Loading...
Multifunctional poly(methacrylate) polyplex libraries: A platform for gene delivery inspired by nature.
Favretto, Marco E. Krieg, Andreas Schubert, Stephanie Schubert, Ulrich Brock, Roland
Favretto, Marco E.
Krieg, Andreas
Schubert, Stephanie
Schubert, Ulrich
Brock, Roland
Citations
Altmetric:
Advisors
Editors
Other Contributors
EPub Date
Publication Date
2015-07-10
Submitted Date
Collections
Files
Other Titles
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.
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
Research Unit
PubMed ID
PubMed Central ID
Type
Article
Language
en
Description
Series/Report no.
ISSN
0168-3659
EISSN
1873-4995