Non-covalent hitchhiking on endogenous carriers as a protraction mechanism for antiviral macromolecular prodrugs

Camilla Kaas Frich; Franziska Krüger; Raoul Walther; Cecilie Domar; Anna H. F. Andersen; Anne  Tvilum; Frederik Dagnæs-Hansen; Paul W. Denton; Martin Tolstrup; Søren Riis Paludan; jJan Münch; Alexander N. Zelikin

doi:10.1016/j.jconrel.2018.12.016

Non-covalent hitchhiking on endogenous carriers as a protraction mechanism for antiviral macromolecular prodrugs

Camilla Kaas Frich, Franziska Krüger, Raoul Walther, Cecilie Domar, Anna H. F. Andersen, Anne Tvilum, Frederik Dagnæs-Hansen, Paul W. Denton, Martin Tolstrup, Søren Riis Paludan, jJan Münch, Alexander N. Zelikin

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

17 Citations (Scopus)

Abstract

Albumin is a highly successful tool of drug delivery providing drastically extended body and blood residence time for the associated cargo, but it only traffics single drug copies at a time. In turn, macromolecular prodrugs (MP) are advantaged in carrying a high drug payload but offering only a modest extension of residence time to the conjugated drugs. In this work, we engineer MP to contain terminal groups that bind to albumin via non-covalent association and reveal that this facile measure affords a significant protraction for the associated polymers. This methodology is applied to MP of acyclovir, a successful drug against herpes simplex virus infection but with poor pharmacokinetics. Resulting albumin-affine MP were efficacious agents against herpes simplex virus type 2 (HSV-2) both in vitro and in vivo. In the latter case, sub-cutaneous administration of MP resulted in local (vaginal) antiviral effects and a systemic protection. Presented benefits of non-covalent association with albumin are readily transferrable to a wide variety of MP in development for drug delivery as anticancer, anti-inflammatory, and anti-viral measures.

Original language	English
Journal	Journal of Controlled Release
Volume	294
Pages (from-to)	298-310
Number of pages	13
ISSN	0168-3659
DOIs	https://doi.org/10.1016/j.jconrel.2018.12.016
Publication status	Published - 28 Jan 2019

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10.1016/j.jconrel.2018.12.016

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Frich, C. K., Krüger, F., Walther, R., Domar, C., Andersen, A. H. F., Tvilum, A., Dagnæs-Hansen, F., Denton, P. W., Tolstrup, M., Paludan, S. R., Münch, JJ., & Zelikin, A. N. (2019). Non-covalent hitchhiking on endogenous carriers as a protraction mechanism for antiviral macromolecular prodrugs. Journal of Controlled Release, 294, 298-310. https://doi.org/10.1016/j.jconrel.2018.12.016

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title = "Non-covalent hitchhiking on endogenous carriers as a protraction mechanism for antiviral macromolecular prodrugs",

abstract = "Albumin is a highly successful tool of drug delivery providing drastically extended body and blood residence time for the associated cargo, but it only traffics single drug copies at a time. In turn, macromolecular prodrugs (MP) are advantaged in carrying a high drug payload but offering only a modest extension of residence time to the conjugated drugs. In this work, we engineer MP to contain terminal groups that bind to albumin via non-covalent association and reveal that this facile measure affords a significant protraction for the associated polymers. This methodology is applied to MP of acyclovir, a successful drug against herpes simplex virus infection but with poor pharmacokinetics. Resulting albumin-affine MP were efficacious agents against herpes simplex virus type 2 (HSV-2) both in vitro and in vivo. In the latter case, sub-cutaneous administration of MP resulted in local (vaginal) antiviral effects and a systemic protection. Presented benefits of non-covalent association with albumin are readily transferrable to a wide variety of MP in development for drug delivery as anticancer, anti-inflammatory, and anti-viral measures.",

