Cargando…
Toxicology and Drug Delivery by Cucurbit[n]uril Type Molecular Containers
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 β-CD and its derivatives have been widely used in the formulation of hydrophobic pharmaceuticals...
Autores principales: | , , , , , , |
---|---|
Formato: | Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2010
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2865549/ https://www.ncbi.nlm.nih.gov/pubmed/20463906 http://dx.doi.org/10.1371/journal.pone.0010514 |
_version_ | 1782180856801001472 |
---|---|
author | Hettiarachchi, Gaya Nguyen, Duc Wu, Jing Lucas, Derick Ma, Da Isaacs, Lyle Briken, Volker |
author_facet | Hettiarachchi, Gaya Nguyen, Duc Wu, Jing Lucas, Derick Ma, Da Isaacs, Lyle Briken, Volker |
author_sort | Hettiarachchi, Gaya |
collection | PubMed |
description | 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 β-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. |
format | Text |
id | pubmed-2865549 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-28655492010-05-12 Toxicology and Drug Delivery by Cucurbit[n]uril Type Molecular Containers Hettiarachchi, Gaya Nguyen, Duc Wu, Jing Lucas, Derick Ma, Da Isaacs, Lyle Briken, Volker PLoS One Research Article 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 β-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. Public Library of Science 2010-05-06 /pmc/articles/PMC2865549/ /pubmed/20463906 http://dx.doi.org/10.1371/journal.pone.0010514 Text en Hettiarachchi et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Hettiarachchi, Gaya Nguyen, Duc Wu, Jing Lucas, Derick Ma, Da Isaacs, Lyle Briken, Volker Toxicology and Drug Delivery by Cucurbit[n]uril Type Molecular Containers |
title | Toxicology and Drug Delivery by Cucurbit[n]uril Type Molecular Containers |
title_full | Toxicology and Drug Delivery by Cucurbit[n]uril Type Molecular Containers |
title_fullStr | Toxicology and Drug Delivery by Cucurbit[n]uril Type Molecular Containers |
title_full_unstemmed | Toxicology and Drug Delivery by Cucurbit[n]uril Type Molecular Containers |
title_short | Toxicology and Drug Delivery by Cucurbit[n]uril Type Molecular Containers |
title_sort | toxicology and drug delivery by cucurbit[n]uril type molecular containers |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2865549/ https://www.ncbi.nlm.nih.gov/pubmed/20463906 http://dx.doi.org/10.1371/journal.pone.0010514 |
work_keys_str_mv | AT hettiarachchigaya toxicologyanddrugdeliverybycucurbitnuriltypemolecularcontainers AT nguyenduc toxicologyanddrugdeliverybycucurbitnuriltypemolecularcontainers AT wujing toxicologyanddrugdeliverybycucurbitnuriltypemolecularcontainers AT lucasderick toxicologyanddrugdeliverybycucurbitnuriltypemolecularcontainers AT mada toxicologyanddrugdeliverybycucurbitnuriltypemolecularcontainers AT isaacslyle toxicologyanddrugdeliverybycucurbitnuriltypemolecularcontainers AT brikenvolker toxicologyanddrugdeliverybycucurbitnuriltypemolecularcontainers |