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Toxicology and drug delivery by cucurbit[n]uril type molecular containers.

Hettiarachchi G, Nguyen D, Wu J, Lucas D, Ma D, Isaacs L, Briken V - PLoS ONE (2010)

Bottom Line: This result suggests that CB[7]-bound drug molecules can be released from the container to find their intracellular target.It demonstrates the uptake of containers by cells and intracellular release of container-loaded drugs.These results provide initial proof-of-concept towards the use of CB[n] molecular containers as an advanced drug delivery system.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, United States of America.

ABSTRACT

Background: Many drug delivery systems are based on the ability of certain macrocyclic compounds - such as cyclodextrins (CDs) - to act as molecular containers for pharmaceutical agents in water. Indeed beta-CD and its derivatives have been widely used in the formulation of hydrophobic pharmaceuticals despite their poor abilities to act as a molecular container (e.g., weak binding (K(a)<10(4) M(-1)) and their challenges toward chemical functionalization. Cucurbit[n]urils (CB[n]) are a class of molecular containers that bind to a variety of cationic and neutral species with high affinity (K(a)>10(4) M(-1)) and therefore show great promise as a drug delivery system.

Methodology: In this study we investigated the toxicology, uptake, and bioactivity of two cucurbit[n]urils (CB[5] and CB[7]) and three CB[n]-type containers (Pentamer 1, methyl hexamer 2, and phenyl hexamer 3). All five containers demonstrated high cell tolerance at concentrations of up to 1 mM in cell lines originating from kidney, liver or blood tissue using assays for metabolic activity and cytotoxicity. Furthermore, the CB[7] molecular container was efficiently internalized by macrophages indicating their potential for the intracellular delivery of drugs. Bioactivity assays showed that the first-line tuberculosis drug, ethambutol, was as efficient in treating mycobacteria infected macrophages when loaded into CB[7] as when given in the unbound form. This result suggests that CB[7]-bound drug molecules can be released from the container to find their intracellular target.

Conclusion: Our study reveals very low toxicity of five members of the cucurbit[n]uril family of nanocontainers. It demonstrates the uptake of containers by cells and intracellular release of container-loaded drugs. These results provide initial proof-of-concept towards the use of CB[n] molecular containers as an advanced drug delivery system.

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Related in: MedlinePlus

Structures of the five containers.CB7, CB5, Pentamer (1), Me-Hexamer (2), and Ph- Hexamer (3) and FITC (4) and Alexa555 (5) conjugates.
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pone-0010514-g001: Structures of the five containers.CB7, CB5, Pentamer (1), Me-Hexamer (2), and Ph- Hexamer (3) and FITC (4) and Alexa555 (5) conjugates.

Mentions: We selected two CB[n] compounds, CB[5] and CB[7] (Fig. 1), for this initial study because of their excellent solubility in water. From the CB[n]-type compounds available in the Isaacs lab we also selected acyclic glycoluril pentamer (1) and two hexamers (2 and 3). Compounds 1–3 retained the ability to bind strongly to their targets but did so with faster kinetics due to their acyclic structures [23], [24]. In order to allow for the tracking of these CB[n] molecular containers inside cells we synthesized compounds 4 [25] and 5. Compounds 4 and 5 contain fluorescein or Alexa Fluor 555 dyes covalently attached to spermidine and adamantaneamine subunits that resulted in tight non-covalent binding to CB[n]-type compounds.


Toxicology and drug delivery by cucurbit[n]uril type molecular containers.

Hettiarachchi G, Nguyen D, Wu J, Lucas D, Ma D, Isaacs L, Briken V - PLoS ONE (2010)

Structures of the five containers.CB7, CB5, Pentamer (1), Me-Hexamer (2), and Ph- Hexamer (3) and FITC (4) and Alexa555 (5) conjugates.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2865549&req=5

pone-0010514-g001: Structures of the five containers.CB7, CB5, Pentamer (1), Me-Hexamer (2), and Ph- Hexamer (3) and FITC (4) and Alexa555 (5) conjugates.
Mentions: We selected two CB[n] compounds, CB[5] and CB[7] (Fig. 1), for this initial study because of their excellent solubility in water. From the CB[n]-type compounds available in the Isaacs lab we also selected acyclic glycoluril pentamer (1) and two hexamers (2 and 3). Compounds 1–3 retained the ability to bind strongly to their targets but did so with faster kinetics due to their acyclic structures [23], [24]. In order to allow for the tracking of these CB[n] molecular containers inside cells we synthesized compounds 4 [25] and 5. Compounds 4 and 5 contain fluorescein or Alexa Fluor 555 dyes covalently attached to spermidine and adamantaneamine subunits that resulted in tight non-covalent binding to CB[n]-type compounds.

Bottom Line: This result suggests that CB[7]-bound drug molecules can be released from the container to find their intracellular target.It demonstrates the uptake of containers by cells and intracellular release of container-loaded drugs.These results provide initial proof-of-concept towards the use of CB[n] molecular containers as an advanced drug delivery system.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, United States of America.

ABSTRACT

Background: Many drug delivery systems are based on the ability of certain macrocyclic compounds - such as cyclodextrins (CDs) - to act as molecular containers for pharmaceutical agents in water. Indeed beta-CD and its derivatives have been widely used in the formulation of hydrophobic pharmaceuticals despite their poor abilities to act as a molecular container (e.g., weak binding (K(a)<10(4) M(-1)) and their challenges toward chemical functionalization. Cucurbit[n]urils (CB[n]) are a class of molecular containers that bind to a variety of cationic and neutral species with high affinity (K(a)>10(4) M(-1)) and therefore show great promise as a drug delivery system.

Methodology: In this study we investigated the toxicology, uptake, and bioactivity of two cucurbit[n]urils (CB[5] and CB[7]) and three CB[n]-type containers (Pentamer 1, methyl hexamer 2, and phenyl hexamer 3). All five containers demonstrated high cell tolerance at concentrations of up to 1 mM in cell lines originating from kidney, liver or blood tissue using assays for metabolic activity and cytotoxicity. Furthermore, the CB[7] molecular container was efficiently internalized by macrophages indicating their potential for the intracellular delivery of drugs. Bioactivity assays showed that the first-line tuberculosis drug, ethambutol, was as efficient in treating mycobacteria infected macrophages when loaded into CB[7] as when given in the unbound form. This result suggests that CB[7]-bound drug molecules can be released from the container to find their intracellular target.

Conclusion: Our study reveals very low toxicity of five members of the cucurbit[n]uril family of nanocontainers. It demonstrates the uptake of containers by cells and intracellular release of container-loaded drugs. These results provide initial proof-of-concept towards the use of CB[n] molecular containers as an advanced drug delivery system.

Show MeSH
Related in: MedlinePlus