‘Sweet as a Nut’: Production and use of nanocapsules made of glycopolymer or polysaccharide shell
Graphical abstract
Introduction
In the last decades, remarkable advances have been made in the synthesis and the modification of submicronic carriers (typically, ranging from 10 to 500 nm) [1,2]. Developments in colloids engineering led to fruitful achievements in agriculture, food, cosmetic and pharmaceutical domains [3], [4], [5], [6]. Among them, polymer-based nanocapsules (including polymer vesicles, so-called ‘polymersomes’), are a class of core/shell structures, in which the core is protected by a (preferably solid) polymer shell. The tailored variation of both core and polymeric shell provides capsules with attractive diversity in properties and function: the polymer shell can be obtained from various synthetic or natural polymers, whereas the inner part of the capsules can be filled with an aqueous, an oily, a solid or a gaseous phase. The presence of an inner reservoir, in stark contrast to plain nanoparticles, allows high loading and delivery capability. Polymeric nanocapsules thus represent a powerful platform for encapsulation and delivery of actives (including genes, proteins, drugs, imaging agents and others) for pharmaceutical, diagnostic or nanomedicine applications [7]. Polymeric nanocapsules enable the i) protection of cargos against degradation and elimination; ii) enhancement of the stability of nanocarriers (as compared with liposomes); iii) reduction of the toxicity of cargos and iv) better control of the delivery and release of cargos in target areas.
Together with genes and proteins, carbohydrates are key molecules in living organisms. However, in contrast to the rapid development of areas such as “genomics” and “proteomics”, research in “glycomics” has progressed slowlier. This can be attributed to the inherent complexity of glycan structures and exclusive biosynthetic pathways. Still, tremendous achievements in interpreting the information of the “glyco-code” and understanding fundamental functions of carbohydrates have been made [8], [9], [10]. Beyond their essential role in energy storage, carbohydrates are also known to take part in cell communication, biological recognition events [11], immune function [12] and signal transduction [13]. Since monovalent interactions of carbohydrates with their receptors are weak, Nature usually employs multivalent interactions, thanks to the presentation of multiple carbohydrate residues, to improve binding affinity to lectins [14].
Incorporation of carbohydrates on the surface of nano-objects allows mimicking the glycocalyx (a carbohydrate-enriched layer covering the cell membrane). Specific interactions of carbohydrates allow both targeting and cumulative uptake by selective cells. Moreover, carbohydrate shells have been shown to confer stealth properties to nanocapsules, thus diminishing immune elimination and prolonging their circulation time in the body. Last but not least, the use of biocompatible and biodegradable macromolecular building blocks (such as polysaccharides) opens the way to clinical use.
Glycopolymers and polysaccharides with multiple copies of carbohydrates units have been engaged in constructing myriads of nano-objects since the last century. With the concerns expressed by the possible toxicity of PEG polymers, the advent of green chemistry and the use of natural degradable polymers, this field is literally blooming nowadays. In 2004, P. Couvreur gave a very comprehensive review on the preparation and applications of polysaccharide-decorated nanoparticles [15]. From then on, several other reviews have been published over the last decade [16], [17], [18], [19], [20], all of them describing achievements of carbohydrate-functionalized ‘sweet’ nanoparticles as therapeutic agents, drug carriers, bioimaging agents, etc. Thanks to their facile synthesis, carbohydrate-functionalized inorganic nanoparticles (e.g. magnetic glyconanoparticles, glyco-quantum dots) have rightly received attention [21,22], but their usual intrinsic toxicity and non-degradable character restricted further applications in bio-applications. In contrast, carbohydrate-based organic polymeric nanocapsules (or “glyconanocapsules”) benefit from their functional core/shell nanostructures and biocompatibility but inevitably require more energy and ingenuity for precise construction, which explains that they were hardly mentioned in these reviews.
In this article, recent advances in the development of sugar-based nanocapsules are reviewed (Scheme 1). This manuscript is structured as follows: First, a summary of the important strategies for constructing core/shell carbohydrate-based nano-objects, from naturally-occurring polysaccharides to synthetic glycopolymers, and their use in biomedical applications is presented. The focus of the discussion will be specifically on functional nanocapsules whose polymeric shell is comprised of glycopolymers and/or polysaccharides. Approaches relying on post-surface incorporation, functionalization with polysaccharides or cyclodextrin-based colloids will not be described here [23], [24], [25].
Chemical or/and physical approaches to sugar-based nanocapsules as well as glyco-polymersomes, are described, including well-established methods such as i) self-assembly of amphiphilic copolymers into polymersomes or core-degradable micelles, ii) layer-by-layer deposition of polymers on sacrificial template particles, iii) interfacial polymerization under miniemulsion conditions, and iv) newly emerging techniques. In the second and third part, strategies to use capsules as reservoir for aqueous or oil phases will be presented, respectively. The final part addresses some biomedical applications of these glyconanocapsules, including i) the design of drug delivery systems promoting specific targeting and extended circulation times in vivo, ii) the development of colloids for anti-microbial therapy and iii) the construction of bioimaging tools for visualizing physiological and pathological processes.
It is noted that most techniques described in this review require the modification of polysaccharides, to render them more hydrophobic, or the use of amphiphilic glycopolymers. The choice of the protocol is highly polymer-dependent, and cannot be compared with another that would not use the same polymer. Even in cases where the same polymer is used, the different routes lead to different architectures that may not compare again.
Section snippets
Water-filled sugar-based nanocapsules
Nanocapsules with an aqueous core have been long studied for their potential to encapsulate diverse hydrophilic cargos such as drugs, proteins or DNA, to design artificial cells or biomimetic nanoreactors. This chapter summarizes the most relevant methods to prepare such type of capsules.
Oil-filled sugar-based nanocapsules
Considering the medical applications of nanocapsules, especially in anti-tumor therapy via controlled release of anti-cancer drug (most of which show poor solubility in water), the construction of oil-filled nanocapsules has been extensively reported to facilitate the administration of medicine.
Applications of sugar-based nanocapsules
Sugar-based nanocapsules have been extensively studied as nanocarriers for biomedical applications owing to their specific targeting properties, stealth capabilities, high biostability and enhanced cell uptake. Here we summarize the different outputs, independent on the nature of carbohydrate polymers or the technique of capsule preparation.
Conclusion
This review has presented all the technologies of interest for the construction of carbohydrate-based nanocapsules and recent achievements in the field of nanomedicine. Indeed, thanks to the presence of sugar ligands on their outer layer, glyconanocapsules are rather unique functional nanocarriers capable i) to extend circulation life time in vivo, ii) to mimic glycan signatures, establish specific interactions with cells and promote targeting (to cells, organs), and consequently iii) to
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
We thank the support from the National Natural Science Foundation of China (Grant 21902117) and the French Agency for National Research (ANR) (PREPROPOSAL, ANR-15-CE09-0021). L.C. acknowledges the CSC for a PhD grant. The thesis of the first author [Xibo Yan thesis] [232] affords a more comprehensive description of some of the subjects of the Review, some segments of which were included in the present text.
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