Chemical Design of Non‐Ionic Polymer Brushes as Biointerfaces: Poly(2‐oxazine)s Outperform Both Poly(2‐oxazoline)s and PEG

Morgese, Giulia; Verbraeken, Bart; Ramakrishna, Shivaprakash N.; Gombert, Yvonne; Cavalli, Emma; Rosenboom, Jan‐Georg; Zenobi‐Wong, Marcy; Spencer, Nicholas D.; Hoogenboom, Richard; Benetti, Edmondo M.

doi:10.1002/ange.201805620

Cited by 26 publications

(46 citation statements)

References 46 publications

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“…One such alternative are hydrophilic poly(2oxazoline)s (POx), in particular poly(2-methyl-2-oxazoline) (pMeOx) and poly(2-ethyl-2-oxazoline) (pEtOx). More recently, poly(2-oxazine)s, their higher main-chain homologues have also raised some interest [24][25][26][27]. In fact, POx based amphiphiles have high potential for drug formulation development, demonstrated in various tumor models [28][29][30][31][32][33].…”

Section: Introductionmentioning

confidence: 99%

Think Beyond the Core: The Impact of the Hydrophilic Corona on the Drug Solubilization Using Polymer Micelles

Haider¹,

Lübtow²,

Endres³

et al. 2019

Preprint

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Polymeric micelles are typically characterized as core-shell structures. The hydrophobic inner core is considered as depot for hydrophobic molecules such as drugs or catalysts and the corona forming block acts as protective, stabilizing and solubilizing interface between the hydrophobic core and the external aqueous milieu. Tremendous efforts have been made to tune the hydrophobic block to increase the drug loading and stability of the micelles, while the role of hydrophilic blocks regarding drug loading and stability of micelles is rarely studied in detail. To do so, we investigated a small library of structurally similar A-B-A type amphiphiles based on poly(2-oxazoline)s and poly(2-oxazine)s by varying the hydrophilic block A utilizing poly(2-methyl-2-oxazoline) (A) or poly(2-ethyl-2-oxazoline) (A*), both excellently water-soluble polymers that are able to provide beneficial stealth properties. Surprisingly, major differences in loading capacities from A-B-A > A*-B-A > A*-B-A* highlight the impact of the hydrophilic corona of the polymer micelles on drug loading and stability. 1H-NMR spectroscopy revealed that the hydrophilic pEtOx exhibits a stronger interaction with the cargo compared with its more hydrophilic counterpart pMeOx, reducing colloidal stability of the drug loaded micelles at lower drug loading. To gain more insights, formulations were also characterized by diffusion ordered and nuclear Overhauser effect NMR spectroscopy, dynamic light scattering and (micro) differential scanning calorimetry. Our findings suggest that the interaction between the hydrophilic block and the guest molecule should be considered an important but previously largely ignored factor for the rational design of polymeric micelles.<br>

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Section: Introductionmentioning

confidence: 99%

Think Beyond the Core: The Impact of the Hydrophilic Corona on the Drug Solubilization Using Polymer Micelles

Haider¹,

Lübtow²,

Endres³

et al. 2019

Preprint

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“…17 These properties are often superior to those of the other polymers extensively used in biomedical research (e.g., polyethylene oxide or poly(N-(2hydroxypropyl) methacrylamide)). 16,18 Well-defined PAOx can be synthesized by living cationic ring-opening polymerization (CROP) of their respective monomers with alkyl tosylates being the most common initiators. 12 The polymerization is terminated by nucleophiles providing an easy route for introduction of chain-end functionality by simply selecting the appropriate terminating agent.…”

Section: Introductionmentioning

confidence: 99%

Straightforward Route to Superhydrophilic Poly(2-oxazoline)s via Acylation of Well-Defined Polyethylenimine

et al. 2018

Self Cite

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Herein, we describe a new method for the synthesis of superhydrophilic poly(2-alkyl-2oxazoline)s (PAOx) from poly(2-ethyl-2-oxazoline) (PEtOx). A well-defined linear polyethylenimine was prepared from PEtOx by controlled acidic hydrolysis of its side-chains followed by re-acylation with different carboxylic acids. Using this protocol, we obtained a series of new hydrophilic PAOx containing side-chain ether groups with potential in the biomaterials science. The relative hydrophilicity of polymers was assessed, revealing that poly(2-methoxymethyl-2-oxazoline) (PMeOMeOx) is the most hydrophilic PAOx to date. Additionally, the amorphous poly(2-methoxy-ethoxy-ethoxymethyl-2-oxazoline) (PDEGOx) shows the lowest reported glass transition temperature (-25 °C) within the PAOx family to date. The biomedical potential of prepared polymers was further fortified by an in vitro cytotoxicity study, where all polymers appeared to be non-cytotoxic. The described synthetic protocol is universal and can be extremely versatile, especially for PAOx that are difficult to prepare by conventional cationic ring opening polymerization due to the monomer interference and/or degradation.

