Poly(2-ethyl-2-oxazoline-<i>co-N</i>-propylethylene imine)s by controlled partial reduction of poly(2-ethyl-2-oxazoline): synthesis, characterization and cytotoxicity

Halupczok, Sebastian; Ringhand, Annemarie; Fetsch, Corinna; Cubukova, Alevtina; Appelt‐Menzel, Antje; Luxenhofer, Robert

doi:10.1039/d0py01258k

Cited by 6 publications

(4 citation statements)

References 52 publications

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“…80 Case in point, after (partial) reduction of POx polymers to poly(N-alkyl ethylene imine)s, which yields freely inverting tertiary amines lower Tg values are observed. 81,82 Furthermore, the increased double-bond character of the thioamides is corroborated by IR spectroscopy. The absorbance of C-N str,amide at 1060 cm -1 83 is decreased noticeably with increased thionation degree with a new band emerging at 950 cm -1 , which we attributed to C-N str thioamide (Figure S3).…”

Section: Thionation Of Petoxmentioning

confidence: 77%

Thionation of poly(2-ethyl-2-oxazoline) and its effect on solubility and cloud point

Hacioglu,

Baddam,

Kerr

et al. 2024

Preprint

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Many water-soluble polymers undergo phase separation above their lower critical solution temperature (LCST) in aqueous solutions. Generally, the LCST is controlled via the polymer-solvent interactions, which in turn are highly structure dependent and typically tuned via the polymer side chain. For example, the LCST for the poly(2-oxazoline) family can be tuned via the length of the polymer side chain. In particular, the LCST of poly(2-ethyl-2-oxazoline) varies between 60-100 °C, depending on its molar mass, polymer architecture and concentration. Here, we introduce LCST adjustment via modification of the carbonyl of the amide moiety of poly(2-oxazoline)s. We introduce poly(2-ethyl-2-oxazoline-co-N-propiothioacetyl ethylene imine), synthesized from poly(2-ethyl-2-oxazoline) using Lawesson’s reagent. The degree of thionation of the polymers was varied and characterized using spectroscopic methods and elemental analysis. While the glass transition temperatures of the copolymers increase with increasing thionation degree, decomposition temperatures decrease. Interestingly, polymers with less than 20% thionation degree were soluble in water with LCST behavior. The cloud point temperatures decrease with increasing thionation degree, due to weaker hydrogen bonding ability of thioamides and decreased polarity.

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Section: Thionation Of Petoxmentioning

confidence: 77%

Thionation of poly(2-ethyl-2-oxazoline) and its effect on solubility and cloud point

Hacioglu,

Baddam,

Kerr

et al. 2024

Preprint

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Section: Self‐assembled Poly(2‐oxazoline)smentioning

confidence: 99%

“…Similar to partially hydrolyzed POx, the cytotoxicity of partially reduced PEtOx was found to be very low for low reduction degrees but quite considerable when the degree of reduction exceeds 30%. [ 128 ] Therefore, the partially reduced POx appear to be slightly more toxic compared to the corresponding hydrolyzed ones.…”

Section: Self‐assembled Poly(2‐oxazoline)smentioning

confidence: 99%

Poly(2‐oxazoline)‐ and Poly(2‐oxazine)‐Based Self‐Assemblies, Polyplexes, and Drug Nanoformulations—An Update

Zahoranová

Luxenhofer

2021

Adv Healthcare Materials

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For many decades, poly(2‐oxazoline)s and poly(2‐oxazine)s, two closely related families of polymers, have led the life of a rather obscure research topic with only a few research groups world‐wide working with them. This has changed in the last five to ten years, presumably triggered significantly by very promising clinical trials of the first poly(2‐oxazoline)‐based drug conjugate. The huge chemical and structural toolbox poly(2‐oxazoline)s and poly(2‐oxazine)s has been extended very significantly in the last few years, but their potential still remains largely untapped. Here, specifically, the developments in macromolecular self‐assemblies and non‐covalent drug delivery systems such as polyplexes and drug nanoformulations based on poly(2‐oxazoline)s and poly(2‐oxazine)s are reviewed. This highly dynamic field benefits particularly from the extensive synthetic toolbox poly(2‐oxazoline)s and poly(2‐oxazine)s offer and also may have the largest potential for a further development. It is expected that the research dynamics will remain high in the next few years, particularly as more about the safety and therapeutic potential of poly(2‐oxazoline)s and poly(2‐oxazine)s is learned.

