Current Topics in Medicinal Chemistry - Volume 14, Issue 4, 2014

Cyclodextrins are natural cyclic oligosaccharides that play a relevant role in different fields as pharmacy, medicine, chemistry, material, food or agricultural science. From the point of view of pharmaceutical and medical applications cyclodextrins have interest for their ability to form inclusion complexes with different host molecules as drugs. In the pharmaceutical industry, cyclodextrins has been used classically as solubilizes of hydrophobic drugs or as stabilizers of some labile molecules but can also offer interesting possibilities for drug control release of both hydrophobic and hydrophilic drugs. New and interesting perspectives for their use is being developed in recent years by the development of novel cyclodextrin derivatives including the polymeric one. The proposed topic for this special number of CTMC aims to provide new successes, challenges and recent advances on the design and applications of new CDs derivatives into the biomedical and pharmaceutical field .

Recently, various cyclodextrin (CyD)-grafted polymers and supramolecules have been developed as gene and oligonucleotide carriers. We have demonstrated that among the various polyamidoamine starburstTM dendrimers (dendrimers) conjugates with CyDs (CDEs), the dendrimer (G2 or G3) conjugate with α-CyD showed high gene and oligonucleotide transfer activity with negligible cytotoxicity. In addition, to develop tissue- or cell-specific gene transfer carriers, we also prepared α-CDEs modified with functional molecules, such as mannose, fucose, galactose, lactose, polyethylene glycol (PEG) and folate-PEG. Moreover, polypseudorotaxane-appended α-CDEs were developed as sustained release systems for DNA and siRNA. Interestingly, glucronylglucosyl-β-CyD conjugates with dendrimer (G2) (GUG-β-CDE (G2)) showed high gene transfer activity compared to α-CDE (G2) and β-CDE (G2). In this review, we focus on the potential use of various CDEs as DNA and oligonucleotide transfer carriers.

For years, great efforts have been made by scientists to construct various novel interlocked supramolecular systems. A wide range of pseudorotaxanes and rotaxanes [1-7], full of challenging constructions and potential applications in areas such as nanostructured functional materials [8,9], molecular switches [10-14], molecular logic gates [15-19], molecular wires [20-22], memory devices Willner [23] and biomedical applications [24,25] have been reported recently. Cyclodextrin polyrotaxantes or polypseudorotaxanes there are not only nice and interesting supramolecular architectures but they also have a high interest for biomaterials application that allow to opened up new approaches for tissue regeneration, drug and gene delivery. The use of the supramolecular cyclodextrins complexes has given rise to interesting studies to design and develop new biomaterials with advanced properties. In this review we will update the recent advances in the use of CDs-supramolecular structures for develop new and advanced drug and gene delivery systems and for use in tissue engineering.

The design of syringeable cyclodextrin (CD) gels is a developing area in the drug delivery and tissue engineering fields, since they offer the possibility of being administered with minimally invasive maneuvers to form depots that can remain for prolonged time in the implantation site. Two different supramolecular systems can be obtained exploiting the capability of CDs to form inclusion complexes. (i) The threading of free CDs on certain blocks or side chains of copolymers leads to polypseudorotaxanes, which can assembly via regular stacking of the threaded CDs. The resultant assemblies can be reversible broken under a certain shear stress and reformed at rest, exhibiting thixotropy that enables the flow through the syringe and the gel recovery in the implantation site. (ii) CDs grafted to polymer chains can develop their ability to form inclusion complexes with complementary guest moieties in other polymeric structures. The result is a ladder- or zipper-like arrangement, which can be also broken and reformed under certain stress conditions. Both types of CDsupramolecular gels can load and stabilize a variety of drugs via interaction with available polymer functional groups or with the CDs that are not participating in other complexes. Moreover, since the complex formation depends on various external and internal variables of the body, the syringeable CD gels can also provide stimuli-responsive drug release. This review focuses on the two main types of syringeable CD gels, prepared via self-aggregation of poly(pseudo)rotaxanes and via zipper-like assembly of CD-functionalized and guest-functionalized macromolecules, and analyzes the mechanisms and variables involved in the gelling processes and the most recent applications in the drug delivery field.

The main interest of cyclodextrins results from their ability to form inclusion complexes with hydrophobic molecules. This property is employed in pharmaceutical industry to facilitate the formulation of poorly-soluble and/or fragile drugs. Cyclodextrins are also used to form or stabilise dispersed systems. An original multiparticulate system named “beads” is obtained thanks to the interactions occurring between the molecules of α cyclodextrin and the triglycerides of vegetable oils. Beads are prepared by a simple process involving the external shaking of a mixture of an aqueous solution of α cyclodextrin with soybean oil. This is done without any organic solvent or surface-active agent. Once freezedried, beads have a diameter of 1.6 mm and a high lipid content. They consist in a partially crystalline matrix of cyclodextrin surrounding microdomains of oil. The coating of beads with a layer of α cyclodextrin improves their resistance in gastro- intestinal fluids and prolongs the release of drugs. Beads can also be manufactured from mineral oils with α cyclodextrin and from silicone oils with γ cyclodextrin. Poorly-soluble drugs which do not form inclusion complexes with α cyclodextrin are encapsulated in beads with high efficiency and drug loading. In rats, the oral bioavailability of isotretinoin is twofold enhanced with uncoated beads as compared to the lipid content of a soft capsule. The relative oral bioavailability of indomethacin is improved with both coated and uncoated beads versus a commercial hard capsule. Beads demonstrate an important potential for the encapsulation of poorly-soluble and/or fragile compounds and their delivery by oral route.

This mini-review paper does not consider classical work concerning the formation of inclusion complexes between pharmaceuticals and cyclodextrins. Instead, it highlights recent reports concerning the association of these host:guest systems with other carrier systems such as liposomes and nanoparticles showing the state of art of this subject with examples of developed systems and the advantages of these strategy in order to be potential systems as drug carriers.

Nowadays, colloidal drug carriers represent an alternative to solve drug bioavailabily problems. During the past two decades, colloidal drug carriers have proved to improve the therapeutic index of drugs and thus increase their efficacy and/or reduce their toxicity. However, the major challenge in the development of these drug carriers remains the search for materials able to self-organize into stable nanoscale systems. In particular, amphiphilic α-, β- and γ-cyclodextrins (CDs), grafted on their secondary or primary side with different aliphatic chains, have been investigated as drug delivery vehicles due to their ability to self-assemble and form various stable colloidal systems such as micellar aggregates, nanoreservoirs or nanoparticles exhibiting a matricial, multilamellar or hexagonal supramolecular organization. These self-assembled CD-based nanodevices show some advantages in terms of stability, good ability to associate lipophilic drugs and good in vivo tolerance. This review focuses on the potential of the structured nanoparticles obtained from nonionic amphiphilic CDs in drug delivery and targeting. We discuss the synthesis and characterization of the building blocks as well as the preparation and characterization of colloidal particles made from these materials. We also considered some pharmaceutical applications and identified opportunities for an optimum use of this CD-based nanotechnology approach in addressing worldwide priority health problems.

The aim of the present review is to give an overview of a new class of polysaccharidic CD-based systems and to address the use of these systems in drug delivery. First, we review miscellaneous methods to obtain and synthesize the structural modification of natural polysaccharides, mainly, with cyclodextrins. In a second part of this review, we provide a summary of recent findings not only in the field of drug delivery, but in also how these systems have displayed different applications in the biomedical and pharmaceutical fields.