Dataset Information

Near-IR Light-Mediated Cleavage of Antibody-Drug Conjugates Using Cyanine Photocages.

ABSTRACT: Despite significant progress in the clinical application of antibody drug conjugates (ADCs), novel cleavage strategies that provide improved selectivity are still needed. Herein is reported the first approach that uses near-IR light to cleave a small molecule from a biomacromolecule, and its application to the problem of ADC linkage. The preparation of cyanine antibody conjugates, drug cleavage mediated by 690?nm light, and initial in vitro and in vivo evaluation is described. These studies provide the critical chemical underpinning from which to develop this near-IR light cleavable linker strategy.

SUBMITTER: Nani RR

PROVIDER: S-EPMC4743669 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Publications

Near-IR Light-Mediated Cleavage of Antibody-Drug Conjugates Using Cyanine Photocages.

Nani Roger R RR Gorka Alexander P AP Nagaya Tadanobu T Kobayashi Hisataka H Schnermann Martin J MJ

Angewandte Chemie (International ed. in English) 20150925 46

Despite significant progress in the clinical application of antibody drug conjugates (ADCs), novel cleavage strategies that provide improved selectivity are still needed. Herein is reported the first approach that uses near-IR light to cleave a small molecule from a biomacromolecule, and its application to the problem of ADC linkage. The preparation of cyanine antibody conjugates, drug cleavage mediated by 690 nm light, and initial in vitro and in vivo evaluation is described. These studies prov ...[more]

PMID: 26403799

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Project description:A series of Ru(ii) complexes bearing the tridentate 2,6-di(quinolin-2-yl)pyridine (dqpy) ligand were designed to undergo photoinduced ligand dissociation with red/near-IR light. The complexes [Ru(dqpy)(L)(CH3CN)]2+, where L = 2,2'-bipyridine (bpy, 1), 4,4'dimethyl-2,2'-bipyridine (Me2bpy, 2), and 1,10-phenanthroline (phen, 3). Complexes 1-3 exhibit red-shifted lowest energy metal-to-ligand charge transfer (MLCT) absorption maxima at ?600 nm, as compared to the corresponding tpy (2,2';6',2''-terpyridine) complexes with MLCT bands at ?565 nm which appear as shoulders to the MLCT bands at ?455 nm. This shift is attributed to the lower energy LUMO afforded by the dqpy ligand when compared to tpy, as evidenced by the shift of the first reduction wave to ?0.3 V more positive potentials in the former. In addition, the lowest MLCT maximum of [Ru(dqpy)(acac)(CH3CN)]+ (4; acac- = acetylacetonate) is observed at 770 nm, attributed to the additional increase in energy of the HOMO afforded by the presence of the ?-donating acac- ligand and supported by calculations. Complexes 1-3 undergo ligand substitution upon irradiation with red light, ? irr ? 610 nm, and the ligand substitution photochemistry of 4 is accessible with near-IR light, ? irr ? 715 nm and ? irr = 735 nm. Complexes 1-4 exhibit similar quantum yields of ligand exchange, ? L, with 450 and 600 nm irradiation, however, that of 4 is 2-3 times greater than those measured for 1-3. This enhancement is explained by the difference in ligand contributions to the HOMO. Density functional theory calculations predict partial dqpy ??* character in the MLCT states of 1-3 and a mixed Ru/acac- ? dqpy metal/ligand-to-ligand charge transfer (ML-LCT) state in 4. The photoreactivity of 1-4 with tissue-penetrating red and near-IR light, together with their exceptional dark stability (>48 h), makes the new Ru(ii)-dqpy platform ideal for the development of new complexes for photoinduced drug release and for other applications that require broad absorption from the ultraviolet and visible ranges into the near-IR, such as solar energy conversion.

Dataset Information

Near-IR Light-Mediated Cleavage of Antibody-Drug Conjugates Using Cyanine Photocages.

Publications

Near-IR Light-Mediated Cleavage of Antibody-Drug Conjugates Using Cyanine Photocages.

Similar Datasets

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