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“…8 However, the amine units of PEI are amenable to chemical modification. Indeed, chemical modifications, or partial hydrolysis and partial reduction 9 of a poly(2-oxazoline) precursor, 10 can serve to lower the charge density thus reducing toxic effects 6,11,12 , and modulating polyplex properties, increasing transfection efficacy. For example, inclusion of hydrophobic groups onto polycations has been shown to strongly influence transfection, 13 presumably due to strengthening self-assembly behavior of the polyplex and modulation of polyplex-cell interactions.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of ionizable lipopolymers using split-Ugi reaction for pulmonary delivery of various size RNAs and gene editing

Vlasova,

Kerr,

Pennock

et al. 2024

Preprint

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We present an efficient approach for synthesizing cationic poly(ethylene imine) derivatives using the multicomponent split-Ugi reaction to rapidly create a library of complex functional ionizable lipopolymers. We synthesized a diverse library of 155 polymers, formulated them into polyplexes to establish structure-activity relationships crucial for endosomal escape and efficient transfection. After discovering a lead structure, lipopolymer-lipid hybrid nanoparticles are introduced to preferentially deliver to and elicit effective mRNA transfection in lung endothelium and immune cells, including T cells with lowin vivotoxicity. The lipopolymer-lipid hybrid nanoparticles showed 300-fold improvement in systemic mRNA delivery to the lung compared toin vivo-JetPEI®. Lipopolymer-lipid hybrid nanoparticles demonstrated efficient delivery of mRNA-based therapeutics for treatment of two different disease models. Lewis Lung cancer progression was significantly delayed after treatment with loaded IL-12 mRNA in U155@lipids after repeated i.v. administration. Systemic delivery of human CFTR (hCFTR) mRNA resulted in production of functional form of CFTR protein in the lungs. The functionality of hCFTR protein was confirmed by restoration of CFTR- mediated chloride secretion in conductive airway epithelia in CFTR knockout mice after nasal instillation of hCFTR mRNA loaded U155@lipids. We further showed that, U155@lipids nanoparticles can deliver complex CRISPR-Cas9 based RNA cargo to the lung, achieving 5.6 ± 2.4 % gene editing in lung tissue. Moreover, we demonstrated successful PD-1 gene knockout of T cellsin vivo. Our results highlight a versatile delivery platform for systemic delivering of mRNA of various sizes for gene therapy for a variety of therapeutics.

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Poly(2-ethyl-2-oxazoline-co-N-propylethylene imine)s by controlled partial reduction of poly(2-ethyl-2-oxazoline): synthesis, characterization and cytotoxicity

Abstract: The partial reduction of poly(2-ethyl-2-oxazoline) was investigated. A series of poly(2-ethyl-2-oxazoline-co-N-propylethylene imine)s were synthesized by direct reduction using lithium aluminum hydride or borane/dimethylsulfide (BH3/DMS), respectively. It is shown that the degree...

Cited by 6 publications

References 52 publications

Thionation of poly(2-ethyl-2-oxazoline) and its effect on solubility and cloud point

Thionation of poly(2-ethyl-2-oxazoline) and its effect on solubility and cloud point

Poly(2‐oxazoline)‐ and Poly(2‐oxazine)‐Based Self‐Assemblies, Polyplexes, and Drug Nanoformulations—An Update

Synthesis of ionizable lipopolymers using split-Ugi reaction for pulmonary delivery of various size RNAs and gene editing

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