title: Ionically Cross-Linked Polymer Networks for the Multiple-Month Release of Small Molecules.
abstract: Long-term (multiple-week or -month) release of small, water-soluble molecules from hydrogels remains a significant pharmaceutical challenge, which is typically overcome at the expense of more-complicated drug carrier designs. Such approaches are payload-specific and include covalent conjugation of drugs to base materials or incorporation of micro- and nanoparticles. As a simpler alternative, here we report a mild and simple method for achieving multiple-month release of small molecules from gel-like polymer networks. Densely cross-linked matrices were prepared through ionotropic gelation of poly(allylamine hydrochloride) (PAH) with either pyrophosphate (PPi) or tripolyphosphate (TPP), all of which are commonly available commercial molecules. The loading of model small molecules (Fast Green FCF and Rhodamine B dyes) within these polymer networks increases with the payload/network binding strength and with the PAH and payload concentrations used during encapsulation. Once loaded into the PAH/PPi and PAH/TPP ionic networks, only a few percent of the payload is released over multiple months. This extended release is achieved regardless of the payload/network binding strength and likely reflects the small hydrodynamic mesh size within the gel-like matrices. Furthermore, the PAH/TPP networks show promising in vitro cytocompatibility with model cells (human dermal fibroblasts), though slight cytotoxic effects were exhibited by the PAH/PPi networks. Taken together, the above findings suggest that PAH/PPi and (especially) PAH/TPP networks might be attractive materials for the multiple-month delivery of drugs and other active molecules (e.g., fragrances or disinfectants).
authors.affiliation: Department of Chemical and Environmental Engineering, University of Toledo , Toledo, Ohio 43606, United States.
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Lawrence
authors.affiliation: Department of Chemical and Biomolecular Engineering, University of Akron , Akron, Ohio 44325, United States.
authors.forename: Pritam S
authors.initials: PS
authors.lastname: Patil
authors.affiliation: Department of Chemical and Biomolecular Engineering, University of Akron , Akron, Ohio 44325, United States.
authors.forename: Nic D
authors.initials: ND
authors.lastname: Leipzig
authors.affiliation: Department of Chemical and Environmental Engineering, University of Toledo , Toledo, Ohio 43606, United States.|School of Green Chemistry and Engineering, University of Toledo , Toledo, Ohio 43606, United States.
authors.forename: Yakov
authors.initials: Y
authors.lastname: Lapitsky
mesh_terms: D001672:Biocompatible Materials / Q000737:chemistry* / Q000627:therapeutic use; D048271:Chitosan / Q000737:chemistry; D011756:Diphosphates / Q000737:chemistry; D016503:Drug Delivery Systems; D065546:Drug Liberation; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D020100:Hydrogels / Q000737:chemistry / Q000627:therapeutic use; D011073:Polyamines / Q000737:chemistry
chemical_list: D001672:Biocompatible Materials; D011756:Diphosphates; D020100:Hydrogels; D011073:Polyamines; C063994:polyallylamine; C107241:diphosphoric acid; D048271:Chitosan
keywords: coacervates; gels; ionic cross-linking; long-term release; small molecules
references.citation: J Control Release. 2002 Feb 19;79(1-3):7-27
references.pmid: 11853915
references.citation: Pharm Res. 1988 Sep;5(9):592-7
references.pmid: 3247322
references.citation: J Craniomaxillofac Surg. 2012 Dec;40(8):e229-35
references.pmid: 22082730
