title: Toxicology and drug delivery by cucurbit[n]uril type molecular containers.
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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, United States of America.
authors.forename: Gaya
authors.initials: G
authors.lastname: Hettiarachchi
authors.forename: Duc
authors.initials: D
authors.lastname: Nguyen
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.forename: Derick
authors.initials: D
authors.lastname: Lucas
authors.forename: Da
authors.initials: D
authors.lastname: Ma
authors.forename: Lyle
authors.initials: L
authors.lastname: Isaacs
authors.forename: Volker
authors.initials: V
authors.lastname: Briken
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001952:Bridged-Ring Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity*; D002460:Cell Line; D016503:Drug Delivery Systems; D004977:Ethambutol / Q000494:pharmacology; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D020102:Mycobacterium smegmatis / Q000187:drug effects; D018675:Toxicity Tests
chemical_list: D001952:Bridged-Ring Compounds; D004977:Ethambutol
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