Antimicrobial peptide encapsulation and sustained release from polymer network particles prepared in supercritical carbon dioxide

© 2018 Antimicrobial peptide loaded poly(2-hydroxyethyl methacrylate) particles were synthesized in supercritical carbon dioxide via one-pot free-radical dispersion polymerisation of 2-hydroxyethyl methacrylate and a cross-linker. Discrete particles with a well-defined spherical morphology and a diameter as low as 450 nm have been obtained in mild conditions. The encapsulation and release of the peptide were confirmed by antimicrobial tests that demonstrated for the first time a sustained release of the peptide from poly(2-hydroxyethyl methacrylate) microgels prepared by one-pot dispersion polymerization in supercritical carbon dioxide and then dispersed in water

Microfluidic formulation: offering new biomedical perspectives to poly(phospho)ester microparticles

Drug-loaded microspheres based on biocompatible and biodegradable polymers, mainly aliphatic polyesters, have demonstrated an increasing interest for producing devices with controlled or sustained release profiles of an active ingredient. They rely on the availability of scalable and robust production techniques. Microfluidic technology meets all these requirements and is characterized by high drug encapsulation efficiency and low particles size dispersity. As a result, this formulation process will become increasingly important in the near future for producing commercially available drug delivery systems even though optimizing the formulation process can be time-consuming. Various microspheres parameters, such as size, polydispersity, composition, structure and shape, have a significant influence on drug release kinetics. The microfluidic technique enables precise control of these parameters which is essential for sustained and predictable drug-release. To modulate the release profile of microfluidically-formulated polylactide (PLA) microspheres, the incorporation of a more hydrophilic polyphosphoester (PPE) component was investigated. On the one hand, a PLA-PPE block copolymer was used as an additive to the polyester microsphere matrix. On the other hand, core-shell microspheres were formulated by adapting the microfluidic chip, enabling a PLA core to be coated with a layer of photo-crosslinked PPE. The impact of this PPE component and its localization on the encapsulation and release profile of model molecules was studied. The developed microfluidic technologies were further used to produce poly(-caprolactone) (PCL) microspheres with shape memory properties. Two types of shape-memory microspheres were designed: (i) a PCL core coated with a crosslinked shell of PPE, and (ii) photo-crosslinked functionalized-PCL microspheres. For both systems, the stimulus for triggering shape memory is temperature (Tm (PCL) ≈ 45°C), which is not always suitable for biomedical applications. To overcome this limitation, a poly(ethylene oxide) (PEO) component was incorporated into PCL to form a hybrid network. In this way, shape memory can be triggered at room temperature by simple immersion in an aqueous medium

Cross-reactive poly(ethylene oxide) and poly(ε-caprolactone) stars towards covalent adaptative networks exhibiting water and temperature triggered shape-memory properties

The abstract is provided in additional informationsInterreg EMR - Interreg Euregio Meuse-Rhine [NL] in the frame of the " IN FLOW " projec

Design of poly(HEMA) particles in supercritical carbon dioxide for protein delivery

