Enhanced cellular uptake and photochemotherapeutic potential of a lipophilic strained Ru(<scp>ii</scp>) polypyridyl complex

Mehanna, Stephanie; Mansour, Najwa; Audi, Hassib; Bodman‐Smith, Kikki; Mroueh, Mohamad; Taleb, Robin I.; Daher, Costantine F.; Khnayzer, Rony S.

doi:10.1039/c9ra02615k

Cited by 34 publications

(27 citation statements)

References 70 publications

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“…In this context, we applied a combined experimental and theoretical approach to design new suitable Ru-based PDT PSs. Based on the already well-established biological activity of the complex [Ru(phen) 3 ] 2+ (phen = 1,10-phenanthroline) as a minor groove binder and [Ru(bphen) 3 ] 2+ (bphen = 4,7-diphenyl-1,10-phenanthroline) as a mitochondria and lysosome targeting agent and their ability to be effective PDT PSs, − we decided to use [Ru(phen) 2 (bipy)] 2+ and [Ru(bphen) 2 (bipy)] 2+ (bipy = 2,2′-bipyridine) derivatives as basic scaffolds. In this investigation, the electronic properties, the origin, and the magnitude of red shift toward the biologic spectral window are disclosed.…”

Section: Introductionmentioning

confidence: 99%

Rationally Designed Long-Wavelength Absorbing Ru(II) Polypyridyl Complexes as Photosensitizers for Photodynamic Therapy

et al. 2020

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The utilization of photodynamic therapy (PDT) for the treatment of various types of cancer has gained increasing attention over the last decades. Despite the clinical success of approved photosensitizers (PSs), their application is sometimes limited due to poor water solubility, aggregation, photodegradation, and slow clearance from the body. To overcome these drawbacks, research efforts are devoted toward the development of metal complexes and especially Ru(II) polypyridine complexes based on their attractive photophysical and biological properties. Despite the recent research developments, the vast majority of complexes utilize blue or UV-A light to obtain a PDT effect, limiting the penetration depth inside tissues and, therefore, the possibility to treat deep-seated or large tumors. To circumvent these drawbacks, we present the first example of a DFT guided search for efficient PDT PSs with a substantial spectral red shift toward the biological spectral window. Thanks to this design, we have unveiled a Ru(II) polypyridine complex that causes phototoxicity in the very low micromolar to nanomolar range at clinically relevant 595 nm, in monolayer cells as well as in 3D multicellular tumor spheroids.

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Section: Introductionmentioning

confidence: 99%

Rationally Designed Long-Wavelength Absorbing Ru(II) Polypyridyl Complexes as Photosensitizers for Photodynamic Therapy

et al. 2020

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“…Bathophenanthroline (BPhen) has been frequently used in ruthenium complexes for its lipophilic properties (20, 25–27). [(BPhen) 2 Ru(dppz)] 2+ was used to study the mechanism of cellular uptake for ruthenium complexes due to its luminescence and good uptake into cells with log P = 1.3 which is significantly better than [(phen) 2 Ru(dppz)] 2+ with log P = −1.48 (28, 29).…”

Section: Introductionmentioning

confidence: 99%

Light‐responsive and Protic Ruthenium Compounds Bearing Bathophenanthroline and Dihydroxybipyridine Ligands Achieve Nanomolar Toxicity towards Breast Cancer Cells^†

Oladipupo

Brown

Lamb

et al. 2021

Photochem & Photobiology

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We report new ruthenium complexes bearing the lipophilic bathophenanthroline (BPhen) ligand and dihydroxybipyridine (dhbp) ligands which differ in the placement of the OH groups ([(BPhen)2Ru(n,n′‐dhbp)]Cl2 with n = 6 and 4 in 1A and 2A, respectively). Full characterization data are reported for 1A and 2A and single crystal X‐ray diffraction for 1A. Both 1A and 2A are diprotic acids. We have studied 1A, 1B, 2A, and 2B (B = deprotonated forms) by UV‐vis spectroscopy and 1 photodissociates, but 2 is light stable. Luminescence studies reveal that the basic forms have lower energy 3MLCT states relative to the acidic forms. Complexes 1A and 2A produce singlet oxygen with quantum yields of 0.05 and 0.68, respectively, in acetonitrile. Complexes 1 and 2 are both photocytotoxic toward breast cancer cells, with complex 2 showing EC50 light values as low as 0.50 μM with PI values as high as >200 vs. MCF7. Computational studies were used to predict the energies of the 3MLCT and 3MC states. An inaccessible 3MC state for 2B suggests a rationale for why photodissociation does not occur with the 4,4′‐dhbp ligand. Low dark toxicity combined with an accessible 3MLCT state for 1O2 generation explains the excellent photocytotoxicity of 2.

