In Vivo Gold Complex Catalysis within Live Mice Tsubokura, Kazuki; Vong, Kenward K. H.; Pradipta, Ambara R. ...
Angewandte Chemie International Edition,
March 20, 2017, Letnik:
56, Številka:
13
Journal Article
Recenzirano
Metal complex catalysis within biological systems is largely limited to cell and bacterial systems. In this work, a glycoalbumin–AuIII complex was designed and developed that enables organ‐specific, ...localized propargyl ester amidation with nearby proteins within live mice. The targeted reactivity can be imaged through the use of Cy7.5‐ and TAMRA‐linked propargyl ester based fluorescent probes. This targeting system could enable the exploitation of other metal catalysis strategies for biomedical and clinical applications.
The first metal‐catalyzed reaction that proceeds within live mice is based on a targeting approach with glycans. Glycoalbumin–AuIII complexes can be accumulated in specific organs where they catalyze amide bond formation between a propargyl ester probe and amine groups on nearby proteins. The selective targeting was confirmed by whole body fluorescence imaging and analysis of dissected tissues.
This study presents the early framework of selective cell tagging (SeCT) therapy, which is the concept of preferentially labeling specific cells in vivo with chemical moieties that can elicit a ...therapeutic response. Using glycosylated artificial metalloenzyme (GArM)-based protein labeling, this study reports two separate functional strategies. In one approach, early tumor onset can be suppressed by tagging cancer cells in living mice with an integrin-blocking cyclic-Arg-Gly-Asp (cRGD) moiety, thereby disrupting cell adhesion onto the extracellular matrix. In another approach, tumor growth in mice can be reduced by tagging with a cytotoxic doxorubicin moiety. Subsequent cell death occurs following internalization and drug release. Overall, experiments have shown that mouse populations receiving the mixture of SeCT labeling reagents exhibited a significant delay/reduction in tumor onset and growth compared with controls. Highlighting its adaptability, this work represents a foundational step for further development of SeCT therapy and its potential therapeutic applications.
In the field of molecular imaging, selectivity for target cells is a key determinant of the degree of imaging contrast. Previously, we developed a pre-targeted method by which target cells could be ...selectively imaged using a labeled N-glycan that was ligated in situ with an integrin-targeted cyclic RGD peptide on the cell surface. Here we demonstrate the power of our method in discriminating various cancerous and non-cancerous cells that cannot be distinguished using conventional RGD ligands. Using four cyclic RGDyK peptides with various linker lengths with five N-glycans, we identify optimal combinations to discriminate six types of α
β
integrin-expressing cells on 96-well plates. The optimal combinations of RGD and N-glycan ligands for the target cells are fingerprinted on the plates, and then used to selectively image tumors in xenografted mouse models. Using this method, various N-glycan molecules, even those with millimolar affinities for their cognate lectins, could be used for selective cancer cell differentiation.
Structurally well‐defined heterogeneous N‐glycoclusters are prepared on albumin via a double click procedure. The number of glycan molecules present, in addition to the spatial arrangement of glycans ...in the heterogeneous glycoclusters, plays an important role in the in vivo kinetics and organ‐selective accumulation through glycan pattern recognition mechanisms.
Advanced glycation end products (AGEs) are associated with various diseases, especially during aging and the development of diabetes and uremia. To better understand these biological processes, ...investigation of the in vivo kinetics of AGEs, i.e., analysis of trafficking and clearance properties, was carried out by molecular imaging. Following the preparation of Cy7.5-labeled AGE-albumin and intravenous injection in BALB/cA-nu/nu mice, noninvasive fluorescence kinetics analysis was performed. In vivo imaging and fluorescence microscopy analysis revealed that non-enzymatic AGEs were smoothly captured by scavenger cells in the liver, i.e., Kupffer and other sinusoidal cells, but were unable to be properly cleared from the body. Overall, these results highlight an important link between AGEs and various disorders associated with them, which may serve as a platform for future research to better understand the processes and mechanisms of these disorders.
In Vivo Gold Complex Catalysis within Live Mice Tsubokura, Kazuki; Vong, Kenward K. H.; Pradipta, Ambara R. ...
