Design of dextran-covered nanocapsules for biomedical application – Nanocapdex

Dextran-covered nanocapsules with controlled morphology including a dextran coverage, a sensitive polymer shell and an internal liquid oily-core, were obtained by combining the use of a controlled radical miniemulsion polymerization process with a multi-reactive surfactant dextran derivative, acting both as macromolecular transfer agent and miniemulsion stabilizer.
The choice of the oily-core oil as well as the design of the dextrane derivative are essential to obtain for these nano-objects both adequate size distribution and stability during and after the polymerization.
The second challenge for such nanocapsules is the control of the core-shell morphology. That can be ensured both by phase segregation as well as by confinement of the polymerization at the liquid/liquid interface thanks to the multi-reactive stabilizer. The control of the polymerization will be the last challenge, which should enable the control of graft length and thus of the shell thickness. The use of the macro transfer agent enables it by choosing the appropriate polymerization conditions.

Biocompatible and pH-sensitive oily-core nanocapsules (NCs) were produced by controlled radical miniemulsion polymerization interfacially confined at liquid/liquid interface using a multi-reactive polysaccharidic stabilizer. These objects were characterized in terms of size, polysaccharidic coverage, colloidal stability and morphology. Potential of these nano-objects for biomedical applications was evaluated (encapsulation and release of a model substance, surface functionalization cytotoxicity…).

There is currently no doubt that medicine will require new treatments in the near future. And in this prospect Drug delivery systems and nanomedicine are one of the key developments, especially in oncology. To answer this need, the present project describes the breakthrough work that has led to a new platform of nanocapsules for drug delivery systems. The scientific and technical outcomes of this project have greatly increased knowledge in nanomedicine in different ways:
-From the one hand, this project has assessed a new process based on transurf combining the use of controlled radical polymerization and polymerization in miniemulsion. The limit of this process have been tested in direct emulsion with a new family of transurfs. A better fundamental understanding has been established between the caracteristics of the obtained nanocapsules and the experimental conditions (type of transurf, polymerization conditions, formulation…). Thus it would serve as a bench mark to produce well-defined nanocapsules in the future.
- On the other hand, it will enable the development of dextran-covered nanocapsules which could be functionalized for specific applications, especially for the delivery of cancer drugs. Such nanocapsules should be tested in vivo in the future by biologists.

The multidisciplinary character of the project give to the obtained results a strong added value. Therefore, it has already led to 15 conferences or poster, 3 papers and a PhD dissertation. Other potential scientific dissemination are ongoing. Being mainly a fundamental research project, it doesn’t have immediate impact on industrial and economical world, but it may have future developments, especially in the biomedical field.

The area of nanomedicine has become extremely important in recent years because of potential for effective cancer therapies. Research in this area, specially the design of new Drug Delivery Systems (DDS) has attracted high attention in the last decades. Among these DDS, nanocapsules are nano-vesicular systems exhibiting a core-shell structure, the core acting as a liquid reservoir for drugs and the shell as a protective membrane. Nanocapsules appear as very promising potential carriers because of the versatile character of their inner liquid core, their high encapsulation efficiency and their reduced amount of solid content compared to other systems. In this context, this project intends to develop a new platform of dextran-covered nanocapsules with controlled morphology including a dextran coverage, a sensitive polymer shell and an internal liquid oil-core.
This original approach combines the use of miniemulsion polymerization process combined with an advanced controlled radical polymerization technique (CRP) and a reactive surfactant called transurf. In miniemulsion process the polymerization is located only inside the nanodroplets obtained after the emulsification. The main advantage of this process is its ability to produce a final dispersion of nano-objects, whose size distribution is roughly a copy of the initial monomer emulsion. The transurf will be a dextran derivative that stabilizes the miniemulsion as well as acts as transfer agent during the polymerization. Located at the nanodroplet interface, the transurf will enable the segregation of the polymerization at this interface resulting in nanocapsule formation. Thanks to the multifunctional character of the transurf, grafted copolymers will be synthesized at the interface and its grafts will constitute the inner polymeric shell linked to the dextran coverage. Transurf together with the use of a controlled polymerization (Reversible Addition Fragmentation Chain Transfer –RAFT polymerization) should facilitate the control of nanocapsule morphology especially the shell thickness.
Our expected outcomes on scientific level are to produce a technological platform of dextran-covered oil-core nanocapsules. These nanocapsules will be obtained by direct miniemulsion polymerization using water-soluble dextran transurfs. Then they will be characterized and relationships between their morphology and synthesis conditions will be expounded. Fluorescent probes will be encapsulated inside the nanocapsules during their synthesis to mimic future potential drug. Potential of these new nano-objects as DDS will be also studied for different features: firstly the stability of these nano-objects in physiological medium will be checked depending on their morphology. Secondly, their probe release profiles will be studied in vitro sink conditions, and then stealthy properties of these dextran-covered nanocapsules will be examined. At the end, these nanocapsules could be modified on their surface by model fluorescent probe as mimic of targeting ligand and the easiness to modify the surface of these objects will be investigated. For all of that, first work of this project will be the design of an appropriate family of water-soluble dextran derivatives as transurfs. Such macromolecules will contain both RAFT functionalities and hydrophobic groups to be both multi-functional macro-RAFT agent and surfactant. In addition, other functionalities will serve as linker to facilitate the post-modification of the nanocapsules at their surface.
This project will be an opportunity to develop a new synthetic way to obtain polysaccharide-covered nanocapsules with controlled and complex morphology. To the best of our knowledge it will be the first dextran-covered nanocapsule platform developped by combined use of miniemulsion polymerization conditions, reactive surfactants based on polysaccharide and CRP and the first study utilizing multi-functional polysaccharide transurf for CRP in dispersed medium.