Dataset Information

Facile Click-Mediated Cell Imaging Strategy of Liposomal Azido Mannosamine Lipids via Metabolic or Nonmetabolic Glycoengineering.

ABSTRACT: Two Ac₄ManNAz (AAM) derivatives with octadecanoic ester (C18 ester) and octadecyl ether (C18 ether) attached to the anomeric hydroxyl groups were synthesized and used in preparation of liposomes. Both liposomes show strong cell-labeling efficiencies on MDA-MB-231 cancer cells. The cell surface-anchored azide group can react with DBCO-Cy5 via Cu-free click chemistry. The two liposomes exhibit different azide placement mechanisms; C18-ether-AAM-treated cells have azido placement through direct insertion, while C18-ester-AAM-treated cells express azido more through metabolic glycoengineering.

SUBMITTER: Shen L

PROVIDER: S-EPMC7301605 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Facile Click-Mediated Cell Imaging Strategy of Liposomal Azido Mannosamine Lipids via Metabolic or Nonmetabolic Glycoengineering.

Shen Li L Cai Kaimin K Yu Jin J Cheng Jianjun J

ACS omega 20200604 23

Two Ac4ManNAz (AAM) derivatives with octadecanoic ester (C18 ester) and octadecyl ether (C18 ether) attached to the anomeric hydroxyl groups were synthesized and used in preparation of liposomes. Both liposomes show strong cell-labeling efficiencies on MDA-MB-231 cancer cells. The cell surface-anchored azide group can react with DBCO-Cy5 via Cu-free click chemistry. The two liposomes exhibit different azide placement mechanisms; C18-ether-AAM-treated cells have azido placement ...[more]

PMID: 32566878

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Project description:The specificity of antibodies have made immunoconjugates promising vectors for the delivery of radioisotopes to cancer cells; however, their long pharmacologic half-lives necessitate the use of radioisotopes with long physical half-lives, a combination that leads to high radiation doses to patients. Therefore, the development of targeting modalities that harness the advantages of antibodies without their pharmacokinetic limitations is desirable. To this end, we report the development of a methodology for pretargeted PET imaging based on the bioorthogonal Diels-Alder click reaction between tetrazine and transcyclooctene.A proof-of-concept system based on the A33 antibody, SW1222 colorectal cancer cells, and (64)Cu was used. The huA33 antibody was covalently modified with transcyclooctene, and a NOTA-modified tetrazine was synthesized and radiolabeled with (64)Cu. Pretargeted in vivo biodistribution and PET imaging experiments were performed with athymic nude mice bearing A33 antigen-expressing, SW1222 colorectal cancer xenografts.The huA33 antibody was modified with transcyclooctene to produce a conjugate with high immunoreactivity, and the (64)Cu-NOTA-labeled tetrazine ligand was synthesized with greater than 99% purity and a specific activity of 9-10 MBq/?g. For in vivo experiments, mice bearing SW1222 xenografts were injected with transcyclooctene-modified A33; after allowing 24 h for accumulation of the antibody in the tumor, the mice were injected with (64)Cu-NOTA-labeled tetrazine for PET imaging and biodistribution experiments. At 12 h after injection, the retention of uptake in the tumor (4.1 ± 0.3 percent injected dose per gram), coupled with the fecal excretion of excess radioligand, produced images with high tumor-to-background ratios. PET imaging and biodistribution experiments performed using A33 directly labeled with either (64)Cu or (89)Zr revealed that although absolute tumor uptake was higher with the directly radiolabeled antibodies, the pretargeted system yielded comparable images and tumor-to-muscle ratios at 12 and 24 h after injection. Further, dosimetry calculations revealed that the (64)Cu pretargeting system resulted in only a fraction of the absorbed background dose of A33 directly labeled with (89)Zr (0.0124 mSv/MBq vs. 0.4162 mSv/MBq, respectively).The high quality of the images produced by this pretargeting approach, combined with the ability of the methodology to dramatically reduce nontarget radiation doses to patients, marks this system as a strong candidate for clinical translation.

Dataset Information

Facile Click-Mediated Cell Imaging Strategy of Liposomal Azido Mannosamine Lipids via Metabolic or Nonmetabolic Glycoengineering.

Publications

Facile Click-Mediated Cell Imaging Strategy of Liposomal Azido Mannosamine Lipids <i>via</i> Metabolic or Nonmetabolic Glycoengineering.

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