Since many decades, polymers proved to be excellent candidates for the development of drug carriers in the pharmaceutical field. Indeed, the range of biocompatible polymers available on the market place allows to prospect new developments of drug carriers for active principle. A vast majority of the polymer nanocarriers have been designed and developed for the controlled and targeted release of hydrophobic drugs. Indeed, the development of delivery systems allowing (i) the solubilization of poorly soluble drugs, (ii) their transport and (iii) selective release to a specific site is a major challenge in the pharmaceutical field. Therefore, several types of nanosized vehicles have been developed, typically nanoparticles, dendrimers, or self-assembling systems such as liposomes or polymer micelles. However, there are still some challenges to design appropriate carriers for the delivery of therapeutic proteins or peptides. Although the history of the protein/peptide-based drugs dates back to insulin production, they have taken great attention since the last decades due to their possible broad range of therapeutic applications. They might offer more specific and safer therapies in comparison to small molecules drugs. Nonetheless, their encapsulation remains challenging specially to preserve their specific structure and activity in the formulations. For this purpose, hydrogel particles (nano-/microgels) have emerged as promising polymer carriers for such proteins. This work focuses on the synthesis of nano-/microgels encapsulating therapeutic proteins and peptides in supercritical carbon dioxide which confers environmentally benign features to the synthesis method. More precisely, hydrogel particles were obtained by free-radical dispersion polymerization of 2-hydroxyethyl methacrylate (HEMA) in supercritical carbon dioxide in presence of a crosslinker and a suitable stabilizer. Typically, the stabilizer, a block copolymer presenting a CO2-philic and a hydrophilic block, have been especially designed to present a photocleavable bond at the junction of the two blocks with the purpose to remove the fluorinated block after particles synthesis and as a consequence allows the poly(HEMA) particles to swell in water. The optimization of the dispersion polymerization conditions led to well-defined cross-linked particles. The process was robust enough to incorporate a drug or a peptide to encapsulate in one-pot synthesis into the particle network. In a subsequent step such drug loaded particles were dispersed successfully in aqueous media and shown sustained release of their content. This was demonstrated notably for the release of a bactericidal peptide

Comparative study of PCL shape-memory networks with Diels-Alder or Alder-ene adducts

Shape-memory polymers (SMPs) are remarkable stimuli-responsive materials able to switch from one stable macroscopic shape to another one, which can find application as smart medical devices. For this purpose, poly(ε-caprolactone) (PCL) networks are widely studied because PCL is biocompatible, degradable and has good mechanical properties. The integration of reversible bonds in these networks allows (re)processing and recycling of the SMP material. In this work, different reversible reactions, i.e. Diel-Alder (DA) addition of TAD-anthracene or maleimide-Anthracene and Alder-ene (AE) addition of TAD-indole, were used for the synthesis of reprocessable SMPs. Bis-TAD and star-shaped PCL end-capped by maleimide, anthracene or indole were synthesized as reported elsewhere. They were melt blended at 120°C in a mini-extruder in equimolar ratio followed by thermal curing at 65°C for blend 1. The cross-linking density of the resulting networks was determined by swelling experiments, their crystallinity by DSC and SMP properties by DMA. The 3 blends reached a similar swelling rate (around 1000%) typical of a highly cross-linked network. Remarkably, it is reached directly after extrusion for blends 2 and 3 thanks to the fast DA and AE additions while a post-curing of 24h at 65°C is required for blend 1. Expectedly, all the three networks exhibited a similar crystallinity degree above 35%, accounting for the good fixity of these SMPs. If recovery ratios higher than 99% were measured for the three samples, a creep effect was observed for the blend 3 upon reaching the temporary shape originating from the stress-sensitive AE adducts able to break upon deformation at 90°C. Finally, the reprocessing of these networks at 120°C was achieved only for blends 2 and 3 thanks to their fast retro-reaction. Various DA or AE reactions were investigated to introduce reversible bonds in PCL networks leading all to SMPs with high fixity and recovery. Among them, the anthracene-TAD equilibrium combines (i) fast addition to build the network, (ii) high stress stability at 90°C avoiding creep phenomena during processing of the temporary shape, (iii) high reversibility above 120°C offering efficient modification of the permanent shape and material (re)processing and recycling

Efficient moisture-sensitive shape-memory materials composed of supramolecular network of poly(ε-caprolactone) and poly(ethylene oxide)

Shape-memory polymers (SMPs) are remarkable stimuli-responsive materials able to switch from one stable macroscopic shape to another one, which can find application as smart medical devices. For this purpose, covalent crosslinked poly(ε-caprolactone) (PCL) is widely studied because it is biocompatible, degradable, exhibits efficient thermally triggered shape memory properties, i.e. high fixity of the temporary shape, high recovery of the permanent shape and has good mechanical properties. In this work, an hydrophilic component, i.e. poly(ethylene oxide), is introduced into PCL networks in order to impart an additional shape transition triggered by hydration of the material at constant temperature. The network of both materials is formed by reaction of the maleimide end-capped PCL stars with furan end-capped PEO stars. After melt-mixing and a post-curing of 48h, this material shows high crosslinking density as demonstrated by swelling behavior, good mechanical properties and excellent shape memory properties,. Moreover, moisture triggered shape transition is observed in addition to conventional thermal shape memory properties

