Disulfide Conjugation Chemistry: A Mixed Blessing for Therapeutic Drug delivery?

Danial, Maarten; Postma, Almar

doi:10.4155/tde-2017-0003

Cited by 19 publications

(15 citation statements)

References 24 publications

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“…10 Whilst hindered disulfides have (to some extent) addressed the issue of stability of disulfide linkers in blood they are, to the best of our knowledge, not viable for application as extracellular cleavable linkers, i.e., they only cleave post-internalisation into an intracellular environment. 15,16 Val-Cit linkers are also susceptible to other protease-related activity, which can hamper their stability in blood plasma. 10 An alternative system explored within the context of cleavable linkers is that of maleimide-thiol linkages ( Fig.…”

mentioning

confidence: 99%

Use of pyridazinediones as extracellular cleavable linkers through reversible cysteine conjugation

et al. 2019

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mentioning

confidence: 99%

Use of pyridazinediones as extracellular cleavable linkers through reversible cysteine conjugation

et al. 2019

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“…A number of elegant conjugation chemistries have been developed for precise therapeutic release in response to certain cellular environments or stimuli, including redox responsive disulfide bonds which are known to cleave in the presence of intracellular levels of glutathione. 73,74 For successful DNA transfection the DNA needs to pass the double membrane nuclear envelope and enter the nucleus to be transcribed.…”

Section: Intracellular Barriersmentioning

confidence: 99%

Branched and Dendritic Polymer Architectures: Functional Nanomaterials for Therapeutic Delivery

Cook

Perrier

2019

Adv Funct Materials

124

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Barriers to therapeutic transport in biological systems can prevent accumulation of drugs at the intended site, thus limiting the therapeutic effect against various diseases. Advances in synthetic chemistry techniques have recently increased the accessibility of complex polymer architectures for drug delivery systems, including branched polymer architectures. This article first outlines drug delivery concepts, and then defines and illustrates all forms of branched polymers including highly branched polymers, hyperbranched polymers, dendrimers, and branched–linear hybrid polymers. Many new types of branched and dendritic polymers continue to be reported; however, there is often confusion about how to accurately describe these complex polymer architectures, particularly in the interdisciplinary field of nanomedicine where not all researchers have in‐depth polymer chemistry backgrounds. In this context, the present review describes and compares different branched polymer architectures and their application in therapeutic delivery in a simple and easy‐to‐understand way, with the aim of appealing to a multidisciplinary audience.

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“…Significant efforts to apply disulfide linkers led to the approval and clinical testing of several agents . These include the first approved ADC, the acute myeloid leukemia therapy gemtuzumab ozogamicin (Mylotarg), which contains a hindered disulfide. − However, some reports suggest that certain disulfides can be cleaved in circulation, leading to premature payload release and nonspecific uptake. − Concurrent with these efforts, cathepsin-cleavable peptide linkers have been incorporated in four approved ADCs, including the Hodgkins lymphoma drug brentuximab vedotin (Adcetris). While these two classes of linkers have been investigated extensively, we are not aware of any reports directly comparing the relative cleavage of payloads in a solid tumor setting.…”

Section: Resultsmentioning

confidence: 99%

“…[44][45][46] However, some reports suggest that disulfides can be cleaved in circulation, leading to premature payload release and non-specific uptake. [46][47][48][49] Concurrent with these efforts, cathepsin-cleavable peptide linkers have been incorporated in four approved ADCs, including the Hodgins lymphoma drug Brentuximab Vedotin (Adcetris). While these two classes of linkers have been investigated extensively, we are not aware of any reports directly comparing the relative cleavage of payloads in a solid tumor setting.…”

Section: Quantitative Comparison Of Adc Linkersmentioning

confidence: 99%

Targeted Fluorogenic Cyanine Carbamates Enable In Vivo Analysis of Antibody–Drug Conjugate Linker Chemistry

et al. 2021

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Antibody-drug conjugates (ADCs) are a rapidly emerging therapeutic platform. The chemical linker between the antibody and the drug payload plays an essential role in the efficacy and tolerability of these agents. New methods that quantitively assess cleavage efficiency in complex tissue settings could provide valuable insights into the ADC design process. Here we report the development of a near-infrared (NIR) optical imaging approach that measures the site and extent of linker cleavage in mouse models. This approach is enabled by a superior variant of our recently devised cyanine carbamate (CyBam) platform. We identify a novel tertiary amine-containing norcyanine, the product of CyBam cleavage, that exhibits dramatically increased cellular signal due to improved cellular permeability and lysosomal accumulation. The resulting cyanine lysosome-targeting carbamates (CyLBams) are ~50X brighter in cells, and we find this strategy is essential for high-contrast in vivo targeted imaging. Finally, we compare a panel of several common ADC linkers across two antibodies and tumor models. These studies indicate that cathepsin-cleavable linkers provide dramatically higher tumor activation relative to hindered or non-hindered disulfides -an observation that is only apparent with in vivo imaging. This strategy enables quantitative comparisons of cleavable linker chemistries in complex tissue settings with implications across the drug delivery landscape.

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Disulfide Conjugation Chemistry: A Mixed Blessing for Therapeutic Drug delivery?

Cited by 19 publications

References 24 publications

Use of pyridazinediones as extracellular cleavable linkers through reversible cysteine conjugation

Use of pyridazinediones as extracellular cleavable linkers through reversible cysteine conjugation

Branched and Dendritic Polymer Architectures: Functional Nanomaterials for Therapeutic Delivery

Targeted Fluorogenic Cyanine Carbamates Enable In Vivo Analysis of Antibody–Drug Conjugate Linker Chemistry

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