author = "Frich, {Camilla Kaas} and Franziska Kr{\"u}ger and Raoul Walther and Cecilie Domar and Andersen, {Anna H. F.} and Anne Tvilum and Frederik Dagn{\ae}s-Hansen and Denton, {Paul W.} and Martin Tolstrup and Paludan, {S{\o}ren Riis} and jJan M{\"u}nch and Zelikin, {Alexander N.}",

year = "2019",

month = jan,

day = "28",

doi = "10.1016/j.jconrel.2018.12.016",

language = "English",

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Frich, CK, Krüger, F, Walther, R, Domar, C , Andersen, AHF, Tvilum, A, Dagnæs-Hansen, F, Denton, PW, Tolstrup, M , Paludan, SR, Münch, JJ & Zelikin, AN 2019, 'Non-covalent hitchhiking on endogenous carriers as a protraction mechanism for antiviral macromolecular prodrugs', Journal of Controlled Release, vol. 294, pp. 298-310. https://doi.org/10.1016/j.jconrel.2018.12.016

Non-covalent hitchhiking on endogenous carriers as a protraction mechanism for antiviral macromolecular prodrugs. / Frich, Camilla Kaas; Krüger, Franziska; Walther, Raoul et al.
In: Journal of Controlled Release, Vol. 294, 28.01.2019, p. 298-310.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Non-covalent hitchhiking on endogenous carriers as a protraction mechanism for antiviral macromolecular prodrugs

AU - Frich, Camilla Kaas

AU - Krüger, Franziska

AU - Walther, Raoul

AU - Domar, Cecilie

AU - Andersen, Anna H. F.

AU - Tvilum, Anne

AU - Dagnæs-Hansen, Frederik

AU - Denton, Paul W.

AU - Tolstrup, Martin

AU - Paludan, Søren Riis

AU - Münch, jJan

AU - Zelikin, Alexander N.

PY - 2019/1/28

Y1 - 2019/1/28

N2 - Albumin is a highly successful tool of drug delivery providing drastically extended body and blood residence time for the associated cargo, but it only traffics single drug copies at a time. In turn, macromolecular prodrugs (MP) are advantaged in carrying a high drug payload but offering only a modest extension of residence time to the conjugated drugs. In this work, we engineer MP to contain terminal groups that bind to albumin via non-covalent association and reveal that this facile measure affords a significant protraction for the associated polymers. This methodology is applied to MP of acyclovir, a successful drug against herpes simplex virus infection but with poor pharmacokinetics. Resulting albumin-affine MP were efficacious agents against herpes simplex virus type 2 (HSV-2) both in vitro and in vivo. In the latter case, sub-cutaneous administration of MP resulted in local (vaginal) antiviral effects and a systemic protection. Presented benefits of non-covalent association with albumin are readily transferrable to a wide variety of MP in development for drug delivery as anticancer, anti-inflammatory, and anti-viral measures.

AB - Albumin is a highly successful tool of drug delivery providing drastically extended body and blood residence time for the associated cargo, but it only traffics single drug copies at a time. In turn, macromolecular prodrugs (MP) are advantaged in carrying a high drug payload but offering only a modest extension of residence time to the conjugated drugs. In this work, we engineer MP to contain terminal groups that bind to albumin via non-covalent association and reveal that this facile measure affords a significant protraction for the associated polymers. This methodology is applied to MP of acyclovir, a successful drug against herpes simplex virus infection but with poor pharmacokinetics. Resulting albumin-affine MP were efficacious agents against herpes simplex virus type 2 (HSV-2) both in vitro and in vivo. In the latter case, sub-cutaneous administration of MP resulted in local (vaginal) antiviral effects and a systemic protection. Presented benefits of non-covalent association with albumin are readily transferrable to a wide variety of MP in development for drug delivery as anticancer, anti-inflammatory, and anti-viral measures.

U2 - 10.1016/j.jconrel.2018.12.016

DO - 10.1016/j.jconrel.2018.12.016

M3 - Journal article

C2 - 30552954

SN - 0168-3659

VL - 294

SP - 298

EP - 310

JO - Journal of Controlled Release

JF - Journal of Controlled Release

ER -