Bi‐Enzymatic Embolization Beads for Two‐Armed Enzyme‐Prodrug Therapy

Morten Tobias Jarlstad Olesen; Anna Winther; Betina Fejerskov; Frederik Dagnæs-Hansen; Ulf Simonsen; Alexander N. Zelikin

doi:10.1002/adtp.201800023

Bi‐Enzymatic Embolization Beads for Two‐Armed Enzyme‐Prodrug Therapy

Morten Tobias Jarlstad Olesen, Anna Winther, Betina Fejerskov, Frederik Dagnæs-Hansen, Ulf Simonsen, Alexander N. Zelikin

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

11 Citationer (Scopus)

Abstract

Embolic beads, a successful tool for localized, site-specific drug delivery, are engineered herein to contain the toolbox of enzyme-prodrug therapy (EPT). EPT offers facile means to synthesize diverse drugs at their nominated concentrations; individually, in sequence, or in a combination. The authors investigate alginate beads as embolic bodies and screen alginate type and bead production parameters as factors to control activity of the immobilized enzymes. Engineered embolic bodies are armed with bi-enzymatic EPT such that two enzymes perform biosynthesis of drugs with an independent control over each enzyme. Enzymatic synthesis of nitric oxide (NO) performed by embolic bodies is accomplished herein for the first time and is fine-tuned such that flux of NO afforded by the beads matches that of healthy human endothelium. Ensuing vasodilation is illustrated ex vivo using rat mesenteric arteries. Independently, the production of SN-38 is used to control the antiproliferative effects elicited by the beads. Bi-enzymatic EPT engineered into embolic bodies thus affords opportunities for combination therapy and personalized treatment (adjusted combinations and concentrations of drugs) that go well beyond the state-of-the-art of current embolic bodies and hold much promise for biomedical applications, specifically the treatment of hepatocellular carcinoma.

Originalsprog	Dansk
Artikelnummer	1800023
Tidsskrift	Advanced Therapeutics
Vol/bind	1
Nummer	4
Antal sider	9
ISSN	2366-3987
DOI	https://doi.org/10.1002/adtp.201800023
Status	Udgivet - 1 aug. 2018

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10.1002/adtp.201800023

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Citationsformater

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abstract = "Embolic beads, a successful tool for localized, site-specific drug delivery, are engineered herein to contain the toolbox of enzyme-prodrug therapy (EPT). EPT offers facile means to synthesize diverse drugs at their nominated concentrations; individually, in sequence, or in a combination. The authors investigate alginate beads as embolic bodies and screen alginate type and bead production parameters as factors to control activity of the immobilized enzymes. Engineered embolic bodies are armed with bi-enzymatic EPT such that two enzymes perform biosynthesis of drugs with an independent control over each enzyme. Enzymatic synthesis of nitric oxide (NO) performed by embolic bodies is accomplished herein for the first time and is fine-tuned such that flux of NO afforded by the beads matches that of healthy human endothelium. Ensuing vasodilation is illustrated ex vivo using rat mesenteric arteries. Independently, the production of SN-38 is used to control the antiproliferative effects elicited by the beads. Bi-enzymatic EPT engineered into embolic bodies thus affords opportunities for combination therapy and personalized treatment (adjusted combinations and concentrations of drugs) that go well beyond the state-of-the-art of current embolic bodies and hold much promise for biomedical applications, specifically the treatment of hepatocellular carcinoma.",

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AU - Olesen, Morten Tobias Jarlstad

AU - Winther, Anna

AU - Fejerskov, Betina

AU - Dagnæs-Hansen, Frederik

AU - Simonsen, Ulf

AU - Zelikin, Alexander N.

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N2 - Embolic beads, a successful tool for localized, site-specific drug delivery, are engineered herein to contain the toolbox of enzyme-prodrug therapy (EPT). EPT offers facile means to synthesize diverse drugs at their nominated concentrations; individually, in sequence, or in a combination. The authors investigate alginate beads as embolic bodies and screen alginate type and bead production parameters as factors to control activity of the immobilized enzymes. Engineered embolic bodies are armed with bi-enzymatic EPT such that two enzymes perform biosynthesis of drugs with an independent control over each enzyme. Enzymatic synthesis of nitric oxide (NO) performed by embolic bodies is accomplished herein for the first time and is fine-tuned such that flux of NO afforded by the beads matches that of healthy human endothelium. Ensuing vasodilation is illustrated ex vivo using rat mesenteric arteries. Independently, the production of SN-38 is used to control the antiproliferative effects elicited by the beads. Bi-enzymatic EPT engineered into embolic bodies thus affords opportunities for combination therapy and personalized treatment (adjusted combinations and concentrations of drugs) that go well beyond the state-of-the-art of current embolic bodies and hold much promise for biomedical applications, specifically the treatment of hepatocellular carcinoma.

AB - Embolic beads, a successful tool for localized, site-specific drug delivery, are engineered herein to contain the toolbox of enzyme-prodrug therapy (EPT). EPT offers facile means to synthesize diverse drugs at their nominated concentrations; individually, in sequence, or in a combination. The authors investigate alginate beads as embolic bodies and screen alginate type and bead production parameters as factors to control activity of the immobilized enzymes. Engineered embolic bodies are armed with bi-enzymatic EPT such that two enzymes perform biosynthesis of drugs with an independent control over each enzyme. Enzymatic synthesis of nitric oxide (NO) performed by embolic bodies is accomplished herein for the first time and is fine-tuned such that flux of NO afforded by the beads matches that of healthy human endothelium. Ensuing vasodilation is illustrated ex vivo using rat mesenteric arteries. Independently, the production of SN-38 is used to control the antiproliferative effects elicited by the beads. Bi-enzymatic EPT engineered into embolic bodies thus affords opportunities for combination therapy and personalized treatment (adjusted combinations and concentrations of drugs) that go well beyond the state-of-the-art of current embolic bodies and hold much promise for biomedical applications, specifically the treatment of hepatocellular carcinoma.

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