Comparison of different reversible reactions for the elaboration of recyclable PCL-based shape-memory materials

Shape-memory polymers (SMPs) are remarkable stimuli-responsive materials able to switch from one stable macroscopic shape to another one, which can find application as smart medical device or in packaging. For this purpose, poly(ε-caprolactone) (PCL) networks are widely studied because PCL is biocompatible, degradable and has good mechanical properties. The integration of reversible bonds in these networks allows (re)processing and recycling of the SMP material. In this work, different reversible reactions, i.e. Diel-Alder (DA) addition of TAD-anthracene or maleimide-Anthracene and Alder-ene (AE) addition of TAD-indole, were used for the synthesis of reprocessable SMPs. Bis-TAD and star-shaped PCL end-capped by maleimide, anthracene or indole were synthesized as reported elsewhere. They were melt blended at 120°C in a mini-extruder in equimolar ratio followed by thermal curing at 65°C for blend 1. The cross-linking density of the resulting networks was determined by swelling experiments, their crystallinity by DSC and SMP properties by DMA. The 3 blends reached a similar swelling rate (around 1000%) typical of a highly cross-linked network. Remarkably, it is reached directly after extrusion for blends 2 and 3 thanks to the fast DA and AE additions while a post-curing of 24h at 65°C is required for blend 1. Expectedly, all the three networks exhibited a similar crystallinity degree above 35%, accounting for the good fixity of these SMPs. If recovery ratios higher than 99% were measured for the three samples, a creep effect was observed for the blend 3 upon reaching the temporary shape originating from the stress-sensitive AE adducts able to break upon deformation at 90°C. Finally, the reprocessing of these networks at 120°C was achieved only for blends 2 and 3 thanks to their fast retro-reaction. Various DA or AE reactions were investigated to introduce reversible bonds in PCL networks leading all to SMPs with high fixity and recovery. Among them, the anthracene-TAD equilibrium combines (i) fast addition to build the network, (ii) high stress stability at 90°C avoiding creep phenomena during processing of the temporary shape, (iii) high reversibility above 120°C offering efficient modification of the permanent shape and material (re)processing and recycling

Supramolecular network of poly(ε-caprolactone) and poly(ethylene oxide) biomaterials with efficient thermo- and moisture-sensitive shape-memory

Covalent networks of poly(ε-caprolactone) (PCL) are shape-memory polymers (SMP) widely studied for smart medical devices thanks to their biocompatibility, degradability and efficient thermally triggered shape-memory properties, i.e. high fixity of the temporary shape and high recovery of the permanent shape1. As an answer to the increasingly demanding biomedical field, we aim at providing to such PCL SMP an additional shape transition triggered by the presence of water at constant temperature. For this purpose, a hydrophilic component, namely poly(ethylene oxide) (PEO) has been introduced in the PCL network

Synthesis of supramolecular networks of poly(e-caprolactone) and poly(ethylene oxide) as moisture sensitive shape-memory materials

Shape-memory polymers (SMPs) are remarkable stimuli-responsive materials able to switch from one stable macroscopic shape to another one, which can find application as smart medical devices. For this purpose, the covalent crosslinked poly(ε-caprolactone) (PCL) is widely studied because it is biocompatible, degradable, exhibit efficient thermally triggered shape memory properties, i.e. exhibit high fixity of the temporary shape and high recovery of the permanent shape and has good mechanical properties. In this work, an hydrophilic component, i.e. poly(ethylene oxide), is introduced into PCL networks in order to impart an additional shape transition triggered by hydration of the material at constant temperature. The network of both materials is formed by reaction of the maleimide end-capped PCL stars with and furan end-capped PEO stars. This material exhibits high crosslinking density and excellent shape memory properties, after a post-curing of 48h. Moisture triggered shape transition is observed in addition to conventional thermal shape memory properties