Chemical Approaches to Synthetic Drug Delivery Systems for Systemic Applications

Braatz, Daniel; Cherri, Mariam; Tully, Michael; Dimde, Mathias; Ma, Guoxin; Mohammadifar, Ehsan; Reisbeck, Felix; Ahmadi, Vahid; Schirner, Michael; Haag, Rainer

doi:10.1002/anie.202203942

Cited by 37 publications

(30 citation statements)

References 297 publications

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“…Poly(2-oxazoline)s (PAOx) are a class of polymers with tremendous potential for biomedical applications. Even though the conjugation of poly(ethylene glycol) (PEG) to proteins and peptides (PEGylation) remains the most popular technique for blood half-life extension of drugs and carriers, the rather broad occurrence of PEG antibodies in the human population makes it important to develop alternative hydrophilic polymers [ 1 , 2 , 3 , 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

Conformational Parameters and Hydrodynamic Behavior of Poly(2-Methyl-2-Oxazoline) in a Broad Molar Mass Range

et al. 2023

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In this work, we report our results on the hydrodynamic behavior of poly(2-methyl-2-oxazoline) (PMeOx). PMeOx is gaining significant attention for use as hydrophilic polymer in pharmaceutical carriers as an alternative for the commonly used poly(ethylene glycol) (PEG), for which antibodies are found in a significant fraction of the human population. The main focus of the current study is to determine the hydrodynamic characteristics of PMeOx under physiological conditions, which serves as basis for better understanding of the use of PMeOx in pharmaceutical applications. This goal was achieved by studying PMeOx solutions in phosphate-buffered saline (PBS) as a solvent at 37 °C. This study was performed based on two series of PMeOx samples; one series is synthesized by conventional living cationic ring-opening polymerization, which is limited by the maximum chain length that can be achieved, and a second series is obtained by an alternative synthesis strategy based on acetylation of well-defined linear poly(ethylene imine) (PEI) prepared by controlled side-chain hydrolysis of a defined high molar mass of poly(2-ethyl-2-oxazoline). The combination of these two series of PMeOx allowed the determination of the Kuhn–Mark–Houwink–Sakurada equations in a broad molar mass range. For intrinsic viscosity, sedimentation and diffusion coefficients, the following expressions were obtained: η=0.015M0.77, s0=0.019M0.42 and D0=2600M−0.58, respectively. As a result, it can be concluded that the phosphate-buffered saline buffer at 37 °C represents a thermodynamically good solvent for PMeOx, based on the scaling indices of the equations. The conformational parameters for PMeOx chains were also determined, revealing an equilibrium rigidity or Kuhn segment length, (A) of 1.7 nm and a polymer chain diameter (d) of 0.4 nm. The obtained value for the equilibrium rigidity is very similar to the reported values for other hydrophilic polymers, such as PEG, poly(vinylpyrrolidone) and poly(2-ethyl-2-oxazoline), making PMeOx a relevant alternative to PEG.

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Section: Introductionmentioning

confidence: 99%

Conformational Parameters and Hydrodynamic Behavior of Poly(2-Methyl-2-Oxazoline) in a Broad Molar Mass Range

et al. 2023

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“…Dendritic PGs with different terminal groups were extensively studied by Haag’s group. ,,,− The preparation of linear PG was carried out using anionic polymerization according to the previously published method by Carlotti et al To afford the finalized therapeutic polymers, the pendant alcohol groups were modified. For LPG-Sulf, the polymer was sulfated using the sulfur trioxide pyridine complex and for LPG-Sia, alkyne groups were introduced to allow for copper azide alkyne cycloaddition of azide-containing clickable 2,3 sialyl oligosaccharides.…”

Section: Resultsmentioning

confidence: 99%

Sulfated Hyperbranched and Linear Polyglycerols Modulate HMGB1 and Morphological Plasticity in Neural Cells

Maysinger

Zhang

et al. 2023

ACS Chem. Neurosci.