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“…In this context, we applied a combined experimental and theoretical approach to design new suitable Ru-based PDT PSs. Based on the already well-established biological activity of the complex [Ru(phen)3] 2+ (phen = 1,10-phenanthroline) as a minor groove binder 41 and [Ru(bphen)3] 2+ (bphen = 4,7-diphenyl-1,10-phenanthroline) as a mitochondria and lysosome targeting agent 42 and their ability to be effective PDT PSs [43][44][45] , we decided to use [Ru(phen)2(bipy)] 2+ and [Ru(bphen)2(bipy)] 2+ (bipy = 2,2'-bipyridine) derivatives as basic scaffolds. In this investigation, the electronic properties, the origin, and the magnitude of red shift towards the biologic spectral window are disclosed.…”

mentioning

confidence: 99%

Rationally Designed Long-Wavelength Absorbing Ru(II) Polypyridyl Complexes as Photosensitizers for Photodynamic Therapy

Karges¹,

Heinemann²,

Jakubaszek³

et al. 2019

Preprint

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The utilization of Photodynamic Therapy (PDT) for the treatment of various types of cancer has gained increasing attention over the last decades. Despite the clinical success of approved photosensitizers (PSs), their application is limited due to poor water solubility, aggregation, photodegradation, and slow clearance from the body. To overcome these drawbacks, research efforts are devoted towards the development of metal complexes and especially Ru(II) polypyridine complexes based on their attractive photophysical and biological properties. Despite the recent research developments, the vast majority of complexes utilize blue or UV-A light to obtain a PDT effect, limiting the penetration depth inside the tissue and therefore, the possibility to treat deep-seated or large tumors. To circumvent these drawbacks, we present the first example of the DFT guided search for efficient PDT PSs with a substantial spectral red shift towards the biological spectral window. Thanks to this design, we have unveiled a Ru(II) polypyridine complex, which causes phototoxicity in the very-low micromolar-to-nanomolar range at clinically relevant 595 nm, in monolayer cells as well as in 3D multicellular tumor spheroids.<br>

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Enhanced cellular uptake and photochemotherapeutic potential of a lipophilic strained Ru(ii) polypyridyl complex

Abstract: A strained Ru(ii) prodrug exhibited enhanced cellular uptake and phototoxicity due to its lipophilic properties.

Cited by 34 publications

References 70 publications

Rationally Designed Long-Wavelength Absorbing Ru(II) Polypyridyl Complexes as Photosensitizers for Photodynamic Therapy

Rationally Designed Long-Wavelength Absorbing Ru(II) Polypyridyl Complexes as Photosensitizers for Photodynamic Therapy

Light‐responsive and Protic Ruthenium Compounds Bearing Bathophenanthroline and Dihydroxybipyridine Ligands Achieve Nanomolar Toxicity towards Breast Cancer Cells^†

Rationally Designed Long-Wavelength Absorbing Ru(II) Polypyridyl Complexes as Photosensitizers for Photodynamic Therapy

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Enhanced cellular uptake and photochemotherapeutic potential of a lipophilic strained Ru(ii) polypyridyl complex

Abstract: A strained Ru(ii) prodrug exhibited enhanced cellular uptake and phototoxicity due to its lipophilic properties.

Cited by 34 publications

References 70 publications

Rationally Designed Long-Wavelength Absorbing Ru(II) Polypyridyl Complexes as Photosensitizers for Photodynamic Therapy

Rationally Designed Long-Wavelength Absorbing Ru(II) Polypyridyl Complexes as Photosensitizers for Photodynamic Therapy

Light‐responsive and Protic Ruthenium Compounds Bearing Bathophenanthroline and Dihydroxybipyridine Ligands Achieve Nanomolar Toxicity towards Breast Cancer Cells†

Rationally Designed Long-Wavelength Absorbing Ru(II) Polypyridyl Complexes as Photosensitizers for Photodynamic Therapy

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Light‐responsive and Protic Ruthenium Compounds Bearing Bathophenanthroline and Dihydroxybipyridine Ligands Achieve Nanomolar Toxicity towards Breast Cancer Cells^†