title: Multistage pH-responsive mucoadhesive nanocarriers prepared by aerosol flow reactor technology: A controlled dual protein-drug delivery system.
abstract: Nanotechnology based drug delivery systems are anticipated to overcome the persistent challenges in oral protein and peptide administration, and lead to the development of long awaited non-invasive therapies. Herein, an advanced single-step aerosol flow reactor based technology was used to develop a multifunctional site specific dual protein-drug delivery nanosystem. For this purpose, mucoadhesive porous silicon (PSi) nanoparticles encapsulated into a pH-responsive polymeric nanomatrix was developed for advanced oral type 2 diabetes mellitus therapy with an antidiabetic peptide, glucagon like peptide-1 (GLP-1), and the enzyme inhibitor, dipeptidyl peptidase-4 (DPP4). Chitosan surface modification inherited the mucoadhesiveness to the nanosystem which led to enhanced cellular interactions and increased cellular compatibility. An advanced aerosol flow reactor technology was used to encapsulate the chitosan modified nanoparticles into an enteric polymeric nanomatrix. The pH-sensitive polymeric matrix simultaneously prevented the gastric degradation of the encapsulated peptide and also preserved the mucoadhesive functionality of the chitosan-modified PSi nanoparticles in the harsh stomach environment. The multidrug loaded nanosystem showed augmented intestinal permeability of GLP-1, evaluated in an in vitro cell-based intestinal epithelium model, attributed to the permeation enhancer effect of chitosan and inhibition of GLP-1 degradation by the DPP4 inhibitor. The applied technology resulted in the development of a dual-drug delivery nanosystem that synergizes the antidiabetic effect of the loaded peptide and the enzyme inhibitor, thereby indicating high clinical potential of the system and preparation technique.
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, FI-00014, University of Helsinki, Finland.
authors.forename: Neha
authors.initials: N
authors.lastname: Shrestha
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, FI-00014, University of Helsinki, Finland.
authors.forename: Mohammad-Ali
authors.initials: MA
authors.lastname: Shahbazi
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, FI-00014, University of Helsinki, Finland; INEB - Instituto de Engenharia Biomédica, NewTherapies Group, Universidade do Porto, Rua do Campo Alegre, 823, 4150-180 Porto, Portugal; ICBAS - Instituto Ciências Biomédicas Abel Salazar, University of Porto, Portugal.
authors.forename: Francisca
authors.initials: F
authors.lastname: Araújo
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, FI-00014, University of Helsinki, Finland; Laboratory of Industrial Physics, Department of Physics and Astronomy, FI-20014, University of Turku, Finland.
authors.forename: Ermei
authors.initials: E
authors.lastname: Mäkilä
authors.affiliation: Department of Applied Physics, FI-00076, Aalto University School of Science, Finland.
authors.forename: Janne
authors.initials: J
authors.lastname: Raula
authors.affiliation: Department of Applied Physics, FI-00076, Aalto University School of Science, Finland.
authors.forename: Esko I
authors.initials: EI
authors.lastname: Kauppinen
authors.affiliation: Laboratory of Industrial Physics, Department of Physics and Astronomy, FI-20014, University of Turku, Finland.
authors.forename: Jarno
authors.initials: J
authors.lastname: Salonen
authors.affiliation: INEB - Instituto de Engenharia Biomédica, NewTherapies Group, Universidade do Porto, Rua do Campo Alegre, 823, 4150-180 Porto, Portugal; IINFACTS - Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Instituto Superior de Ciências da Saúde-Norte, Department of Pharmaceutical Sciences, CESPU, Rua Central de Gandra, 1317, 4585-116 Gandra, Portugal.
authors.forename: Bruno
authors.initials: B
authors.lastname: Sarmento
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, FI-00014, University of Helsinki, Finland.
authors.forename: Jouni
authors.initials: J
authors.lastname: Hirvonen
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, FI-00014, University of Helsinki, Finland. Electronic address: helder.santos@helsinki.fi.
authors.forename: Hélder A
authors.initials: HA
authors.lastname: Santos
mesh_terms: D000284:Administration, Oral; D000336:Aerosols / Q000737:chemistry; D018938:Caco-2 Cells; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000138:chemical synthesis*; D004058:Diffusion; D018819:Dipeptidyl Peptidase 4 / Q000008:administration & dosage* / Q000737:chemistry; D004338:Drug Combinations; D004339:Drug Compounding / Q000379:methods; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage* / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000737:chemistry; D007408:Intestinal Absorption; D007413:Intestinal Mucosa; D044085:Microfluidics / Q000379:methods*; D053769:Nanocapsules / Q000008:administration & dosage / Q000737:chemistry* / Q000648:ultrastructure; D010316:Particle Size; D012825:Silicon / Q000737:chemistry
chemical_list: D000336:Aerosols; D003692:Delayed-Action Preparations; D004338:Drug Combinations; D007004:Hypoglycemic Agents; D053769:Nanocapsules; D052216:Glucagon-Like Peptide 1; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D012825:Silicon
keywords: Aerosol flow reactor technology; Dipeptidyl peptidase-4; Glucagon-like peptide-1; Oral protein drug delivery; Porous silicon nanoparticles