title: Microfluidic Assembly of a Multifunctional Tailorable Composite System Designed for Site Specific Combined Oral Delivery of Peptide Drugs.
abstract: Multifunctional tailorable composite systems, specifically designed for oral dual-delivery of a peptide (glucagon-like peptide-1) and an enzymatic inhibitor (dipeptidyl peptidase 4 (DPP4)), were assembled through the microfluidics technique. Both drugs were coloaded into these systems for a synergistic therapeutic effect. The systems were composed of chitosan and cell-penetrating peptide modified poly(lactide-co-glycolide) and porous silicon nanoparticles as nanomatrices, further encapsulated in an enteric hydroxypropylmethylcellulose acetylsuccinate polymer. The developed multifunctional systems were pH-sensitive, inherited by the enteric polymer, enabling the release of the nanoparticles only in the simulated intestinal conditions. Moreover, the encapsulation into this polymer prevented the degradation of the nanoparticles' modifications. These nanoparticles showed strong and higher interactions with the intestinal cells in comparison with the nonmodified ones. The presence of DPP4 inhibitor enhanced the peptide permeability across intestinal cell monolayers. Overall, this is a promising platform for simultaneously delivering two drugs from a single formulation. Through this approach peptides are expected to increase their bioavailability and efficiency in vivo both by their specific release at the intestinal level and also by the reduced enzymatic activity. The use of this platform, specifically in combination of the two antidiabetic drugs, has clinical potential for the therapy of type 2 diabetes mellitus.
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki , FI-00014 Helsinki, Finland.|Instituto de Investigação e Inovação em Saúde, Universidade do Porto , 4150-180 Porto, Portugal.|INEB - Instituto de Engenharia Biomédica, University of Porto , 4150-180 Porto, Portugal.|ICBAS - Instituto Ciências Biomédicas Abel Salazar, University of Porto , 4150-180 Porto, Portugal.
authors.forename: Francisca
authors.initials: F
authors.lastname: Araújo
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki , FI-00014 Helsinki, Finland.
authors.forename: Neha
authors.initials: N
authors.lastname: Shrestha
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki , FI-00014 Helsinki, Finland.
authors.forename: Mohammad-Ali
authors.initials: MA
authors.lastname: Shahbazi
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki , FI-00014 Helsinki, Finland.
authors.forename: Dongfei
authors.initials: D
authors.lastname: Liu
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki , FI-00014 Helsinki, Finland.
authors.forename: Bárbara
authors.initials: B
authors.lastname: Herranz-Blanco
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki , FI-00014 Helsinki, Finland.|Laboratory of Industrial Physics, University of Turku , FI-20014 Turku, Finland.
authors.forename: Ermei M
authors.initials: EM
authors.lastname: Mäkilä
authors.affiliation: Laboratory of Industrial Physics, University of Turku , FI-20014 Turku, Finland.
authors.forename: Jarno J
authors.initials: JJ
authors.lastname: Salonen
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki , FI-00014 Helsinki, Finland.
authors.forename: Jouni T
authors.initials: JT
authors.lastname: Hirvonen
authors.affiliation: Instituto de Investigação e Inovação em Saúde, Universidade do Porto , 4150-180 Porto, Portugal.|INEB - Instituto de Engenharia Biomédica, University of Porto , 4150-180 Porto, Portugal.|ICBAS - Instituto Ciências Biomédicas Abel Salazar, University of Porto , 4150-180 Porto, Portugal.
authors.forename: Pedro L
authors.initials: PL
authors.lastname: Granja
authors.affiliation: Instituto de Investigação e Inovação em Saúde, Universidade do Porto , 4150-180 Porto, Portugal.|INEB - Instituto de Engenharia Biomédica, University of Porto , 4150-180 Porto, Portugal.|CESPU , Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, 4585-116 Gandra, Portugal.
authors.forename: Bruno
authors.initials: B
authors.lastname: Sarmento
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki , FI-00014 Helsinki, Finland.
authors.forename: Hélder A
authors.initials: HA
authors.lastname: Santos
mesh_terms: D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects; D057846:Cell-Penetrating Peptides / Q000737:chemistry; D048271:Chitosan / Q000737:chemistry; D018920:Coculture Techniques; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D004339:Drug Compounding / Q000379:methods; D016503:Drug Delivery Systems / Q000379:methods*; D065546:Drug Liberation; D004357:Drug Synergism; D052216:Glucagon-Like Peptide 1 / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D019073:HT29 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008747:Methylcellulose / Q000031:analogs & derivatives / Q000737:chemistry; D044085:Microfluidics / Q000379:methods*; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D010539:Permeability; D011098:Polyglactin 910 / Q000737:chemistry; D016062:Porosity; D012825:Silicon / Q000737:chemistry
chemical_list: D057846:Cell-Penetrating Peptides; D011098:Polyglactin 910; C048331:hydroxypropylmethylcellulose acetate succinate; D052216:Glucagon-Like Peptide 1; D008747:Methylcellulose; D048271:Chitosan; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D012825:Silicon
keywords: PLGA; chitosan; dual-delivery; microfluidics; porous silicon