title: In vivo dual-delivery of glucagon like peptide-1 (GLP-1) and dipeptidyl peptidase-4 (DPP4) inhibitor through composites prepared by microfluidics for diabetes therapy.
abstract: Oral delivery of proteins is still a challenge in the pharmaceutical field. Nanoparticles are among the most promising carrier systems for the oral delivery of proteins by increasing their oral bioavailability. However, most of the existent data regarding nanosystems for oral protein delivery is from in vitro studies, lacking in vivo experiments to evaluate the efficacy of these systems. Herein, a multifunctional composite system, tailored by droplet microfluidics, was used for dual delivery of glucagon like peptide-1 (GLP-1) and dipeptidyl peptidase-4 inhibitor (iDPP4) in vivo. Oral delivery of GLP-1 with nano- or micro-systems has been studied before, but the simultaneous nanodelivery of GLP-1 with iDPP4 is a novel strategy presented here. The type 2 diabetes mellitus (T2DM) rat model, induced through the combined administration of streptozotocin and nicotinamide, a non-obese model of T2DM, was used. The combination of both drugs resulted in an increase in the hypoglycemic effects in a sustained, but prolonged manner, where the iDPP4 improved the therapeutic efficacy of GLP-1. Four hours after the oral administration of the system, blood glucose levels were decreased by 44%, and were constant for another 4 h, representing half of the glucose area under the curve when compared to the control. An enhancement of the plasmatic insulin levels was also observed 6 h after the oral administration of the dual-drug composite system and, although no statistically significant differences existed, the amount of pancreatic insulin was also higher. These are promising results for the oral delivery of GLP-1 to be pursued further in a chronic diabetic model study.
authors.affiliation: I3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal. bruno.sarmento@ineb.up.pt and INEB - Instituto de Engenharia Biomédica, Universidade do Porto, 4200-135 Porto, Portugal and ICBAS - Instituto Ciências Biomédicas Abel Salazar, Universidade do Porto, 4150-180 Porto, Portugal and Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, FI-00790 Helsinki, Finland.
authors.forename: F
authors.initials: F
authors.lastname: Araújo
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, FI-00790 Helsinki, Finland.
authors.forename: N
authors.initials: N
authors.lastname: Shrestha
authors.affiliation: I3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal. bruno.sarmento@ineb.up.pt and INEB - Instituto de Engenharia Biomédica, Universidade do Porto, 4200-135 Porto, Portugal and ICBAS - Instituto Ciências Biomédicas Abel Salazar, Universidade do Porto, 4150-180 Porto, Portugal.
authors.forename: M J
authors.initials: MJ
authors.lastname: Gomes
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, FI-00790 Helsinki, Finland.
authors.forename: B
authors.initials: B
authors.lastname: Herranz-Blanco
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, FI-00790 Helsinki, Finland.
authors.forename: D
authors.initials: D
authors.lastname: Liu
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, FI-00790 Helsinki, Finland.
authors.forename: J J
authors.initials: JJ
authors.lastname: Hirvonen
authors.affiliation: I3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal. bruno.sarmento@ineb.up.pt and INEB - Instituto de Engenharia Biomédica, Universidade do Porto, 4200-135 Porto, Portugal and ICBAS - Instituto Ciências Biomédicas Abel Salazar, Universidade do Porto, 4150-180 Porto, Portugal.
authors.forename: P L
authors.initials: PL
authors.lastname: Granja
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, FI-00790 Helsinki, Finland.
authors.forename: H A
authors.initials: HA
authors.lastname: Santos
authors.affiliation: I3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal. bruno.sarmento@ineb.up.pt and INEB - Instituto de Engenharia Biomédica, Universidade do Porto, 4200-135 Porto, Portugal and CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, 4585-116 Gandra, Portugal.
authors.forename: B
authors.initials: B
authors.lastname: Sarmento
mesh_terms: D000818:Animals; D001786:Blood Glucose; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage*; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D052216:Glucagon-Like Peptide 1 / Q000037:antagonists & inhibitors*; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D007328:Insulin; D008297:Male; D044085:Microfluidics; D051381:Rats; D017208:Rats, Wistar
chemical_list: D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; D052216:Glucagon-Like Peptide 1