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 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.
Hettiarachchi
Gaya
G
Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, United States of America.
Nguyen
Duc
D
Wu
Jing
J
Lucas
Derick
D
Ma
Da
D
Isaacs
Lyle
L
Briken
Volker
V
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
D001952:Bridged-Ring Compounds; D004977:Ethambutol
Anticancer Res. 2009 Jan;29(1):343-7
19331171
J Antimicrob Chemother. 2003 Dec;52(6):981-6
14613962
Org Biomol Chem. 2005 Jun 7;3(11):2122-5
15917899
J Infect Dev Ctries. 2009 May 01;3(4):278-84
19759491
Nat Rev Drug Discov. 2002 Jun;1(6):469-75
12119749
Drug Discov Today. 2007 Apr;12(7-8):289-94
17395088
Nano Lett. 2006 Aug;6(8):1794-807
16895376
Br J Pharmacol. 2005 Jan;144(1):80-7
15644871
J Org Chem. 2001 Nov 30;66(24):8094-100
11722210
J Phys Chem B. 2009 Oct 29;113(43):14172-9
19788172
Toxicol In Vitro. 2006 Sep;20(6):1051-9
16504461
J Inorg Biochem. 2008 Dec;102(12):2060-6
18653238
Dalton Trans. 2009 Jul 14;(26):5190-8
19562181
Toxicol Pathol. 2008 Jan;36(1):30-42
18337219
J Pharm Pharmacol. 2005 Apr;57(4):489-95
15831210
Molecules. 2005 Jan 31;10(1):65-80
18007277
Int J Tuberc Lung Dis. 2009 Nov;13(11):1320-30
19861002
Angew Chem Int Ed Engl. 2007;46(39):7393-5
17722124
Angew Chem Int Ed Engl. 2005 Aug 5;44(31):4844-70
16052668
J Am Chem Soc. 2005 Nov 16;127(45):15959-67
16277540
J Am Chem Soc. 2008 Jul 2;130(26):8446-54
18529059
Dalton Trans. 2009 May 14;(18):3584-9
19381421
Chem Commun (Camb). 2004 Jun 21;(12):1424-5
15179496
Nat Rev Drug Discov. 2007 Aug;6(8):636-49
17643090
Photochem Photobiol Sci. 2009 Dec;8(12):1743-7
20024172
Chem Soc Rev. 2007 Feb;36(2):267-79
17264929
Curr Pharm Des. 2009;15(25):2958-69
19754372
Opt Lett. 2008 Dec 15;33(24):2961-3
19079506
J Med Chem. 2009 Nov 26;52(22):7122-31
19883083
Eur J Med Chem. 2010 Jan;45(1):326-34
19889480
AAPS PharmSciTech. 2005 Oct 14;6(2):E329-57
16353992
Colloids Surf B Biointerfaces. 2005 Mar 25;41(2-3):189-96
15737546
Nat Rev Drug Discov. 2003 Jul;2(7):542-53
12815380
Chem Commun (Camb). 2009 Jan 7;(1):71-3
19082002
Annu Rev Med. 2009;60:307-20
19630575
Clin Cancer Res. 2008 Mar 1;14(5):1310-6
18316549
J Pharmacol Toxicol Methods. 2005 May-Jun;51(3):187-200
15862464
Am J Respir Crit Care Med. 2005 Dec 15;172(12):1487-90
16151040
Acta Pharmacol Sin. 2008 Aug;29(8):990-7
18664332
Clin Infect Dis. 2009 Aug 15;49(4):574-83
19583517
J Control Release. 2002 Feb 19;79(1-3):7-27
11853915
Drug Metab Dispos. 2009 Dec;37(12):2275-83
19741037
Nucleic Acids Res. 2010 Jan;38(1):159-71
19854946
Org Biomol Chem. 2008 Dec 21;6(24):4509-15
19039358
PLoS Pathog. 2007 Jul;3(7):e110
17658950
J Infect Dev Ctries. 2009 Feb 28;3(1):5-15
19749443