Photophysics and Release Kinetics of Enzyme-Activatable Optical Probes Based on H-Dimerized Fluorophores on Self-Immolative Linkers

Sloniec, Jagoda; Resch‐Genger, Ute; Hennig, Andréas

doi:10.1021/jp409388b

Cited by 14 publications

(24 citation statements)

References 70 publications

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“…Enzyme activationp roved to be highly sensitivet o sterich indrance:T he half-life associatedw ithe nzymatic activationb yp lasmind ropped from 42 to 4min whent he activationw as combinedw itht he cyclizationo fN , N ' -ethylenediamine.A ntibody3 8C2-mediateda ctivation by ar etroaldol retro-Michael reactionhas been implementedtoliberate drugs or 4-nitrophenol (entry2,T able 2). [42,45,[100][101][102][103] Penicillin Ga midase (PGA) andB ovine Serum Albumin( BSA) have beenu sedt oc leave the phenylacetamide moiety (entry3,T able2) [34,38,44,45,55,92,96,99,100,[104][105][106][107][108] and ac arbamate [109] (entry 4, Table2), andl iberatev ariouss ubstrates. b-Glucuronidase (b-GUS) [33,40,43] (entry 5, Table2)a nd b-Galactosidase [110][111][112] (entry 6, Table2)h aveb eens uccessfully implementedtospecifically deliver bioactive substrates in tumors and in bacteria.…”

Section: Enzymatic Activationmentioning

confidence: 99%

“…Antibody 38C2‐mediated activation by a retro‐aldol retro‐Michael reaction has been implemented to liberate drugs or 4‐nitrophenol (entry 2, Table 2). 42, 45, 100–103 Penicillin G amidase (PGA) and Bovine Serum Albumin (BSA) have been used to cleave the phenylacetamide moiety (entry 3, Table 2)34, 38, 44, 45, 55, 92, 96, 99, 100, 104–108 and a carbamate109 (entry 4, Table 2), and liberate various substrates. β‐Glucuronidase (β‐GUS)33, 40, 43 (entry 5, Table 2) and β‐Galactosidase110–112 (entry 6, Table 2) have been successfully implemented to specifically deliver bioactive substrates in tumors and in bacteria 110.…”

Section: Kinetic Analysis Of Self‐immolationmentioning

confidence: 99%

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Self‐Immolative Spacers: Kinetic Aspects, Structure–Property Relationships, and Applications

et al. 2015

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Self-immolative spacers are covalent assemblies tailored to correlate the cleavage of two chemical bonds after activation of a protective part in a precursor: Upon stimulation, the protective moiety is removed, which generates a cascade of disassembling reactions leading to the temporally sequential release of smaller molecules. Originally introduced to overcome limitations for drug delivery, self-immolative spacers have gained wide interest in medicinal chemistry, analytical chemistry, and material science. For most applications, the kinetics of the disassembly of the activated self-immolative spacer governs functional properties. This Review addresses kinetic aspects of self-immolation. It provides information for selecting a particular self-immolative motif for a specific demand. Moreover, it should help researchers design kinetic experiments and fully exploit the rich perspectives of self-immolative spacers.

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Section: Enzymatic Activationmentioning

confidence: 99%

Section: Kinetic Analysis Of Self‐immolationmentioning

confidence: 99%

Self‐Immolative Spacers: Kinetic Aspects, Structure–Property Relationships, and Applications

et al. 2015

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“…42, 45, 100–103 Durch Verwendung von Penicillin‐G‐Amidase (PGA) und Rinderserumalbumin (BSA) wurde eine Phenylacetamideinheit (Nr. 3, Tabelle 2)34, 38, 44, 45, 55, 92, 96, 99, 100, 104–108 bzw. ein Carbamat109 (Nr.…”

Section: Kinetische Analyse Der Selbstzerlegungunclassified

Selbstzerlegende Spacer: kinetische Aspekte, Struktur‐Eigenschafts‐Beziehungen und Anwendungen

et al. 2015

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Hintergrundinformationen zu diesem Beitrag sind sind im WWW unter http://dx.Abbildung 2. Selbstzerlegende Spacer, deren Abbau auf einer Elektronenkaskade (orthooder para-Delokalisierung) beruht. PG = Schutzgruppe; X = O, NH oder S; LG = Abgangsgruppe, die zur gewünschten Verbindung gehçrt. a) 1,4-Eliminierung; [52][53][54]71] b) 1,6-Eliminierung; [52,54,55,71] c, d) 1,8-Eliminierung. [44,56,57] Bemerkenswerterweise laufen die 1,8-Eliminierung mit einem Naphthalinring (e) und die 1,10-Eliminierung mit einem Biphenyl (f) nicht ab, auch nicht mit einer starken Donorgruppe wie der Aminogruppe. [58] Selbstzerlegende Spacer Angewandte Chemie 7603

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“…New near infrared (NIR) probes, highly sensitive tools for the diagnosis of such conditions, have two fluorescent, self-quenching dyes attached to the probe via a specific self-immolative linker. This linker is cleaved in the targeted tissue, thereby liberating the dye and resulting in a specific fluorescent signal [ 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of ¹¹¹In-Labelled Exendin-4 Derivatives Containing Different Meprin β-Specific Cleavable Linkers

et al. 2015

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BackgroundCleavable linkers, which are specifically cleaved by defined conditions or enzymes, are powerful tools that can be used for various purposes. Amongst other things, they have been successfully used to deliver toxic payloads as prodrugs into target tissues. In this work novel linker sequences targeting meprin β, a metalloprotease expressed in the kidney brush-border membrane, were designed and included in the sequence of three radiolabelled exendin-4 derivatives. As radiolabelled exendin-4 derivatives strongly accumulate in the kidneys, we hypothesised that specific cleavage of the radiolabelled moiety at the kidney brush-border membrane would allow easier excretion of the activity into the urine and therefore improve the pharmacological properties of the peptide.ResultsThe insertion of a cleavable linker did not negatively influence the in vitro properties of the peptides. They showed a good affinity to the GLP-1 receptor expressed in CHL cells, a high internalisation and sufficiently high stability in fresh human blood plasma. In vitro digestion with recombinant meprin β rapidly metabolised the corresponding linker sequences. After 60 min the majority of the corresponding peptides were digested and at the same time the anticipated fragments were formed. The peptides were also quickly metabolised in CD1 nu/nu mouse kidney homogenates. Immunofluorescence staining of meprin β in kidney sections confirmed the expression of the protease in the kidney brush-border membrane. Biodistribution in GLP-1 receptor positive tumour-xenograft bearing mice revealed high specific uptake of the 111In-labelled tracers in receptor positive tissue. Accumulation in the kidneys, however, was still high and comparable to the lead compound 111In-Ex4NOD40.ConclusionIn conclusion, we show that the concept of cleavable linkers specific for meprin β is feasible, as the peptides are rapidly cleaved by the enzyme while retaining their biological properties.

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Photophysics and Release Kinetics of Enzyme-Activatable Optical Probes Based on H-Dimerized Fluorophores on Self-Immolative Linkers

Cited by 14 publications

References 70 publications

Self‐Immolative Spacers: Kinetic Aspects, Structure–Property Relationships, and Applications

Self‐Immolative Spacers: Kinetic Aspects, Structure–Property Relationships, and Applications

Selbstzerlegende Spacer: kinetische Aspekte, Struktur‐Eigenschafts‐Beziehungen und Anwendungen

Evaluation of ¹¹¹In-Labelled Exendin-4 Derivatives Containing Different Meprin β-Specific Cleavable Linkers

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