Angewandte Chemie,
March 20, 2017, Letnik:
129, Številka:
13
Journal Article
Recenzirano
Metal complex catalysis within biological systems is largely limited to cell and bacterial systems. In this work, a glycoalbumin–AuIII complex was designed and developed that enables organ‐specific, ...localized propargyl ester amidation with nearby proteins within live mice. The targeted reactivity can be imaged through the use of Cy7.5‐ and TAMRA‐linked propargyl ester based fluorescent probes. This targeting system could enable the exploitation of other metal catalysis strategies for biomedical and clinical applications.
Die erste Metall‐katalysierte Reaktion in lebenden Mäusen basiert auf der Verwendung von Glycanen. Glycoalbumin‐AuIII‐Komplexe akkumulieren in spezifischen Organen, wo sie die Amidbildung zwischen einer Propargylestersonde und einem Amin eines nahen Proteins katalysieren. Die Organselektivität wurde durch Ganzkörperfluoreszenzbildgebung und die Analyse sezierter Gewebe bestätigt.
Cells are covered with a thick layer of sugar molecules known as glycans. Abnormal glycosylation is a hallmark of cancer, and hypersialylation increases tumor metastasis by promoting immune evasion ...and inducing tumor cell invasion and migration. Inhibiting sialylation is thus a potential anticancer treatment strategy. However, targeting sialic acids is difficult because of the lack of selective delivery tools. Here, we present a prodrug strategy for selectively releasing the global inhibitor of sialylation peracetylated 3F
ax
-Neu5Ac (PFN) in cancer cells using the reaction between phenyl azide and endogenous acrolein, which is overproduced in most cancer cells. The prodrug significantly suppressed tumor growth in mice as effectively as PFN without causing kidney dysfunction, which is associated with PFN. The use of sialylated glycans as immune checkpoints is gaining increasing attention, and the proposed method for precisely targeting aberrant sialylation provides a novel avenue for expanding current cancer treatments.
Chemical regulation of glycan synthesis at the targeted cancer cell surface in mice leading to significant anticancer effects without side effects.
Natural glycoconjugates that form glycocalyx play important roles in various biological processes based on cell surface recognition through pattern recognition mechanisms. This work represents a new ...synthesis‐based screening strategy to efficiently target the cancer cells by higher‐order glycan pattern recognition in both cells and intact animals (mice). The use of the very fast, selective, and effective RIKEN click reaction (6π‐azaelectrocyclization of unsaturated imines) allows to synthesize and screen various structurally well‐defined glycoalbumins containing two and eventually four different N‐glycan structures in a very short time. The importance of glycan pattern recognition is exemplified in both cell‐ and mouse‐based experiments. The use of pattern recognition mechanisms for cell targeting represents a novel and promising strategy for the development of diagnostic, prophylactic, and therapeutic agents for various diseases including cancers.
Very fast and selective RIKEN click reaction allows to synthesize and screen various structurally well‐defined glycoalbumins containing four different N‐glycan structures in a very short time. Pattern recognition mechanisms for cell targeting in mice represent a novel and promising strategy for diagnostic, prophylactic, and therapeutic agents for various diseases, including cancers.
In article number 2004831, Almira Kurbangalieva, Katsunori Tanaka, and co‐workers successfully apply the glycan pattern recognition mechanisms for developing a promising cancer targeting strategy in ...both cell‐ and mouse‐based experiments. The use of the very fast, selective and effective RIKEN click reaction allows to synthesize and screen various structurally well‐defined glycoalbumins containing four different N‐glycan structures in a very short time, as novel diagnostic, prophylactic, and therapeutic agents.
In vivo gold complex catalysis in living mice is described by K. Tanaka and co‐workers in their Communication on page 3579 ff. When attached to a glycocluster, gold catalysts can be delivered to a ...target organ in a higher organism where they perform a chemical transformation. This approach could enable the use of organometallic catalysts in therapy or diagnostics as they could catalyze the uncaging of therapeutic enzymes or the generation of active drugs at a target organ.
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