title: Nanoparticle penetration of human cervicovaginal mucus: the effect of polyvinyl alcohol.
abstract: Therapeutic nanoparticles must rapidly penetrate the mucus secretions lining the surfaces of the respiratory, gastrointestinal and cervicovaginal tracts to efficiently reach the underlying tissues. Whereas most polymeric nanoparticles are highly mucoadhesive, we previously discovered that a dense layer of low MW polyethylene glycol (PEG) conferred a sufficiently hydrophilic and uncharged surface to effectively minimize mucin-nanoparticle adhesive interactions, allowing well-coated particles to rapidly diffuse through human mucus. Here, we sought to investigate the influence of surface coating by polyvinyl alcohol (PVA), a relatively hydrophilic and uncharged polymer routinely used as a surfactant to formulate drug carriers, on the transport of nanoparticles in fresh human cervicovaginal mucus. We found that PVA-coated polystyrene (PS) particles were immobilized, with speeds at least 4000-fold lower in mucus than in water, regardless of the PVA molecular weight or incubation concentration tested. Nanoparticles composed of poly(lactide-co-glycolide) (PLGA) or diblock copolymers of PEG-PLGA were similarly immobilized when coated with PVA (slowed 29,000- and 2500-fold, respectively). PVA coatings could not be adequately removed upon washing, and the residual PVA prevented sufficient coating with Pluronic F127 capable of reducing particle mucoadhesion. In contrast to PVA-coated particles, the similar sized PEG-coated formulations were slowed only ~6- to 10-fold in mucus compared to in water. Our results suggest that incorporating PVA in the particle formulation process may lead to the formation of mucoadhesive particles for many nanoparticulate systems. Thus, alternative methods for particle formulation, based on novel surfactants or changes in the formulation process, should be identified and developed in order to produce mucus-penetrating particles for mucosal applications.
authors.affiliation: Center for Nanomedicine, Johns Hopkins University School of Medicine, 400 N Broadway, Baltimore, MD 21287, USA; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Yang
authors.affiliation: Center for Nanomedicine, Johns Hopkins University School of Medicine, 400 N Broadway, Baltimore, MD 21287, USA; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, 3400 N Charles Street, Baltimore, MD 21218, USA; Center for Cancer Nanotechnology Excellence, Institute for NanoBioTechnology, Johns Hopkins University, 3400 N Charles Street, Baltimore, MD 21218, USA.
authors.forename: Samuel K
authors.initials: SK
authors.lastname: Lai
authors.affiliation: Center for Nanomedicine, Johns Hopkins University School of Medicine, 400 N Broadway, Baltimore, MD 21287, USA; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Yu
authors.affiliation: Center for Nanomedicine, Johns Hopkins University School of Medicine, 400 N Broadway, Baltimore, MD 21287, USA; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, USA.
authors.forename: Ying-Ying
authors.initials: YY
authors.lastname: Wang
authors.affiliation: Department of Chemical and Biomolecular Engineering, Johns Hopkins University, 3400 N Charles Street, Baltimore, MD 21218, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Happe
authors.affiliation: Department of Biomedical Engineering, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, USA.
authors.forename: Weixi
authors.initials: W
authors.lastname: Zhong
authors.affiliation: Department of Chemical and Biomolecular Engineering, Johns Hopkins University, 3400 N Charles Street, Baltimore, MD 21218, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Chemical and Biomolecular Engineering, Johns Hopkins University, 3400 N Charles Street, Baltimore, MD 21218, USA.
authors.forename: Abraham
authors.initials: A
authors.lastname: Anonuevo
authors.affiliation: Department of Chemical and Biomolecular Engineering, Johns Hopkins University, 3400 N Charles Street, Baltimore, MD 21218, USA.
authors.forename: Colleen
authors.initials: C
authors.lastname: Fridley
authors.affiliation: Center for Nanomedicine, Johns Hopkins University School of Medicine, 400 N Broadway, Baltimore, MD 21287, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Hung
authors.affiliation: Center for Nanomedicine, Johns Hopkins University School of Medicine, 400 N Broadway, Baltimore, MD 21287, USA; Department of Ophthalmology, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 400 N Broadway, Baltimore, MD 21287, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Fu
authors.affiliation: Center for Nanomedicine, Johns Hopkins University School of Medicine, 400 N Broadway, Baltimore, MD 21287, USA; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, USA; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, 3400 N Charles Street, Baltimore, MD 21218, USA; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 600 N Wolfe Street, Baltimore, MD 21287, USA; Center for Cancer Nanotechnology Excellence, Institute for NanoBioTechnology, Johns Hopkins University, 3400 N Charles Street, Baltimore, MD 21218, USA; Department of Ophthalmology, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 400 N Broadway, Baltimore, MD 21287, USA. Electronic address: hanes@jhu.edu.
