Nanoassemblies made of bioesterified cyclodextrins: potential applications for nanomedicine – CYDEXCAR

Nowadays, there is a surge of academics and industry interest in nanomedicine, which can be defined as the use of nanoscale or nanostructured materials in medicine that, depending on their structure, will exhibit specific medical effects. Undoubtedly, drug delivery and targeting represent the dominant research field in nanomedicine. For example, systemic cancer therapy was significantly improved using nanomaterials. However, it is well known that tumor localization in human organism as well as their environment vary. In addition, numerous existing anticancer and/or new drugs used for treatments exhibit different physicochemical and pharmacological profiles. For these reasons and despite the valuable and available sophisticated drug nanocarriers that have reached the market, there is still a need to develop new systems to consider potential unsolved medical problems.
In this context, the introduction of cyclodextrins (CDs) in pharmaceutical formulations several years ago opened the opportunity to design new supramolecular assemblies. Indeed, these natural cyclic oligosaccharides and their water-soluble derivatives, whose toxicological profiles and regulatory status are somewhat well established, are able to interact with poorly water-soluble drugs through the formation of inclusion compounds, increasing solubility and, consequently, enhancing bioavailability. Despite the advantages brought by water-soluble inclusion complexes, the hydrophilic character of the CDs reduces their interaction with biological membranes. Owing to the chemical nature of CDs making them prone to be chemically-modified, the grafting of hydrophobic moieties helped overcome this drawback by modulating the external hydrophobicity of the parent CDs. Our recent studies have shown that decanoate beta-CD esters, obtained by thermolysin-catalyzed acylation, could self-assemble into nanospheres with a multilamellar onion-like ultrastructure. We also showed that mixing amphiphilic CDs, acting as cavity based building nanoblocks, with other lipid derivatives could favor the formation of hybrid structures as well as bi- and multicompartment nanodevices. The objective of CYDEXCAR is to explore and confirm the concept of new multifunctional nanoscale devices. The performance of the new nanocarriers will be compared to those of some existing systems.
The main steps of the project are:
- Synthesize substantial amounts of amphiphilic CD derivatives using an enzymatically-assisted approach, characterize their chemical and physical chemistry properties, and evaluate their self-assembling properties. Based on our previous results, we will focus on two main derivatives, namely, beta- and gamma-CDs grafted with C10 alkyl chains.
- Design several types of nanocarriers: i) ß- and gamma-CD-C10-based carriers of first generation for passive targeting. ii) Surface patterning of ß- and gamma-CD-C10 particles, firstly to make them stealth and then to prolong their blood circulation resident time, in the second place, add peripheral ligands to achieve specific site targeting. iii) Multi-compartmented particles from beta- and gamma-CD-C10 and phospholipids as well as hybrid nanoparticles from beta- or gamma-CD-C10 and phospholipids.
- Characterize the morphology and resolve the particle ultrastructure. Knowledge of the auto-organization procedure may help to optimize galenic formulations.
- Study the in vivo behavior of blank and drug-loaded nanocarriers: biodistribution, stealth properties and animals tolerance/toxicology following their administration.