Efficient Transfection via an Unexpected Mechanism by Near Neutral Polypiperazines with Tailored Response to Endosomal pH

GND
1311752374
ORCID
0000-0003-0318-0484
Affiliation
Laboratory of Organic and Macromolecular Chemistry (IOMC) Friedrich Schiller University Jena Humboldtstrasse 10 07743 Jena Germany
Hausig‐Punke, Franziska;
Affiliation
Institute of Bioprocess Engineering and Pharmaceutical Technology University of Applied Sciences Mittelhessen Wiesenstrasse 14 35390 Giessen Germany
Dekevic, Gregor;
GND
1261910222
ORCID
0000-0002-6213-8051
Affiliation
Laboratory of Organic and Macromolecular Chemistry (IOMC) Friedrich Schiller University Jena Humboldtstrasse 10 07743 Jena Germany
Sobotta, Fabian H.;
GND
1311753265
ORCID
0000-0001-9567-4216
Affiliation
Laboratory of Organic and Macromolecular Chemistry (IOMC) Friedrich Schiller University Jena Humboldtstrasse 10 07743 Jena Germany
Solomun, Jana I.;
GND
1279607289
Affiliation
Laboratory of Organic and Macromolecular Chemistry (IOMC) Friedrich Schiller University Jena Humboldtstrasse 10 07743 Jena Germany
Richter, Friederike;
ORCID
0000-0001-9266-1356
Affiliation
Institute of Bioprocess Engineering and Pharmaceutical Technology University of Applied Sciences Mittelhessen Wiesenstrasse 14 35390 Giessen Germany
Salzig, Denise;
GND
1222995409
ORCID
0000-0001-7734-2293
Affiliation
Laboratory of Organic and Macromolecular Chemistry (IOMC) Friedrich Schiller University Jena Humboldtstrasse 10 07743 Jena Germany
Traeger, Anja;
GND
1244829358
ORCID
0000-0002-1206-1375
Affiliation
Laboratory of Organic and Macromolecular Chemistry (IOMC) Friedrich Schiller University Jena Humboldtstrasse 10 07743 Jena Germany
Brendel, Johannes C.

Cationic pH‐responsive polymers promise to overcome critical challenges in cellular delivery. Ideally, the polymers become selectively charged along the endosomal pathway disturbing only the local membrane and avoiding unintended interactions or cytotoxic side effects at physiological conditions. Polypiperazines represent a novel, hydrophilic class of pH‐responsive polymers whose response can be tuned within the relevant pH range (5–7.4). The authors discovered that the polypiperazines are effectively binding plasmid DNA (pDNA) and demonstrate high efficiency in transfection. By design of experiments (DoE), a wide parameter space (pDNA and polymer concentration) is screened to identify the range of effective concentrations for transfection. An isopropyl modified polypiperazine is highly efficient over a wide range of concentrations outperforming linear polyethylenimine (l‐PEI, 25 kDa) in regions of low N*/P ratios. A quantitative polymerase chain reaction (qPCR) surprisingly revealed that the pDNA within the piperazine‐based polyplexes can be amplified in contrast to polyplexes based on l‐PEI. The pDNA must therefore be more accessible and bound differently than for other known transfection polymers. Considering the various opportunities to further optimize their structure, polypiperazines represent a promising platform for designing effective soluble polymeric vectors, which are charge‐neutral at physiological conditions.

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