Hyaluronate siRNA nanoparticles with positive charge display rapid attachment to tumor endothelium and penetration into tumors

Luo, Jie; Schmaus, Johannes; Cui, Mochen; Hörterer, Elisa; Wilk, Ulrich; Höhn, Miriam; Däther, Maike; Berger, Simone; Benli-Hoppe, Teoman; Lun, Peng; Wagner, Ernst

doi:10.1016/j.jconrel.2020.10.022

Cited by 29 publications

(33 citation statements)

References 73 publications

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“…The T‐shaped azido lipo‐OAA 1214 (Scheme 1) with favorable efficacy [ 56 ] was selected for our TfR‐mediated siRNA delivery system. The complexation of siRNA with the cationic 1214 was carried out in HEPES buffered 5% glucose (HBG; 20 × 10 −3 m HEPES , pH 7.4) at an optimal protonatable nitrogen/phosphate (N/P) ratio of 12 as determined in the previous study.…”

Section: Resultsmentioning

confidence: 99%

“…The complexation of siRNA with the cationic 1214 was carried out in HEPES buffered 5% glucose (HBG; 20 × 10 −3 m HEPES , pH 7.4) at an optimal protonatable nitrogen/phosphate (N/P) ratio of 12 as determined in the previous study. [ 56 ] Sizes, polydispersity index (PDI), and zeta potential of siRNA polyplexes were characterized by dynamic and electrophoretic light scattering (DLS, ELS). The nonmodified 1214 /siRNA polyplexes showed a hydrodynamic diameter of around 150 nm with a low PDI of 0.18 and a relatively high positive zeta potential of around +32 mV ( Figure A).…”

Section: Resultsmentioning

confidence: 99%

“…In the first step, siRNA or pDNA were compacted into core nanoparticles (Scheme 1, top) using recently designed sequencedefined T-shaped lipo-OAAs. [55,56] In the second step, the nanoparticles were modified with a shell of PEG-conjugated ligands. Lipo-OAAs (Scheme 1, bottom) contain an N-terminal azido-lysine, which can be utilized for dibenzocyclooctyne (DBCO)-PEG-ligand attachment by strain-promoting alkyneazide cycloaddition.…”

Section: Design and Synthesis Of Sequence-defined Polyplex Core And S...mentioning

confidence: 99%

“…Lipo-OAAs (Scheme 1, bottom) contain an N-terminal azido-lysine, which can be utilized for dibenzocyclooctyne (DBCO)-PEG-ligand attachment by strain-promoting alkyneazide cycloaddition. [56][57][58][59] Ligands such as reTfR or controls are linked with a monodisperse PEG 24 spacer as surface shielding agent via one or two N-terminally attached DBCO groups (Scheme 2). In literature, the click reaction between DBCO and azide units is stated to be selective, holds high yield and has good reaction kinetics.…”

Section: Design and Synthesis Of Sequence-defined Polyplex Core And S...mentioning

confidence: 99%

“…The aim of the present study was to incorporate this small synthetic reTfR ligand as targeting module into nucleic acid polyplexes that are totally based on precise, sequence-defined components. Compacting siRNA or pDNA with previously developed T-shaped lipo-oligoaminoamides (lipo-OOAs) [55,56] into nanoparticles followed by modification with monodisperse polyethylene glycol (PEG) and the reTfR ligand resulted in enhanced gene silencing or gene transfer, respectively, in receptor-expressing cells.…”

Section: Introductionmentioning

confidence: 99%

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Transferrin Receptor Targeted Polyplexes Completely Comprised of Sequence‐Defined Components

Benli-Hoppe

Öztürk

et al. 2021

Macromol. Rapid Commun.

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Design and Synthesis Of Sequence-defined Polyplex Core And S...mentioning

confidence: 99%

Section: Design and Synthesis Of Sequence-defined Polyplex Core And S...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Transferrin Receptor Targeted Polyplexes Completely Comprised of Sequence‐Defined Components

Benli-Hoppe

Öztürk

et al. 2021

Macromol. Rapid Commun.

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Molecular Chameleon Carriers for Nucleic Acid Delivery: The Sweet Spot between Lipoplexes and Polyplexes

et al. 2023

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Taking advantage of effective intracellular delivery mechanisms of both cationizable lipids and polymers, highly potent double pH-responsive nucleic acid carriers are generated by combining at least two lipo amino fatty acids (LAFs) as hydrophobic cationizable motifs with hydrophilic cationizable aminoethylene units into novel sequence-defined molecules. The pH-dependent tunable polarity of the LAF is successfully implemented by inserting a central tertiary amine, which disrupts the hydrophobic character once protonated, resulting in pH-dependent structural and physical changes. This "molecular chameleon character" turns out to be advantageous for dynamic nucleic acid delivery via lipopolyplexes. By screening different topologies (blocks, bundles, T-shapes, U-shapes), LAF types, and LAF/aminoethylene ratios, highly potent pDNA, mRNA, and siRNA carriers are identified, which are up to several 100-fold more efficient than previous carrier generations and characterized by very fast transfection kinetics. mRNA lipopolyplexes maintain high transfection activity in cell culture even in the presence of ≥90% serum at an ultra-low mRNA dose of 3 picogram (≈2 nanoparticles/cell), and thus are comparable in potency to viral nanoparticles. Importantly, they show great in vivo performance with high expression levels especially in spleen, tumor, lungs, and liver upon intravenous administration of 1-3 μg luciferase-encoding mRNA in mice.

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Folate Receptor‐Mediated Delivery of Cas9 RNP for Enhanced Immune Checkpoint Disruption in Cancer Cells

Lin

Wilk

Pöhmerer

et al. 2022

Small

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The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR‐associated protein 9 (Cas9) system offers great opportunities for the treatment of numerous diseases by precise modification of the genome. The functional unit of the system is represented by Cas9/sgRNA ribonucleoproteins (RNP), which mediate sequence‐specific cleavage of DNA. For therapeutic applications, efficient and cell‐specific transport into target cells is essential. Here, Cas9 RNP nanocarriers are described, which are based on lipid‐modified oligoamino amides and folic acid (FolA)‐PEG to realize receptor‐mediated uptake and gene editing in cancer cells. In vitro studies confirm strongly enhanced potency of receptor‐mediated delivery, and the nanocarriers enable efficient knockout of GFP and two immune checkpoint genes, PD‐L1 and PVR, at low nanomolar concentrations. Compared with non‐targeted nanoparticles, FolA‐modified nanocarriers achieve substantially higher gene editing including dual PD‐L1/PVR gene disruption after injection into CT26 tumors in vivo. In the syngeneic mouse model, dual disruption of PD‐L1 and PVR leads to CD8+ T cell recruitment and distinct CT26 tumor growth inhibition, clearly superior to the individual knockouts alone. The reported Cas9 RNP nanocarriers represent a versatile platform for potent and receptor‐specific gene editing. In addition, the study demonstrates a promising strategy for cancer immunotherapy by permanent and combined immune checkpoint disruption.

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Hyaluronate siRNA nanoparticles with positive charge display rapid attachment to tumor endothelium and penetration into tumors

Cited by 29 publications

References 73 publications

Transferrin Receptor Targeted Polyplexes Completely Comprised of Sequence‐Defined Components

Transferrin Receptor Targeted Polyplexes Completely Comprised of Sequence‐Defined Components

Molecular Chameleon Carriers for Nucleic Acid Delivery: The Sweet Spot between Lipoplexes and Polyplexes

Folate Receptor‐Mediated Delivery of Cas9 RNP for Enhanced Immune Checkpoint Disruption in Cancer Cells

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