Cyclodextrin Derivatives in Pharmaceutics

Albers, Eike; Müller, Bernd W.

doi:10.1615/critrevtherdrugcarriersyst.v12.i4.20

Cited by 123 publications

(55 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Previous experiments with unmodified β-cyclodextrins have shown broad, but not universal, potential for encapsulation of hydrophobic compounds (29,35,36). However, other forms of cyclodextrins, such as α-or γ-forms, have pockets of different sizes, in theory affording encapsulation of additional compounds.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Remote loading of preencapsulated drugs into stealth liposomes

Sur

Fries

Kinzler

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

123

View full text Add to dashboard Cite

Loading drugs into carriers such as liposomes can increase the therapeutic ratio by reducing drug concentrations in normal tissues and raising their concentrations in tumors. Although this strategy has proven advantageous in certain circumstances, many drugs are highly hydrophobic and nonionizable and cannot be loaded into liposomes through conventional means. We hypothesized that such drugs could be actively loaded into liposomes by encapsulating them into specially designed cyclodextrins. To test this hypothesis, two hydrophobic drugs that had failed phase II clinical trials because of excess toxicity at deliverable doses were evaluated. In both cases, the drugs could be remotely loaded into liposomes after their encapsulation (preloading) into cyclodextrins and administered to mice at higher doses and with greater efficacy than possible with the free drugs.T here is currently wide interest in the development of nanoparticles for drug delivery (1-7). This area of research is particularly relevant to cancer drugs, wherein the therapeutic ratio (dose required for effectiveness to dose causing toxicity) is often low. Nanoparticles carrying drugs can increase this therapeutic ratio over that achieved with the free drug through several mechanisms. In particular, drugs delivered by nanoparticles are thought to selectively enhance the concentration of the drugs in tumors as a result of the enhanced permeability and retention (EPR) effect (8-18). The enhanced permeability results from a leaky tumor vascular system, whereas the enhanced retention results from the disorganized lymphatic system that is characteristic of malignant tumors.Much current work in this field is devoted to designing novel materials for nanoparticle generation. This new generation of nanoparticles can carry drugs-particularly those that are insoluble in aqueous medium-that are difficult to incorporate into conventional nanoparticles such as liposomes. However, the older generation of nanoparticles has a major practical advantage in that they have been extensively tested in humans and approved by regulatory agencies such as the Food and Drug Administration in the United States and the European Medicines Agency in Europe. Unfortunately, many drugs cannot be easily or effectively loaded into liposomes, thereby compromising their general use.In general, liposomal drug loading is achieved by either passive or active methods (9,(19)(20)(21)(22). Passive loading involves dissolution of dried lipid films in aqueous solutions containing the drug of interest. This approach can only be used for water-soluble drugs, and the efficiency of loading is often low. In contrast, active loading can be extremely efficient, resulting in high intraliposomal concentrations and minimal wastage of precious chemotherapeutic agents (9,23,24). In active loading, drug internalization into preformed liposomes is typically driven by a transmembrane pH gradient. The pH outside the liposome allows some of the drug to exist in an unionized form, able to migrate across the lipid bi...

show abstract

Section: Discussionmentioning

confidence: 99%

“…Cyclodextrins are a family of cyclic sugars that are commonly used to solubilize hydrophobic drugs (29)(30)(31)(32). They possess a hydrophobic cavity and a hydrophilic surface and are known to stably encapsulate a large variety of hydrophobic organic molecules in aqueous media.…”

mentioning

confidence: 99%

Remote loading of preencapsulated drugs into stealth liposomes

Sur

Fries

Kinzler

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

123

View full text Add to dashboard Cite

show abstract

“…Because of the interest in CDs as drug delivery agents, a large number of modified CDs have been synthesized and characterized (18,103). Most of the modifications are substitutions at the primary and secondary hydroxyl groups at the upper and lower ends of the torus and offer structural variants that differ in size, hydrogen bonding capability, external hydrophobicity, and charge.…”

Section: Discussionmentioning

confidence: 99%

Reversible Pore Block of Connexin Channels by Cyclodextrins

Locke

Koreen

Liu

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

Cyclodextrins (CDs), a series of hollow cyclic glucosaccharides, can reversibly block molecular permeation through channels formed by connexin-32 and/or connexin-26 reconstituted into liposomes. The character of the block changes as a function of the size of the CD relative to the connexin pore diameter, suggesting that the block occurs via entry of the CD into the pore lumen and occlusion of the permeability pathway. The block occurs only when the CD is applied to the side of the pore that is normally cytoplasmic and not from the side that is normally extracellular. The block is potentiated when organic analytes are sequestered in the hydrophobic interior of the CDs. CDs may be useful as molecular tools with which to explore the structure of the connexin pore and to alter molecular movement through connexin channels.

show abstract

“…This property has been extensively exploited to change the physicopharmaceutical properties of lipophilic drugs such as water solubility, bioavailability, improved stability and effectiveness [2], and cyclodextrins at present are widely used as transportactive additives. The covalent attachment of bioactive peptides to cyclodextrins has also been proposed [3,4], although their grafting to the relatively large cyclodextrin carrier might impair recognition by receptor molecules.…”

Section: Introductionmentioning

confidence: 99%

Cyclodextrins as templates for the presentation of protease inhibitors

Schaschke¹,

Hj²,

Assfalg-Machleidt³

et al. 1996

FEBS Letters

View full text Add to dashboard Cite

Mono(6-succinylamido-6-deoxy)-13-cyclodextrin was synthesized by classical carbohydrate chemistry and used as a template mono-functionalized with the linear, fully flexible 4C-spacer carboxylate for covalent linkage of the calpain inhibitor leucyl-leucyl-norleucinal. Spectroscopic analyses of the conjugate do not support a self-inclusion of part of the hydrophobic peptide tail, but confirm its intra-or intermolecular interaction with the template moiety that leads to full water solubility. The inhibitory potency of the ~-cyclodextrin/peptide aldehyde construct was compared with that of the parent Ac-Leu-Leu-Nle-H against cathepsin B and calpain. Despite the large size of the template the inhibition of cathepsin B was only slightly reduced in full agreement with the X-ray structure of this enzyme which shows full accessibility of the S-subsites. For this enzyme the 4C-spacer is apparently sufficient to guarantee optimal interaction of the peptide tail with the binding cleft. Conversely, for gcalpain a significantly decreased inhibitory potency was obtained with the conjugate suggesting steric interference of the template in the binding process. These results show that the beneficial properties of the cyclodextrin template can be retained in conjugates with bioactive peptides if attention is paid to optimize in each case the size and nature of the spacer for optimal recognition of the grafted biomolecule.

show abstract

Cyclodextrin Derivatives in Pharmaceutics

Cited by 123 publications

References 0 publications

Remote loading of preencapsulated drugs into stealth liposomes

Remote loading of preencapsulated drugs into stealth liposomes

Reversible Pore Block of Connexin Channels by Cyclodextrins

Cyclodextrins as templates for the presentation of protease inhibitors

Contact Info

Product

Resources

About