title: Gd-labeled glycol chitosan as a pH-responsive magnetic resonance imaging agent for detecting acidic tumor microenvironments.
abstract: Neoplastic lesions can create a hostile tumor microenvironment with low extracellular pH. It is commonly believed that these conditions can contribute to tumor progression as well as resistance to therapy. We report the development and characterization of a pH-responsive magnetic resonance imaging contrast agent for imaging the acidic tumor microenvironment. The preparation included the conjugation of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid 1-(2,5-dioxo-1-pyrrolidinyl) ester (DOTA-NHS) to the surface of a water-soluble glycol chitosan (GC) polymer, which contains pH-titrable primary amines, followed by gadolinium complexation (GC-NH2-GdDOTA). GC-NH2-GdDOTA had a chelate-to-polymer ratio of approximately1:24 and a molar relaxivity of 9.1 mM(-1) s(-1). GC-NH2-GdDOTA demonstrated pH-dependent cellular association in vitro compared to the control. It also generated a 2.4-fold enhancement in signal in tumor-bearing mice 2 h postinjection. These findings suggest that glycol chitosan coupled with contrast agents can provide important diagnostic information about the tumor microenvironment.
authors.affiliation: Department of Bioengineering, University of Pennsylvania , 240 Skirkanich Hall, 210 South 33rd Street, Philadelphia 19104, Pennsylvania, United States.
authors.forename: Kido
authors.initials: K
authors.lastname: Nwe
authors.forename: Ching-Hui
authors.initials: CH
authors.lastname: Huang
authors.forename: Andrew
authors.initials: A
authors.lastname: Tsourkas
mesh_terms: D000143:Acids / Q000737:chemistry; D000818:Animals; D048271:Chitosan / Q000737:chemistry*; D003287:Contrast Media / Q000737:chemistry*; D005682:Gadolinium / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000737:chemistry / Q000175:diagnosis / Q000000981:diagnostic imaging*; D011859:Radiography; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013388:Succinimides / Q000737:chemistry; D059016:Tumor Microenvironment
chemical_list: D000143:Acids; D003287:Contrast Media; C502492:DOTA-NHS; D013388:Succinimides; C118638:glycol-chitosan; D048271:Chitosan; D005682:Gadolinium
references.citation: Radiology. 2001 Jul;220(1):13-30
references.pmid: 11425968
references.citation: ACS Nano. 2011 Dec 27;5(12):9592-601
references.pmid: 22035454
references.citation: Magn Reson Med. 2012 Mar;67(3):760-8
references.pmid: 22028287
references.citation: Radiology. 1997 Sep;204(3):677-84
references.pmid: 9280243
references.citation: J Magn Reson Imaging. 1994 May-Jun;4(3):381-8
references.pmid: 8061437
references.citation: Angew Chem Int Ed Engl. 2002 Nov 15;41(22):4334-6
references.pmid: 12434381
references.citation: ACS Nano. 2012 Nov 27;6(11):9416-24
references.pmid: 23098069
references.citation: Radiology. 1995 Jul;196(1):115-22
references.pmid: 7784554
references.citation: N Engl J Med. 2005 Oct 27;353(17):1784-92
references.pmid: 16251534
references.citation: Biochim Biophys Acta. 2007 Apr;1770(4):495-505
references.pmid: 17240531
references.citation: Radiology. 2001 Jul;220(1):31-9
references.pmid: 11425969
references.citation: Br J Cancer. 1991 Oct;64(4):663-70
references.pmid: 1911214
references.citation: Bioconjug Chem. 1999 Mar-Apr;10(2):192-9
references.pmid: 10077467
references.citation: Invest Radiol. 2010 Oct;45(10):613-24
references.pmid: 20808234
references.citation: JAMA. 2004 Dec 8;292(22):2735-42
references.pmid: 15585733
references.citation: Radiology. 1990 May;175(2):483-8
references.pmid: 1691513
references.citation: Contrast Media Mol Imaging. 2012 Mar-Apr;7(2):175-84
references.pmid: 22434630
references.citation: J Am Chem Soc. 2006 Nov 29;128(47):15072-3
references.pmid: 17117842
references.citation: Radiology. 1994 Jul;192(1):272-3
references.pmid: 8208952
references.citation: Cancer Res. 2009 Mar 15;69(6):2260-8
references.pmid: 19276390
references.citation: Biomacromolecules. 2007 Dec;8(12):3758-66
references.pmid: 18031015
references.citation: Br J Cancer. 1998 Sep;78(5):606-11
references.pmid: 9744499
references.citation: Radiology. 1993 Jun;187(3):701-6
references.pmid: 8497616
references.citation: J Magn Reson Imaging. 2002 Oct;16(4):430-50
references.pmid: 12353258
references.citation: Br J Cancer. 1999 Jun;80(7):1005-11
references.pmid: 10362108
references.citation: J Am Chem Soc. 2010 Oct 13;132(40):14002-3
references.pmid: 20853833
references.citation: Chem Commun (Camb). 2011 Jul 28;47(28):8130-2
references.pmid: 21629879
references.citation: J Biomed Mater Res A. 2007 Dec 1;83(3):787-98
references.pmid: 17559127
references.citation: Magn Reson Med. 1991 Dec;22(2):282-7; discussion 300-3
references.pmid: 1725917
references.citation: Clin Exp Metastasis. 1996 Mar;14(2):176-86
references.pmid: 8605731
references.citation: Biomaterials. 2012 Jul;33(21):5363-75
references.pmid: 22521487
references.citation: Am J Prev Med. 1996 Sep-Oct;12(5):340-1
references.pmid: 8909643
references.citation: Br J Radiol. 2003;76 Spec No 1:S11-22
references.pmid: 15456710
references.citation: Magn Reson Med. 2002 Apr;47(4):639-48
references.pmid: 11948724
references.citation: NMR Biomed. 1992 Nov-Dec;5(6):351-9
references.pmid: 1489671
references.citation: Nature. 2008 Jun 12;453(7197):940-3
references.pmid: 18509335