title: Polymeric nanocarriers for transport modulation across the pulmonary epithelium: dendrimers, polymeric nanoparticles, and their nanoblends.
abstract: The purpose of this study was to (a) Determine the cellular transport and uptake of amine-terminated generation 3 (G3) poly(amido amine) (PAMAM) dendrimers across an in vitro model of the pulmonary epithelium, and the ability to modulate their transport by forming nanoblends of the dendrimers with biodegradable solid polymeric nanoparticles (NPs) and (b) to formulate dendrimer nanocarriers in portable oral inhalation devices and evaluate their aerosol characteristics. To that end, fluorescein isothiocyanate (FITC)-labeled G3 PAMAM dendrimer nanocarriers (DNCs) were synthesized, and also encapsulated within poly lactide-co-glycolide nanoparticles (NPs). Transport and uptake of both DNCs encapsulated within NPs (nanoblends) and unencapsulated DNCs were tracked across polarized monolayers of airway epithelial cells, Calu-3. DNCs were also formulated as core-shell microparticles in pressurized metered-dose inhalers (pMDIs) and their aerodynamic properties evaluated by Andersen cascade impaction. The apparent permeability of DNCs across the airway epithelial model was similar to that of a paracellular marker of comparable molar mass--order of 10(-7) cm s(-1). The transport and cellular internalization of the DNCs can be modulated by formulating them as nanoblends. The transport of the DNCs across the lung epithelium was completely suppressed within the time of the experiment (5 h) when formulated as blends. The encapsulation also prevents saturation of the cellular internalization profile. Nanoblending may be a potential strategy to modulate the rate of transport and cellular uptake of DNCs, and thus be used as a design strategy to achieve enhanced local or systemic drug delivery.
authors.affiliation: Chemical Engineering and Materials Science, College of Engineering, Wayne State University, Detroit, Michigan, 48202, USA.
authors.forename: Balaji
authors.initials: B
authors.lastname: Bharatwaj
authors.forename: Radovan
authors.initials: R
authors.lastname: Dimovski
authors.forename: Denise S
authors.initials: DS
authors.lastname: Conti
authors.forename: Sandro R P
authors.initials: SR
authors.lastname: da Rocha
mesh_terms: D001693:Biological Transport, Active; D002460:Cell Line; D050091:Dendrimers / Q000737:chemistry; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry; D008168:Lung / Q000378:metabolism*; D036501:Metered Dose Inhalers; D053758:Nanoparticles; D010316:Particle Size; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers; D020545:Respiratory Mucosa / Q000378:metabolism*
chemical_list: D050091:Dendrimers; C104700:PAMAM Starburst; D011108:Polymers; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid