The process of ionic gelation is one of the easiest ways to develop chitosan nanoparticles reported so far in the literature. Its success is mainly due to its one-shot synthesis, and to the mild ...environment required to produce the nanoparticles. The nanoparticle formation all along this process has been therefore thoroughly studied to lead to particles with a nanometric size, a narrow size distribution, and a spherical shape that are ideal for biomedical uses. The purpose of this review is to compile the biomedical applications that have been considered in the literature for these chitosan nanoparticles prepared by ionic gelation using tripolyphosphate as ionic agent. Their intrinsic biological properties such as non-toxicity, antimicrobial activity, mucoadhesivity and haemocompatibility are firstly discussed and compared to those of chitosan solutions. Then, the different bioactive species (drugs and biomacromolecules) incorporated in these chitosan nanoparticles, their maximal incorporation efficiency, their loading capacity, and their principal associated biomedical applications are presented.
Acylhydrazone‐based (macro)molecules display an increasingly broad spectrum of applications, from small therapeutic molecules and metal‐ions probes to self‐healing films and biorelevant dynamic ...polymers. The acylhydrazone function is indeed of prime interest since its unique design combines hydrogen bonds, pH‐dependent reversibility, ability to undergo molecular exchanges, and a possible polyvalency. However, a key parameter of its use in aqueous media is the associated water‐solubility of the resulting (macro)molecule. This property can indeed become a limitation for applications requiring high concentrations or no organic cosolvent. This review first focuses on describing the acylhydrazone function, its properties, and its relevancy in dynamic combinatorial chemistry. Then it details the synthesis strategies (molecular design, cosolvent, reaction conditions) reported in the literature to ensure a sufficient solubilization of both single‐bond and multiple‐bond acylhydrazone (macro)molecules, together with their various applications.
Water‐soluble acylhydrazone‐based (macro)molecules display several properties of prime interest, and an increasingly broad spectrum of applications. However, their poor water‐solubility can be a limiting key parameter for their further use in aqueous media. In this context, this review describes different strategies employed in the literature to ensure a sufficient solubility in water, for single‐bond to multiple‐bond acylhydrazone (macro)molecules, including polyacylhydrazones.
Chitosan and lipid colloids have separately shown a growing interest in the field of drug delivery applications. Their success is mainly due to their interesting physicochemical behaviors, as well as ...their biological properties such as bioactivity and biocompatibility. While chitosan is a well-known cationic polysaccharide with the ability to strongly interact with drugs and biological matrices through mainly electrostatic interactions, lipid colloids are carriers particularly recognized for the drug vectorization. In recent years, the combination of both entities has been considered because it offers new systems which gather the advantages of each of them to efficiently deliver various types of bioactive species. The purpose of this review is to describe these associations between chemically-unmodified chitosan chains (solubilized or dispersed) and lipid colloids (as nanoparticles or organized in lipid layers), as well as their potential in the drug delivery area so far. Three assemblies have mainly been reported in the literature: i) lipid nanoparticles (solid lipid nanoparticles or nanostructured lipid carriers) coated with chitosan chains, ii) lipid vesicles covered with chitosan chains, and iii) chitosan chains structured in nanoparticles with a lipid coating. Their elaboration processes, their physicochemical characterization, and their biological studies are detailed and discussed herein. The different bioactive species (drugs and bio(macro)molecules) incorporated in these assemblies, their maximal incorporation efficiency, and their loading capacity are also presented. This review reveals the versatility of these assemblies. Depending on the organization of lipids (i.e., nanoparticles or vesicles) and the state of polymer chains (i.e., solubilized or dispersed under the form of nanoparticles), a large variety of drugs can be successfully incorporated, and various routes of administration can be considered.
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Dual systems combining Zn(C6F5)2 with an organic base (an amine or a phosphine) promote the controlled ring-opening polymerization of lactide and ε-caprolactone. The Lewis pairs cooperate to activate ...the monomers, affording well-defined high molecular weight cyclic polyesters. Efficient chain-extension gives access to cyclic block copolymers.
Mass spectrometry techniques, specifically matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) and electrospray ionization time-of-flight (ESI-TOF) are of considerable interest for ...characterizing very attractive polymers resulting from controlled radical polymerizations (CRP). This work proposes a systematic and experimental comparison of both ionization methods to analyze polystyrene prepared by five different CRP: nitroxide-mediated polymerization (mediated by N-tert-butyl-N-1-diethylphosphono-(2,2-dimethylpropyl)nitroxide, known as SG1), atom transfer radical polymerization (Cl- and Br-mediated), reversible addition-fragmentation chain transfer polymerization, and reverse iodine transfer polymerization. All polystyrene chain end-groups obtained in each CRP-polymerization, and detected by both mass spectrometry techniques, are described and discussed. Elemental analyses of all CRP-polymers were also carried out to complete these results. It was found that the number of chain end-groups detected is higher by ESI-TOF than MALDI-TOF mass spectrometry in the polystyrene case. Furthermore, the cationization salt as well as the ionization source play a considerable role on the chain end-group fragmentation process occurring in mass spectrometer for the five CRP-polystyrenes. Concerning molecular weight considerations, the MALDI-TOF mass spectrometry is a better alternative to chromatography techniques than ESI-TOF mass spectrometry which under-estimates the average molecular weights.
•Chitosan nanoparticles were synthesized by an ionic gelation method.•The main physicochemical parameters involved in the synthesis were studied.•Aggregates were successfully reduced by a heat ...treatment of the colloidal suspension.•Nanoparticle sphericity was drastically increased through a mild heating.•Optimized nanoparticles were stable at least 135 days at 20°C (pH 4.5).
The elaboration of chitosan (CS) nanoparticles via an ionic gelation process using sodium tripolyphosphate (TPP) as cross-linking agent was thoroughly studied in order to develop colloidally stable, spherical CS nanoparticles with a reproducible sub-micrometer size, and a narrow size distribution. To this end, the most relevant parameters involved in the synthesis such as CS chains concentration and molecular weight as well as ionic strength and pH of CS initial solutions were investigated and optimized. The physicochemical characterization of resulting CS nanoparticles was carried out in terms of size, size distribution, and surface charge by quasi-elastic light scattering (QELS), nanoparticle tracking analysis (NTA), and zeta potential measurements. Morphological characterization using classical and cryogenic transmission electron microscopy (TEM and cryo-TEM) was then performed revealing a high number of aggregates mixed to individualized nanoparticles with drop-like and irregular shapes. These limitations were overcome by applying a specific and optimized thermal treatment which appeared to significantly reduce the aggregate number, and to restructure the CS nanoparticles into highly spherical objects. Based on all these findings, reproducible, cationic (zeta potential=+37±5mV), stable (at least 4 months at 20°C), spherical, and mainly individualized CS nanoparticles of 100±30nm (determined from cryo-TEM images) were obtained.
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•Synthesis of well-defined chitosan oligomers by nitrous acid depolymerization.•Chemical method for the reducing-end functionalization of chitosan oligomers.•Elaboration of ...“clickable” chitosan oligomer-based building blocks.•Synthesis of chitosan oligomer-b-PEG diblock copolymers.•Full characterization of chitosan oligomer derivatives by NMR and MALDI-TOF MS.
Chitooligosaccharides (COS) produced by nitrous acid depolymerization of chitosan are unique chitosan oligomers due to the presence of the 2,5-anhydro-d-mannofuranose (amf) unit at their reducing end. In this work, we focused on the reductive amination and the oximation of the amf aldehyde group towards various functionalized anilines, hydrazides and O-hydroxylamines. The aim of this work was to synthesize new COS-based building blocks functionalized at their reducing end by different “clickable” chemical groups such as alkene, alkyne, azide, hydrazide and thiol. Targeted functionalized COS were synthesized in excellent mass yields and fully characterized by NMR spectroscopy and MALDI-TOF mass spectrometry. Our results showed these functionalizations are quantitative, versatile and can be easily performed in mild reaction conditions. Finally, these COS-based building blocks could be useful intermediates for the development of advanced functional COS-based conjugates, as illustrated in this work by the synthesis of new COS-poly(ethylene glycol) (PEG) diblock copolymers.
