Bioorthogonal Prodrug–Antibody Conjugates for On-Target and On-Demand Chemotherapy

Bioorthogonal cleavage chemistry has been rapidly emerging as a powerful tool for manipulation and gain-of-function studies of biomolecules in living systems. While the initial bond formation-centered bioorthogonal reactions have been widely adopted for labeling, tracing, and capturing biomolecules, the newly developed bond cleavage-enabled bioorthogonal reactions have opened new possibilities for rescuing small molecules as well as biomacromolecules in living systems, allowing multidimensional controls over biological processes in vitro and in vivo . In this Outlook, we first summarized the development and applications of bioorthogonal cleavage reactions (BCRs) that restore the functions of chemical structures as well as more complex networks, including the liberation of prodrugs, release of bioconjugates, and in situ reactivation of intracellular proteins. As we embarked on this fruitful progress, we outlined the unmet scientific needs and future directions along this exciting avenue. We believe that the potential of BCRs will be further unleashed when combined with other frontier technologies, such as genetic code expansion and proximity-enabled chemical labeling.

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“… 120 The conjugated prodrug can be released first via the acidic tumor microenvironment and then further activated within the tumor cell. 120 …”

Section: Bcrs In Animalsmentioning

confidence: 99%

Unleashing the Power of Bond Cleavage Chemistry in Living Systems

et al. 2021

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“…For example, TCO-Dox (106) was linked to Her-2 antibody via a pH-sensitive linker. At low pH, this linker would be cleaved and TCO-Dox was released extracellularly and activated within tumor cells ( Figure 15D) [116]. This ADC was intravenously injected in MDA-MB-231-tumor-bearing mice and exerted cytotoxicity after the administration of tetrazines.…”

Section: Antibody-drug Conjugates (Adcs)mentioning

confidence: 99%

Activation and Delivery of Tetrazine-Responsive Bioorthogonal Prodrugs

Wang

Zhang

et al. 2020

Molecules

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Prodrugs, which remain inert until they are activated under appropriate conditions at the target site, have emerged as an attractive alternative to drugs that lack selectivity and show off-target effects. Prodrugs have traditionally been activated by enzymes, pH or other trigger factors associated with the disease. In recent years, bioorthogonal chemistry has allowed the creation of prodrugs that can be chemically activated with spatio-temporal precision. In particular, tetrazine-responsive bioorthogonal reactions can rapidly activate prodrugs with excellent biocompatibility. This review summarized the recent development of tetrazine bioorthogonal cleavage reaction and great promise for prodrug systems.

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“…4,5 These challenges have inspired the development of theranostic prodrug systems with integrated diagnostic and therapeutic functions for precision cancer medicine. [6][7][8][9][10][11][12] Such systems could respond to cancer-associated stimuli to activate diagnostic imaging and release therapeutic drugs at desired cancer sites. [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] However, despite the overexpression of certain factors in a tumor, endogenous stimuli generally feature nonspecific systemic distribution, 28,29 thus, unable to activate the prodrugs exclusively at the desired tumor location.…”

Section: Introductionmentioning

confidence: 99%