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Transferrin Receptor Targeted Polyplexes Completely Comprised of Sequence‐Defined Components
Author(s) -
BenliHoppe Teoman,
Göl Öztürk Şurhan,
Öztürk Özgür,
Berger Simone,
Wagner Ernst,
Yazdi Mina
Publication year - 2022
Publication title -
macromolecular rapid communications
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.348
H-Index - 154
eISSN - 1521-3927
pISSN - 1022-1336
DOI - 10.1002/marc.202100602
Subject(s) - transferrin receptor , nucleic acid , cationic liposome , chemistry , small interfering rna , gene silencing , biochemistry , peptide , gene delivery , transferrin , receptor , peg ratio , microbiology and biotechnology , transfection , biophysics , biology , gene , economics , finance
Abstract Human transferrin protein (Tf) modified polyplexes have already displayed encouraging potential for receptor‐mediated nucleic acid delivery into tumors. The use of a blood‐derived targeting protein and polydisperse macromolecular cationic subunits however presents a practical challenge for pharmaceutical grade production. Here, Tf receptor (TfR) targeted small interfering RNA (siRNA) polyplexes are designed that are completely composed of synthetic, monodisperse, and sequence‐defined subunits generated by solid‐phase supported synthesis. An optimized cationizable lipo‐oligoaminoamide (lipo‐OAA) is used for siRNA core polyplex formation, and a retro‐enantio peptide (reTfR) attached via a monodisperse polyethylene glycol (PEG) spacer via click chemistry is applied for targeting. Improved gene silencing is demonstrated in TfR‐expressing KB and DU145 cells. Analogous plasmid DNA (pDNA) polyplexes are successfully used for receptor‐mediated gene delivery in TfR‐rich K562 cells and Neuro2a cells. Six lipo‐OAAs differing in their lipidic domain and redox‐sensitive attachment of lipid residues are tested in order to evaluate the impact of core polyplex stability on receptor‐dependent gene transfer.