authors.forename: Justin
authors.initials: J
authors.lastname: Hanes
mesh_terms: D000268:Adhesiveness; D002582:Cervix Mucus / Q000378:metabolism*; D020099:Coated Materials, Biocompatible / Q000737:chemistry / Q000378:metabolism*; D004337:Drug Carriers / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D053758:Nanoparticles / Q000737:chemistry / Q000378:metabolism*; D011091:Polyesters / Q000737:chemistry / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry / Q000378:metabolism; D011098:Polyglactin 910 / Q000737:chemistry / Q000378:metabolism; D011142:Polyvinyl Alcohol / Q000737:chemistry / Q000378:metabolism*
chemical_list: D020099:Coated Materials, Biocompatible; D004337:Drug Carriers; D011091:Polyesters; C000589473:polyethylene glycol-poly(lactide-co-glycolide); D011098:Polyglactin 910; D011092:Polyethylene Glycols; D011142:Polyvinyl Alcohol
keywords: Biodegradable polymers; Drug delivery; Mucoadhesion; Mucus-penetrating particles; Surfactant
references.citation: Adv Drug Deliv Rev. 2009 Feb 27;61(2):75-85
references.pmid: 19135107
references.citation: J Microencapsul. 1992 Jan-Mar;9(1):19-28
references.pmid: 1613640
references.citation: J Control Release. 2013 Sep 10;170(2):279-86
references.pmid: 23751567
references.citation: J Control Release. 2000 Mar 1;65(1-2):63-71
references.pmid: 10699271
references.citation: J Control Release. 2012 Jan 10;157(1):149-59
references.pmid: 21864595
references.citation: Proc Natl Acad Sci U S A. 2010 Jan 12;107(2):598-603
references.pmid: 20018745
references.citation: Adv Healthc Mater. 2014 Jul;3(7):1044-52
references.pmid: 24339398
references.citation: J Aerosol Med. 2004 Summer;17(2):140-52
references.pmid: 15294064
references.citation: FEBS Lett. 1984 Feb 13;167(1):79-82
references.pmid: 6698206
references.citation: J Pharm Sci. 2008 Nov;97(11):4655-69
references.pmid: 18306270
references.citation: Pharm Res. 2007 May;24(5):899-908
references.pmid: 17377747
references.citation: Expert Rev Anticancer Ther. 2008 Oct;8(10):1643-50
references.pmid: 18925855
references.citation: Pharm Res. 1999 Jul;16(7):1114-8
references.pmid: 10450940
references.citation: Food Chem Toxicol. 2003 Mar;41(3):319-26
references.pmid: 12504164
references.citation: J Control Release. 2012 Feb 10;157(3):455-60
references.pmid: 21911015
references.citation: Hum Gene Ther. 2011 Jul;22(7):809-19
references.pmid: 21128743
references.citation: Proc Am Thorac Soc. 2004;1(1):54-61
references.pmid: 16113413
references.citation: Nat Mater. 2009 Jun;8(6):526-33
references.pmid: 19404239
references.citation: Drug Deliv Transl Res. 2012 Apr;2(2):
references.pmid: 24205449
references.citation: Nat Mater. 2009 Jan;8(1):11-3
references.pmid: 19096387
references.citation: Proc Natl Acad Sci U S A. 2006 Apr 18;103(16):6315-20
references.pmid: 16606824
references.citation: J Pharm Pharmacol. 2003 Jul;55(7):895-902
references.pmid: 12906746
references.citation: Adv Drug Deliv Rev. 2008 Dec 14;60(15):1638-49
references.pmid: 18840488
references.citation: Adv Drug Deliv Rev. 2009 Feb 27;61(2):158-71
references.pmid: 19133304
references.citation: Proc Natl Acad Sci U S A. 2009 Nov 17;106(46):19268-73
references.pmid: 19901335
references.citation: Mol Ther. 2014 Aug;22(8):1484-1493
references.pmid: 24869933
references.citation: Int J Pharm. 2008 Dec 8;364(2):298-327
references.pmid: 18621492
references.citation: J Control Release. 2002 Jul 18;82(1):105-14
references.pmid: 12106981
references.citation: Paediatr Respir Rev. 2000 Mar;1(1):27-34
references.pmid: 16263440
references.citation: Proc Natl Acad Sci U S A. 2007 Jan 30;104(5):1482-7
references.pmid: 17244708
references.citation: Sex Transm Dis. 2003 Feb;30(2):107-9
references.pmid: 12567165
references.citation: J Pharm Sci. 2008 Apr;97(4):1530-42
references.pmid: 17722098
references.citation: J Clin Invest. 2002 Mar;109(5):571-7
references.pmid: 11877463
references.citation: Angew Chem Int Ed Engl. 2008;47(50):9726-9
references.pmid: 18979480
references.citation: Biomaterials. 2009 Apr;30(12):2340-8
references.pmid: 19150737
references.citation: Infect Immun. 1974 Dec;10(6):1266-72
references.pmid: 4435956
references.citation: Colloids Surf B Biointerfaces. 2010 Jan 1;75(1):260-7
references.pmid: 19775872