of Abegrin™-based cancer therapy.

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“…125 I-HYK was prepared by labeling the HYK peptide with Na 125 I using the Iodogen method [21]. The experiments were performed on BxPC-3 cells using a previously described method [15].…”

Section: Cell Competitive Binding Assaymentioning

confidence: 99%

A near-infrared phthalocyanine dye-labeled agent for integrin αvβ6-targeted theranostics of pancreatic cancer

Gao

Zhang

et al. 2015

Biomaterials

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In-VitroInternalization andIn-VivoTumor Uptake of Anti-EGFR Monoclonal Antibody LA22 in A549 Lung Cancer Cells and Animal Model

Abstract: The mAb, LA22, is a rapid, high-internalizing antibody, and this property makes it a promising vehicle for tumor-targeted drug delivery.

Cited by 22 publications

References 27 publications

Small-Animal PET of Tumors with ⁶⁴Cu-Labeled RGD-Bombesin Heterodimer

Small-Animal PET of Tumors with ⁶⁴Cu-Labeled RGD-Bombesin Heterodimer

Specific Targeting of Human Integrin αvβ3 with 111In-Labeled Abegrin™ in Nude Mouse Models

A near-infrared phthalocyanine dye-labeled agent for integrin αvβ6-targeted theranostics of pancreatic cancer

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In-VitroInternalization andIn-VivoTumor Uptake of Anti-EGFR Monoclonal Antibody LA22 in A549 Lung Cancer Cells and Animal Model

Abstract: The mAb, LA22, is a rapid, high-internalizing antibody, and this property makes it a promising vehicle for tumor-targeted drug delivery.

Cited by 22 publications

References 27 publications

Small-Animal PET of Tumors with 64Cu-Labeled RGD-Bombesin Heterodimer

Small-Animal PET of Tumors with 64Cu-Labeled RGD-Bombesin Heterodimer

Specific Targeting of Human Integrin αvβ3 with 111In-Labeled Abegrin™ in Nude Mouse Models

A near-infrared phthalocyanine dye-labeled agent for integrin αvβ6-targeted theranostics of pancreatic cancer

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Small-Animal PET of Tumors with ⁶⁴Cu-Labeled RGD-Bombesin Heterodimer

Small-Animal PET of Tumors with ⁶⁴Cu-Labeled RGD-Bombesin Heterodimer