Dendrimer Nanocarriers for Transport Modulation Across Models of the Pulmonary Epithelium

dc.contributor.authorBharatwaj, Balaji
dc.contributor.authorMohammad, Abdul Khader
dc.contributor.authorDimovski, Radovan
dc.contributor.authorCassio, Fernando L. [UNESP]
dc.contributor.authorBazito, Reinaldo C. [UNESP]
dc.contributor.authorConti, Denise
dc.contributor.authorFu, Qiang
dc.contributor.authorReineke, Joshua
dc.contributor.authorRocha, Sandro R. P. da
dc.contributor.institutionWayne State Univ
dc.contributor.institutionUniversidade Estadual Paulista (Unesp)
dc.description.abstractThe purpose of this study was to determine the effect of PEGylation on the interaction of poly(amidoamine) (PAMAM) dendrimer nanocarriers (DNCs) with in vitro and in vivo models of the pulmonary epithelium. Generation-3 PAMAM dendrimers with varying surface densities of PEG 1000 Da were synthesized and characterized. The results revealed that the apical to basolateral transport of DNCs across polarized Calu-3 monolayers increases with an increase in PEG surface density. DNC having the greatest number of PEG groups (n = 25) on their surface traversed at a rate 10-fold greater than its non-PEGylated counterpart, in spite of their larger size. This behavior was attributed to a significant reduction in charge density upon PEGylation. We also observed that PEGylation can be used to modulate cellular internalization. The total uptake of PEG-free DNC into polarized Calu-3 monolayers was 12% (w/w) vs 2% (w/w) for that with 25 PEGs. Polarization is also shown to be of great relevance in studying this in vitro model of the lung epithelium. The rate of absorption of DNCs administered to mice lungs increased dramatically when conjugated with 25 PEG groups, thus supporting the in vitro results. The exposure obtained for the DNC with 25PEG was determined to be very high, with peak plasma concentrations reaching 5 mu gmL(-1) within 3 h. The combined in vitro and in vivo results shown here demonstrate that PEGylation can be potentially used to modulate the internalization and transport of DNCs across the pulmonary epithelium. Modified dendrimers thereby may serve as a valuable platform that can be tailored to target the lung tissue for treating local diseases, or the circulation, using the lung as pathway to the bloodstream, for systemic delivery.en
dc.description.affiliationWayne State Univ, Dept Chem Engn & Mat Sci, Detroit, MI 48202 USA
dc.description.affiliationWayne State Univ, Dept Pharmaceut Sci, Detroit, MI 48202 USA
dc.description.affiliationState Univ Sao Paulo, Dept Chem, Sao Paulo, Brazil
dc.description.affiliationUnespState Univ Sao Paulo, Dept Chem, Sao Paulo, Brazil
dc.description.sponsorshipNational Science Foundation (NSF-CBET)
dc.description.sponsorshipNanoIncubator at WSU
dc.description.sponsorshipNIH center grant
dc.description.sponsorshipPerinatology Research Branch of the National Institutes of Child Health and Development, Wayne State University
dc.description.sponsorshipDepartment of Pharmaceutical Sciences at WSU
dc.description.sponsorshipIdNational Science Foundation (NSF-CBET): 0933144
dc.description.sponsorshipIdNIH center grant: P30CA22453
dc.identifier.citationMolecular Pharmaceutics. Washington: Amer Chemical Soc, v. 12, n. 3, p. 826-838, 2015.
dc.publisherAmer Chemical Soc
dc.relation.ispartofMolecular Pharmaceutics
dc.rights.accessRightsAcesso restrito
dc.sourceWeb of Science
dc.subjectrespiratory drug delivery
dc.subjectpoly(amido amine) dendrimers
dc.subjectin vitro transport
dc.subjectin vivo pharmacokinetics
dc.titleDendrimer Nanocarriers for Transport Modulation Across Models of the Pulmonary Epitheliumen
dcterms.rightsHolderAmer Chemical Soc[8]