Multifunctional poly(methacrylate) polyplex libraries: A platform for gene delivery inspired by nature.

Hdl Handle:
http://hdl.handle.net/10034/605440
Title:
Multifunctional poly(methacrylate) polyplex libraries: A platform for gene delivery inspired by nature.
Authors:
Favretto, Marco E.; Krieg, Andreas; Schubert, Stephanie; Schubert, Ulrich; Brock, Roland
Abstract:
Polymer-based gene delivery systems have enormous potential in biomedicine, but their efficiency is often limited by poor biocompatibility. Poly(methacrylate)s (PMAs) are an interesting class of polymers which allow to explore structure-activity relationships of polymer functionalities for polyplex formation in oligonucleotide delivery. Here, we synthesized and tested a library of PMA polymers, containing functional groups contributing to the different steps of gene delivery, from oligonucleotide complexation to cellular internalization and endosomal escape. By variation of the molar ratios of the individual building blocks, the physicochemical properties of the polymers and polyplexes were fine-tuned to reduce toxicity as well as to increase activity of the polyplexes. To further enhance transfection efficiency, a cell-penetrating peptide (CPP)-like functionality was introduced on the polymeric backbone. With the ability to synthesize large libraries of polymers in parallel we also developed a workflow for a mid-to-high throughput screening, focusing first on safety parameters that are accessible by high-throughput approaches such as blood compatibility and toxicity towards host cells and only at a later stage on more laborious tests for the ability to deliver oligonucleotides. To arrive at a better understanding of the molecular basis of activity, furthermore, the effect of the presence of heparan sulfates on the surface of host cells was assessed and the mechanism of cell entry and intracellular trafficking investigated for those polymers that showed a suitable pharmacological profile. Following endocytic uptake, rapid endosomal release occurred. Interestingly, the presence of heparan sulfates on the cell surface had a negative impact on the activity of those polyplexes that were sensitive to decomplexation by heparin in solution. In summary, the screening approach identified two polymers, which form polyplexes with high stability and transfection capacity exceeding the one of poly(ethylene imine) also in the presence of serum.
Affiliation:
Department of Biochemistry, Radboud University Medical Centre, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands 2 Dutch Polymer Institute (DPI), Eindhoven, The Netherlands 3 Laboratory of Organic and Macromolecular Chemistry (IOMC), Friedrich Schiller University Jena, Jena, Germany 4 Jena Center for Soft Matter, Friedrich Schiller University Jena, Jena, Germany 5 Institute of Pharmacy, Pharmaceutical Technology, Friedrich Schiller University Jena, Jena, Germany
Citation:
Favretto, M. E., Kreig, A., Schubert, S., Schubert, U., & Brock, R. (2015). Multifunctional poly(methacrylate) polyplex libraries: A platform for gene delivery inspired by nature. Journal of Controlled Release, 209, 1-11. http://dx.doi.org/10.1016/j.jconrel.2015.04.005
Publisher:
Elsevier
Journal:
Journal of Controlled Release
Publication Date:
10-Jul-2015
URI:
http://hdl.handle.net/10034/605440
DOI:
10.1016/j.jconrel.2015.04.005
Additional Links:
http://www.sciencedirect.com/science/article/pii/S0168365915002230
Type:
Article
Language:
en
ISSN:
0168-3659
EISSN:
1873-4995
Appears in Collections:
Biological Sciences

Full metadata record

DC FieldValue Language
dc.contributor.authorFavretto, Marco E.en
dc.contributor.authorKrieg, Andreasen
dc.contributor.authorSchubert, Stephanieen
dc.contributor.authorSchubert, Ulrichen
dc.contributor.authorBrock, Rolanden
dc.date.accessioned2016-04-15T11:42:50Zen
dc.date.available2016-04-15T11:42:50Zen
dc.date.issued2015-07-10en
dc.identifier.citationFavretto, M. E., Kreig, A., Schubert, S., Schubert, U., & Brock, R. (2015). Multifunctional poly(methacrylate) polyplex libraries: A platform for gene delivery inspired by nature. Journal of Controlled Release, 209, 1-11. http://dx.doi.org/10.1016/j.jconrel.2015.04.005en
dc.identifier.issn0168-3659en
dc.identifier.doi10.1016/j.jconrel.2015.04.005en
dc.identifier.urihttp://hdl.handle.net/10034/605440en
dc.description.abstractPolymer-based gene delivery systems have enormous potential in biomedicine, but their efficiency is often limited by poor biocompatibility. Poly(methacrylate)s (PMAs) are an interesting class of polymers which allow to explore structure-activity relationships of polymer functionalities for polyplex formation in oligonucleotide delivery. Here, we synthesized and tested a library of PMA polymers, containing functional groups contributing to the different steps of gene delivery, from oligonucleotide complexation to cellular internalization and endosomal escape. By variation of the molar ratios of the individual building blocks, the physicochemical properties of the polymers and polyplexes were fine-tuned to reduce toxicity as well as to increase activity of the polyplexes. To further enhance transfection efficiency, a cell-penetrating peptide (CPP)-like functionality was introduced on the polymeric backbone. With the ability to synthesize large libraries of polymers in parallel we also developed a workflow for a mid-to-high throughput screening, focusing first on safety parameters that are accessible by high-throughput approaches such as blood compatibility and toxicity towards host cells and only at a later stage on more laborious tests for the ability to deliver oligonucleotides. To arrive at a better understanding of the molecular basis of activity, furthermore, the effect of the presence of heparan sulfates on the surface of host cells was assessed and the mechanism of cell entry and intracellular trafficking investigated for those polymers that showed a suitable pharmacological profile. Following endocytic uptake, rapid endosomal release occurred. Interestingly, the presence of heparan sulfates on the cell surface had a negative impact on the activity of those polyplexes that were sensitive to decomplexation by heparin in solution. In summary, the screening approach identified two polymers, which form polyplexes with high stability and transfection capacity exceeding the one of poly(ethylene imine) also in the presence of serum.en
dc.language.isoenen
dc.publisherElsevieren
dc.relation.urlhttp://www.sciencedirect.com/science/article/pii/S0168365915002230en
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.subjectdrug deliveryen
dc.subjectgene deliveryen
dc.subjectpolymersen
dc.subjectscreeningen
dc.titleMultifunctional poly(methacrylate) polyplex libraries: A platform for gene delivery inspired by nature.en
dc.typeArticleen
dc.identifier.eissn1873-4995en
dc.contributor.departmentDepartment of Biochemistry, Radboud University Medical Centre, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands 2 Dutch Polymer Institute (DPI), Eindhoven, The Netherlands 3 Laboratory of Organic and Macromolecular Chemistry (IOMC), Friedrich Schiller University Jena, Jena, Germany 4 Jena Center for Soft Matter, Friedrich Schiller University Jena, Jena, Germany 5 Institute of Pharmacy, Pharmaceutical Technology, Friedrich Schiller University Jena, Jena, Germanyen
dc.identifier.journalJournal of Controlled Releaseen
dc.date.accepted2015-04-04en
or.grant.openaccessNoen
rioxxterms.funderxxen
rioxxterms.identifier.projectxxen
rioxxterms.versionAMen
rioxxterms.licenseref.startdate2016-07-10en
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