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Photoactivation of imatinib-antibody conjugate using low-energy visible light from Ru(ii)-polypyridyl cages.

ABSTRACT: Ru(ii)-polypyridyl cages with sterically bulky bidentate ligands provide efficient photochemical release of the anticancer drug imatinib using low energy visible light, imparting spatiotemporal control over drug bioavailability. The light-activated drug release is maintained when the Ru(ii) cage is covalently coupled to an antibody, which is expected to localize selectively on the tumor.

SUBMITTER: Rohrabaugh TN

PROVIDER: S-EPMC6005383 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Photoactivation of imatinib-antibody conjugate using low-energy visible light from Ru(ii)-polypyridyl cages.

Rohrabaugh Thomas N TN Rohrabaugh Ashley M AM Kodanko Jeremy J JJ White Jessica K JK Turro Claudia C

Chemical communications (Cambridge, England) 20180501 41

Ru(ii)-polypyridyl cages with sterically bulky bidentate ligands provide efficient photochemical release of the anticancer drug imatinib using low energy visible light, imparting spatiotemporal control over drug bioavailability. The light-activated drug release is maintained when the Ru(ii) cage is covalently coupled to an antibody, which is expected to localize selectively on the tumor. ...[more]

PMID: 29707728

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Project description:Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by progressive and irreversible damage to the brain. One of the hallmarks of the disease is the presence of both soluble and insoluble aggregates of the amyloid beta (Aβ) peptide in the brain, and these aggregates are considered central to disease progression. Thus, the development of small molecules capable of modulating Aβ peptide aggregation may provide critical insight into the pathophysiology of AD. In this work we investigate how photoactivation of three distorted Ru(ii) polypyridyl complexes (Ru1-3) alters the aggregation profile of the Aβ peptide. Photoactivation of Ru1-3 results in the loss of a 6,6'-dimethyl-2,2'-bipyridyl (6,6'-dmb) ligand, affording cis-exchangeable coordination sites for binding to the Aβ peptide. Both Ru1 and Ru2 contain an extended planar imidazo[4,5-f][1,10]phenanthroline ligand, as compared to a 2,2'-bipyridine ligand for Ru3, and we show that the presence of the phenanthroline ligand promotes covalent binding to Aβ peptide His residues, and in addition, leads to a pronounced effect on peptide aggregation immediately after photoactivation. Interestingly, all three complexes resulted in a similar aggregate size distribution at 24 h, forming insoluble amorphous aggregates as compared to significant fibril formation for peptide alone. Photoactivation of Ru1-3 in the presence of pre-formed Aβ1-42 fibrils results in a change to amorphous aggregate morphology, with Ru1 and Ru2 forming large amorphous aggregates immediately after activation. Our results show that photoactivation of Ru1-3 in the presence of either monomeric or fibrillar Aβ1-42 results in the formation of large amorphous aggregates as a common endpoint, with Ru complexes incorporating the extended phenanthroline ligand accelerating this process and thereby limiting the formation of oligomeric species in the initial stages of the aggregation process that are reported to show considerable toxicity.

Project description:Effective delivery of luminescent probes for cell imaging requires both cell membrane permeation and directing to discrete target organelles. Combined, these requirements can present a significant challenge for metal complex luminophores, that have excellent properties as imaging probes but typically show poor membrane permeability. Here, we report on highly luminescent Ruthenium polypyridyl complexes based on the parent; [Ru(dpp)2(x-ATAP)](PF6)2 structure, where dpp is 4,7-diphenyl-1,10-phenanthroline and x-ATAP is 5-amino-1,10-phenanthroline with pendant alkyl-acetylthio chains of varying length; where x is 6; 5-Amido-1,10-phenanthroline-(6-acetylthio-hexanyl). 8; 5-Amido-1,10-phenanthroline-(8-acetylthio-octanyl). 11; 5-Amido-1,10-phenanthroline-(11-acetylthio-undecanyl); and 16; 5-Amido-1,10-phenanthroline-(16-acetylthio-hexadecanyl). Soluble in organic media, the alkyl-acetylthiolated complexes form nanoaggregates of low polydispersity in aqueous solution. From dynamic light scattering the nanoaggregate diameter was measured as 189 nm and 135 nm for 5 × 10-6 M aqueous solutions of [Ru(dpp)2(N∧N)](PF6)2 with the hexadecanoyl and hexanyl tails respectivly. The nanoaggregate exhibited dual exponential emission decays with kinetics that matched closely those of the [Ru(dpp)2(16-ATAP)]2+ incorporated into the membrane of a DPPC liposome. Cell permeability and distribution of [Ru(dpp)2(11-ATAP)]2+ or [Ru(dpp)2(16-ATAP)]2+ were evaluated in detail in live HeLa and CHO cell lines and it was found from aqueous media, that the nanoaggregate complexes spontaneously cross the membrane of mammalian cells. This process seems, on the basis of temperature dependent studies to be activated. Fluorescence imaging of live cells reveal that the complexes localize highly specifically within organelles and that organelle localization changes dramatically in switching the pendent alkyl chains from C16 to C11 as well as on cell line identity. Our data suggests that building metal complexes capable of self-assembling into nano-dimensional vesicles in this way may be a useful means of promoting cell membrane permeability and driving selective targeting that is facile and relatively low cost compared to use of biomolecular vectors.

Dataset Information

Photoactivation of imatinib-antibody conjugate using low-energy visible light from Ru(ii)-polypyridyl cages.

Publications

Photoactivation of imatinib-antibody conjugate using low-energy visible light from Ru(ii)-polypyridyl cages.

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