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“…To this end, PLL (MW = 15–30 kDa) was self-assembled to form a monolayer by overnight immersion of freshly cleaned, negatively charged silicon oxide surfaces in a 0.1 mg/mL solution of PLL in 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) buffer (following the procedure reported by Morgese et al. 31 ). Upon modification of the silicon oxide surfaces with PLL, the presence of a thin layer of polymers on the surfaces was confirmed by analytical techniques.…”

Section: Resultsmentioning

confidence: 99%

“…In response to these limitations, Morgese et al published in 2018 a study on polymers with PLL backbones that were grafted with other types of antifouling polymer brushes, such as poly(2-oxazines) and poly(2-oxazolines), to create biointerfaces that resist protein adsorption. 31 However, the promising poly(HPMA) polymer was not included as a candidate in this study, and the authors only considered the grafting-to approach. Therefore, we aimed to develop and investigate a bottlebrush macromolecule with poly(HPMA)-grafted side chains for antifouling properties, together with a PLL backbone for multivalent surface interactions to achieve a strong surface anchoring to silicon oxide surfaces.…”

Section: Introductionmentioning

confidence: 99%

PLL–Poly(HPMA) Bottlebrush-Based Antifouling Coatings: Three Grafting Routes

Roeven

Kuzmyn

Scheres³

et al. 2020

Langmuir

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In this work, we compare three routes to prepare antifouling coatings that consist of poly( l -lysine)–poly( N -(2-hydroxypropyl)methacrylamide) bottlebrushes. The poly( l -lysine) (PLL) backbone is self-assembled onto the surface by charged-based interactions between the lysine groups and the negatively charged silicon oxide surface, whereas the poly( N -(2-hydroxypropyl)methacrylamide) [poly(HPMA)] side chains, grown by reversible addition–fragmentation chain-transfer (RAFT) polymerization, provide antifouling properties to the surface. First, the PLL–poly(HPMA) coatings are synthesized in a bottom-up fashion through a grafting-from approach. In this route, the PLL is self-assembled onto a surface, after which a polymerization agent is immobilized, and finally HPMA is polymerized from the surface. In the second explored route, the PLL is modified in solution by a RAFT agent to create a macroinitiator. After self-assembly of this macroinitiator onto the surface, poly(HPMA) is polymerized from the surface by RAFT. In the third and last route, the whole PLL–poly(HPMA) bottlebrush is initially synthesized in solution. To this end, HPMA is polymerized from the macroinitiator in solution and the PLL–poly(HPMA) bottlebrush is then self-assembled onto the surface in just one step ( grafting-to approach). Additionally, in this third route, we also design and synthesize a bottlebrush polymer with a PLL backbone and poly(HPMA) side chains, with the latter containing 5% carboxybetaine (CB) monomers that eventually allow for additional (bio)functionalization in solution or after surface immobilization. These three routes are evaluated in terms of ease of synthesis, scalability, ease of characterization, and a preliminary investigation of their antifouling performance. All three coating procedures result in coatings that show antifouling properties in single-protein antifouling tests. This method thus presents a new, simple, versatile, and highly scalable approach for the manufacturing of PLL-based bottlebrush coatings that can be synthesized partly or completely on the surface or in solution, depending on the desired production process and/or application.

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Chemical Design of Non‐Ionic Polymer Brushes as Biointerfaces: Poly(2‐oxazine)s Outperform Both Poly(2‐oxazoline)s and PEG

Cited by 26 publications

References 46 publications

Think Beyond the Core: The Impact of the Hydrophilic Corona on the Drug Solubilization Using Polymer Micelles

Think Beyond the Core: The Impact of the Hydrophilic Corona on the Drug Solubilization Using Polymer Micelles

Straightforward Route to Superhydrophilic Poly(2-oxazoline)s via Acylation of Well-Defined Polyethylenimine

PLL–Poly(HPMA) Bottlebrush-Based Antifouling Coatings: Three Grafting Routes

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