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The objective of this study was to establish if polyglycerols with sulfate or sialic acid functional groups interact with high mobility group box 1 (HMGB1), and if so, which polyglycerol could prevent loss of morphological plasticity in excitatory neurons in the hippocampus. Considering that HMGB1 binds to heparan sulfate and that heparan sulfate has structural similarities with dendritic polyglycerol sulfates (dPGS), we performed the experiments to show if polyglycerols can mimic heparin functions by addressing the following questions: (1) do dendritic and linear polyglycerols interact with the alarmin molecule HMGB1? (2) Does dPGS interaction with HMGB1 influence the redox status of HMGB1? (3) Can dPGS prevent the loss of dendritic spines in organotypic cultures challenged with lipopolysaccharide (LPS)? LPS plays a critical role in infections with Gram-negative bacteria and is commonly used to test candidate therapeutic agents for inflammation and endotoxemia. Pathologically high LPS concentrations and other stressful stimuli cause HMGB1 release and post-translational modifications. We hypothesized that (i) electrostatic interactions of hyperbranched and linear polysulfated polyglycerols with HMGB1 will likely involve sites similar to those of heparan sulfate. (ii) dPGS can normalize HMGB1 compartmentalization in microglia exposed to LPS and prevent dendritic spine loss in the excitatory hippocampal neurons. We performed immunocytochemistry and biochemical analyses combined with confocal microscopy to determine cellular and extracellular locations of HMGB1 and morphological plasticity. Our results suggest that dPGS interacts with HMGB1 similarly to heparan sulfate. Hyperbranched dPGS and linear sulfated polymers prevent dendritic spine loss in hippocampal excitatory neurons. MS/MS analyses reveal that dPGS-HMGB1 interactions result in fully oxidized HMGB1 at critical cysteine residues (Cys23, Cys45, and Cys106). Triply oxidized HMGB1 leads to the loss of its proinflammatory action and could participate in dPGS-mediated spine loss prevention. LPG-Sia exposure to HMGB1 results in the oxidation of Cys23 and Cys106 but does not normalize spine density.

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“…1 The altered electronic nature of sulfur containing polymers compared to their lighter oxygen analogues causes amongst others degradability benefits, the potential to scavenge heavy metal contaminants, high refractive indices, stimuli responsiveness in drug delivery systems and enhanced semi-crystallinity. [2][3][4][5][6][7] Moving from oxygenated to sulfurated polymers can furthermore be used to tune the (de)polymerisation equilibria of polymers to facilitate chemical polymer recling. 8-10 Furthermore, using monomers which can be directly sourced from elemental sulfur (such as CS2 from S8 and methane) is also relevant in the context of S8 utilization, a waste product of the petrochemical industry being produced at an annual megaton surplus.…”

Section: Introductionmentioning

confidence: 99%

Cooperative taming of CS2/oxetane copolymerisation: Consequences of main-chain sulfuration on polymer properties and catalysis

Plajer

Fornacon-Wood

Gallizioli

et al. 2023

Preprint

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CS2 promises easy access to degradable sulfur-rich polymers and insights into how main-group derivatisation affects polymer formation and properties, though its ring-opening copolymerisation is plagued by low linkage selectivity and small-molecule by-products. We demonstrate that a cooperative Cr(III)/K catalyst selectively delivers poly(dithiocarbonates) from CS2 and oxetanes while state-of-the-art strategies produce linkage scrambled polymers and heterocyclic by-products. The formal introduction of sulfur centres into the parent polycarbonates results in a net shift of the polymerisation equilibrium towards, and therefore facilitating, depolymerisation. During copolymerisation however the catalyst enables near quantitative generation of the metastable polymers in high sequence selectivity by limiting the lifetime of alkoxide intermediates. Furthermore, linkage selectivity is key to obtain semi-crystalline materials that can be moulded into self-standing objects. Our report demonstrates the potential of cooperative catalysis to produce previously inaccessible main-group rich materials with beneficial chemical and physical properties

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Chemical Approaches to Synthetic Drug Delivery Systems for Systemic Applications

Cited by 37 publications

References 297 publications

Conformational Parameters and Hydrodynamic Behavior of Poly(2-Methyl-2-Oxazoline) in a Broad Molar Mass Range

Conformational Parameters and Hydrodynamic Behavior of Poly(2-Methyl-2-Oxazoline) in a Broad Molar Mass Range

Sulfated Hyperbranched and Linear Polyglycerols Modulate HMGB1 and Morphological Plasticity in Neural Cells

Cooperative taming of CS2/oxetane copolymerisation: Consequences of main-chain sulfuration on polymer properties and catalysis

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