title: Analysis of biotinylated generation 4 poly(amidoamine) (PAMAM) dendrimer distribution in the rat brain and toxicity in a cellular model of the blood-brain barrier.
abstract: Dendrimers are highly customizable nanopolymers with qualities that make them ideal for drug delivery. The high binding affinity of biotin/avidin provides a useful approach to fluorescently label synthesized dendrimer-conjugates in cells and tissues. In addition, biotin may facilitate delivery of dendrimers through the blood-brain barrier (BBB) via carrier-mediated endocytosis. The purpose of this research was to: (1) measure toxicity using lactate dehydrogenase (LDH) assays of generation (G)4 biotinylated and non-biotinylated poly(amidoamine) (PAMAM) dendrimers in a co-culture model of the BBB, (2) determine distribution of dendrimers in the rat brain, kidney, and liver following systemic administration of dendrimers, and (3) conduct atomic force microscopy (AFM) on rat brain sections following systemic administration of dendrimers. LDH measurements showed that biotinylated dendrimers were toxic to cell co-culture after 48 h of treatment. Distribution studies showed evidence of biotinylated and non-biotinylated PAMAM dendrimers in brain. AFM studies showed evidence of dendrimers only in brain tissue of treated rats. These results indicate that biotinylation does not decrease toxicity associated with PAMAM dendrimers and that biotinylated PAMAM dendrimers distribute in the brain. Furthermore, this article provides evidence of nanoparticles in brain tissue following systemic administration of nanoparticles supported by both fluorescence microscopy and AFM.
authors.affiliation: Department of Biological Sciences, Northern Kentucky University, SC 204, Highland Heights, KY 41099, USA. morrisc2@nku.edu.
authors.forename: Ruth
authors.initials: R
authors.lastname: Hemmer
authors.forename: Andrew
authors.initials: A
authors.lastname: Hall
authors.forename: Robert
authors.initials: R
authors.lastname: Spaulding
authors.forename: Brett
authors.initials: B
authors.lastname: Rossow
authors.forename: Michael
authors.initials: M
authors.lastname: Hester
authors.forename: Megan
authors.initials: M
authors.lastname: Caroway
authors.forename: Anthony
authors.initials: A
authors.lastname: Haskamp
authors.forename: Steven
authors.initials: S
authors.lastname: Wall
authors.forename: Heather A
authors.initials: HA
authors.lastname: Bullen
authors.forename: Celeste
authors.initials: C
authors.lastname: Morris
authors.forename: Kristi L
authors.initials: KL
authors.lastname: Haik
mesh_terms: D000818:Animals; D019921:Biotinylation; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D002478:Cells, Cultured; D018920:Coculture Techniques; D050091:Dendrimers / Q000493:pharmacokinetics* / Q000633:toxicity; D004337:Drug Carriers / Q000493:pharmacokinetics* / Q000633:toxicity; D004353:Drug Evaluation, Preclinical; D008954:Models, Biological; D051381:Rats; D014018:Tissue Distribution
chemical_list: D050091:Dendrimers; D004337:Drug Carriers; C104700:PAMAM Starburst
references.citation: Chem Soc Rev. 2011 Jan;40(1):173-90
references.pmid: 20877875
references.citation: J Neurochem. 1987 Feb;48(2):400-4
references.pmid: 3098919
references.citation: J Cell Biol. 1967 Jul;34(1):207-17
references.pmid: 6033532
references.citation: Biomaterials. 2008 Aug-Sep;29(24-25):3469-76
references.pmid: 18501424
references.citation: Eur J Pharm Biopharm. 2010 Feb;74(2):157-63
references.pmid: 19755158
references.citation: Annu Rev Biophys Biomol Struct. 1994;23:115-39
references.pmid: 7919779
references.citation: Mol Cancer Ther. 2006 Jan;5(1):52-9
references.pmid: 16432162
references.citation: Biochim Biophys Acta. 2011 Nov;1808(11):2714-23
references.pmid: 21806962
references.citation: Nanomedicine (Lond). 2010 Nov;5(9):1317-29
references.pmid: 21128716
references.citation: Bioconjug Chem. 1998 Nov-Dec;9(6):813-25
references.pmid: 9815176
references.citation: Pharm Res. 2010 Sep;27(9):1759-71
references.pmid: 20593303
references.citation: Eur J Pharm Biopharm. 2011 Oct;79(2):232-40
references.pmid: 21496485
references.citation: J Biomech. 2010 Nov 16;43(15):2986-92
references.pmid: 20656292
references.citation: J Histochem Cytochem. 1981 Oct;29(10):1196-204
references.pmid: 7028859
references.citation: Neurobiology (Bp). 1997;5(1):1-16
references.pmid: 9302692
references.citation: Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7162-6