Obtaining well-defined Chitooligosaccharides (COS) structures is very important as their physicochemical and biological properties depends strongly on their degree of polymerization (DP) and degree ...of
N-
acetylation (DA). Hydrophilic Interaction Liquid Chromatography (HILIC), that is commonly used for COS analyses, suffers from several drawbacks, related to their complex structure, leading to broadening/splitting of the chromatogram signals. We investigated, herein, on the role of the equilibration step of an amino-based HILIC column on the separation of COS DP ≤ 5. We demonstrated that COS could be separated according to their DP after equilibrating the column by a NaHCO
3
buffer solution (100 mM, pH = 10) and mild elution chromatographic parameters (neutral mobile phase, r.t.); or according to their DA after equilibrating the column by an NH
4
Ac buffer solution (50 mM, pH = 4.5). Also, the nature of the counterion of the column stationary phase was found to affect both retention times and signal profiles of analyzed COS.
The approval of two mRNA vaccines as urgent prophylactic treatments against Covid-19 made them a realistic alternative to conventional vaccination methods. However, naked mRNA is rapidly degraded by ...the body and cannot effectively penetrate cells. Vectors capable of addressing these issues while allowing endosomal escape are therefore needed. To date, the most widely used vectors for this purpose have been lipid-based vectors. Thus, we have designed an innovative vector called LipoParticles (LP) consisting of poly(lactic) acid (PLA) nanoparticles coated with a 15/85 mol/mol DSPC/DOTAP lipid membrane. An in vitro investigation was carried out to examine whether the incorporation of a solid core offered added value compared to liposomes alone. To that end, a formulation strategy that we have named particulate layer-by-layer (pLbL) was used. This method permitted the adsorption of nucleic acids on the surface of LP (mainly by means of electrostatic interactions through the addition of LAH4-L1 peptide), allowing both cellular penetration and endosomal escape. After a thorough characterization of size, size distribution, and surface charge- and a complexation assessment of each vector-their transfection capacity and cytotoxicity (on antigenic presenting cells, namely DC2.4, and epithelial HeLa cells) were compared. LP have been shown to be significantly better transfecting agents than liposomes through pLbL formulation on both HeLa and DC 2.4 cells. These data illustrate the added value of a solid particulate core inside a lipid membrane, which is expected to rigidify the final assemblies and makes them less prone to early loss of mRNA. In addition, this assembly promoted not only efficient delivery of mRNA, but also of plasmid DNA, making it a versatile nucleic acid carrier that could be used for various vaccine applications. Finally, if the addition of the LAH4-L1 peptide systematically leads to toxicity of the pLbL formulation on DC 2.4 cells, the optimization of the nucleic acid/LAH4-L1 peptide mass ratio becomes an interesting strategy-essentially reducing the peptide intake to limit its cytotoxicity while maintaining a relevant transfection efficiency.
MALDI-TOF mass spectrometry analyses revealed the oxidation of thiol-containing polymer chain-ends during sample preparation using THF as solvent. In these conditions, the extent of oxidation was ...hardly reproducible, and led to various types of oxidized compounds. Preparing the samples at the last minute using commercial THF stabilized with an antioxidant led to more reproducible results, with the least oxidation. However, it is demonstrated herein that thiol oxidation can be advantageously taken into profit to further ascertain the presence of the thiol at the polymer chain-end. To force thiol oxidation we used THF without any antioxidant stabilizer, thus more prone to form peroxides. Thiol-containing polymer chains can thereby be indirectly evidenced by the formation of oxidation products such as chain–chain disulfide bonds and sulfonic acid chains-ends. More importantly, in these oxidizing conditions and in the negative mode, sulfonic acid-terminated polymer chains can be more sensitively detected than thiol ones (the low pK a of sulfonic acids facilitating their anionization in MALDI source). In conclusion, performing MALDI-TOF mass spectrometry analyses in oxidizing conditions, as complement to regular analyses, was found to be very useful for the chain-end identification of different thiol-containing polymer chains.
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