references.citation: J Am Chem Soc. 2010 Feb 17;132(6):1929-38
references.pmid: 20092330
references.citation: J Pharm Sci. 2007 Apr;96(4):802-13
references.pmid: 17080411
references.citation: Drugs. 2008;68(1):85-104
references.pmid: 18081374
references.citation: Anal Biochem. 1989 May 15;179(1):131-7
references.pmid: 2757186
references.citation: Br J Anaesth. 1997 Jul;79(1):9-13
references.pmid: 9301381
references.citation: Adv Colloid Interface Sci. 2015 May;219:27-53
references.pmid: 25747522
references.citation: J Am Chem Soc. 2003 Dec 3;125(48):14859-66
references.pmid: 14640663
references.citation: Biomacromolecules. 2011 Nov 14;12(11):4112-20
references.pmid: 22007750
references.citation: J Pharm Sci. 2000 Jul;89(7):910-9
references.pmid: 10861592
references.citation: J Biomater Sci Polym Ed. 1993;4(3):305-22
references.pmid: 8476797
references.citation: Org Biomol Chem. 2005 Aug 21;3(16):2917-20
references.pmid: 16186921
references.citation: Biochem Pharmacol. 2001 Dec 15;62(12):1587-95
references.pmid: 11755111
references.citation: Adv Drug Deliv Rev. 2006 Nov 30;58(12-13):1379-408
references.pmid: 17081649
references.citation: Eur J Pharm Biopharm. 2003 Mar;55(2):229-36
references.pmid: 12637102
references.citation: Polymers (Basel). 2011 Sep 1;3(3):1377-1397
references.pmid: 22577513
references.citation: J Phys Chem B. 2013 Aug 15;117(32):9548-57
references.pmid: 23856000
references.citation: J Control Release. 2014 Sep 28;190:31-2
references.pmid: 25356469
references.citation: Bioconjug Chem. 1999 Sep-Oct;10(5):877-83
references.pmid: 10502356
references.citation: Langmuir. 2014 Jul 8;30(26):7771-7
references.pmid: 24476067
references.citation: J Agric Food Chem. 2005 Sep 21;53(19):7518-25
references.pmid: 16159181
references.citation: Clin Chim Acta. 1980 Nov 6;107(3):149-54
references.pmid: 6893684
references.citation: J Biomed Mater Res A. 2006 Jan;76(1):183-95
references.pmid: 16265650
references.citation: J Phys Chem B. 2005 Apr 7;109(13):6257-61
references.pmid: 16851694
references.citation: Biomacromolecules. 2009 Jan 12;10(1):9-18
references.pmid: 19032110
references.citation: Colloids Surf B Biointerfaces. 2008 Dec 1;67(2):171-8
references.pmid: 18835139
references.citation: PLoS One. 2013;8(5):e63075
references.pmid: 23690982
references.citation: J Control Release. 2008 May 8;127(3):249-56
references.pmid: 18343521
references.citation: Langmuir. 2015 Feb 3;31(4):1564-74
references.pmid: 25569307
references.citation: Adv Mater. 2011 May 24;23(20):2327-31
references.pmid: 21491513
references.citation: Acta Biomater. 2008 May;4(3):745-55
references.pmid: 18291738
references.citation: Langmuir. 2004 Jul 20;20(15):6389-95
references.pmid: 15248727
references.citation: Int J Pharm. 2006 Aug 31;320(1-2):143-9
references.pmid: 16730143
references.citation: AAPS J. 2005;7(1):E231-40
references.pmid: 16146344
references.citation: J Biomater Sci Polym Ed. 1995;7(5):389-99
references.pmid: 8562517
references.citation: Colloids Surf B Biointerfaces. 2007 Apr 1;55(2):212-21
references.pmid: 17223020
references.citation: J Biomed Mater Res A. 2004 Sep 1;70(3):412-9
references.pmid: 15293314
references.citation: Chem Rev. 1999 Nov 10;99(11):3181-98
references.pmid: 11749514
references.citation: J Control Release. 2004 Mar 5;95(2):291-300
references.pmid: 14980777
references.citation: Anesthesiology. 1991 May;74(5):934-6
references.pmid: 2021210
references.citation: J Control Release. 2012 Jul 20;161(2):496-504
references.pmid: 22480607
references.citation: Eur J Pharm Biopharm. 2000 Jul;50(1):27-46
references.pmid: 10840191