references.pmid: 7638161
references.citation: Anal Chem. 2004 Aug 1;76(15):4465-71
references.pmid: 15283589
references.citation: ChemMedChem. 2008 Sep;3(9):1395-403
references.pmid: 18613205
references.citation: Curr Pharm Des. 2009;15(8):917-25
references.pmid: 19275654
references.citation: Cell Tissue Res. 1999 Jun;296(3):511-6
references.pmid: 10370137
references.citation: Analyst. 2011 Jun 7;136(11):2270-6
references.pmid: 21509366
references.citation: J Biotechnol. 1992 Sep;25(3):231-43
references.pmid: 1368802
references.citation: J Control Release. 2006 May 30;112(3):312-9
references.pmid: 16626835
references.citation: Int Rev Cytol. 1991;127:57-109
references.pmid: 1880006
references.citation: Crit Rev Ther Drug Carrier Syst. 2011;28(2):101-64
references.pmid: 21663574
references.citation: Clin Cancer Res. 2001 Nov;7(11):3606-12
references.pmid: 11705883
references.citation: Neuroreport. 2000 Apr 7;11(5):1081-4
references.pmid: 10790886
references.citation: J Am Chem Soc. 2004 Oct 20;126(41):13204-5
references.pmid: 15479057
references.citation: J Cereb Blood Flow Metab. 2009 Dec;29(12):1914-23
references.pmid: 19654588
references.citation: J Biomed Mater Res B Appl Biomater. 2010 Apr;93(1):59-64
references.pmid: 20186802
references.citation: Int J Pharm. 2008 Aug 6;360(1-2):204-12
references.pmid: 18565704
references.citation: Int J Pharm. 2003 Feb 18;252(1-2):263-6
references.pmid: 12550802
references.citation: Int J Anal Chem. 2012;2012:341260
references.pmid: 22505915
references.citation: Chem Biol. 1997 Dec;4(12):951-9
references.pmid: 9427660
references.citation: J Immunol Methods. 1988 Nov 25;115(1):61-9
references.pmid: 3192948
references.citation: Biomaterials. 2010 Mar;31(8):2097-104
references.pmid: 20035997
references.citation: J Appl Biomater Funct Mater. 2012;10(3):163-9
references.pmid: 23242880
references.citation: J Comp Neurol. 2004 May 17;473(1):86-96
references.pmid: 15067720
references.citation: J Pharm Pharmacol. 2009 Aug;61(8):989-1003
references.pmid: 19703342
references.citation: Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3688-93
references.pmid: 10097098
references.citation: Chem Soc Rev. 2004 Jan 10;33(1):43-63
references.pmid: 14737508
references.citation: Neurotoxicology. 2009 Jan;30(1):136-43
references.pmid: 19026682
references.citation: Pharm Res. 1993 Feb;10(2):282-8
references.pmid: 8456078
references.citation: Neurotoxicology. 2011 Dec;32(6):734-41
references.pmid: 21827787
references.citation: Cell Mol Life Sci. 2005 Jun;62(12):1400-8
references.pmid: 15905957
references.citation: Langmuir. 2004 Apr 13;20(8):3264-70
references.pmid: 15875856
references.citation: Neurochem Res. 1988 Mar;13(3):213-9
references.pmid: 3386776
references.citation: CNS Neurol Disord Drug Targets. 2011 Aug;10(5):576-88
references.pmid: 21631401
references.citation: Toxicol Sci. 2010 May;115(1):183-93
references.pmid: 20142434
references.citation: Pharm Res. 2011 Jul;28(7):1500-19
references.pmid: 21181549
references.citation: Adv Drug Deliv Rev. 2005 Dec 14;57(15):2106-29
references.pmid: 16305813
references.citation: Microsc Res Tech. 2011 Jul;74(7):699-708
references.pmid: 21698718
references.citation: Part Fibre Toxicol. 2010 Mar 03;7:3
references.pmid: 20199661
references.citation: Acta Pharmacol Sin. 2011 Aug;32(8):983-90
references.pmid: 21743485
references.citation: Biomaterials. 2009 Oct;30(29):5660-6
references.pmid: 19595449
references.citation: J Med Chem. 2010 Apr 22;53(8):3262-72
references.pmid: 20350006
references.citation: J Neuroimmune Pharmacol. 2008 Jun;3(2):83-94
references.pmid: 18210200
references.citation: Methods Mol Biol. 2008;418:111-28
references.pmid: 18287654
references.citation: Clin Cancer Res. 2007 Mar 15;13(6):1663-74
references.pmid: 17363519
references.citation: J Neurochem. 1970 Feb;17(2):289-90
references.pmid: 5494057
references.citation: Chem Rev. 2010 Apr 14;110(4):1857-959
references.pmid: 20356105
references.citation: Expert Rev Clin Pharmacol. 2011 May;4(3):329-34
references.pmid: 22114779
references.citation: Toxicol In Vitro. 2005 Apr;19(3):299-334
references.pmid: 15713540
references.citation: Anal Biochem. 2000 Jun 15;282(1):121-8
references.pmid: 10860508
references.citation: Toxicol Mech Methods. 2013 Mar;23(3):153-60
references.pmid: 23278213
references.citation: Neuroimage. 2001 Dec;14(6):1348-52
references.pmid: 11707090