Oral hypoglycaemic effect of GLP-1 and DPP4 inhibitor based nanocomposites in a diabetic animal model.
Glucagon-like peptide-1 (GLP-1), an incretin hormone, is used for type 2 diabetes mellitus (T2DM) treatment because of its ability to stimulate insulin secretion and release in a glucose-dependent manner. Despite of its potent insulinotropic effect, oral GLP-1 delivery is greatly limited by its instability in the gastrointestinal tract, poor absorption efficiency and rapid degradation by dipeptidylpeptidase-4 (DPP4) enzyme leading to a short half-life (~2min). Thus, a multistage dual-drug delivery nanosystem was developed to deliver GLP-1 and DPP4 inhibitor simultaneously. The system comprised of chitosan-modified porous silicon (CSUn) nanoparticles, which were coated by an enteric polymer, hydroxypropylmethylcellulose acetate succinate MF, using aerosol flow reactor technology. A non-obese T2DM rat model induced by co-administration of nicotinamide and streptozotocin was used to evaluate the in vivo efficacy of the nanosystem. The oral administration of H-CSUn nanoparticles resulted in 32% reduction in blood glucose levels and ~6.0-fold enhancement in pancreatic insulin content, as compared to the GLP-1+DPP4 inhibitor solution. Overall, these results present a promising system for oral co-delivery of GLP-1 and DPP4 inhibitor that could be further evaluated in a chronic diabetic study.
Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, FI-00014, Finland. Electronic address: neha.shrestha@helsinki.fi.
Neha
N
Shrestha
Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, FI-00014, Finland; i3S - Instituto de Investigação e Inovação em Saúde and INEB - Instituto Nacional de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; ICBAS - Instituto Ciências Biomédicas Abel Salazar, University of Porto, Portugal.
Francisca
F
Araújo
Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, FI-00014, Finland.
Mohammad-Ali
MA
Shahbazi
Laboratory of Industrial Physics, Department of Physics and Astronomy, University of Turku, FI-20014, Finland.
Ermei
E
Mäkilä
i3S - Instituto de Investigação e Inovação em Saúde and INEB - Instituto Nacional de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; ICBAS - Instituto Ciências Biomédicas Abel Salazar, University of Porto, Portugal.
Maria João
MJ
Gomes
Institute of Biotechnology, University of Helsinki, FI-00014 Helsinki, Finland.
Mikko
M
Airavaara
Department of Applied Physics, Aalto University School of Science, FI-00076, Finland.
Esko I
EI
Kauppinen
Department of Applied Physics, Aalto University School of Science, FI-00076, Finland.
Janne
J
Raula
Laboratory of Industrial Physics, Department of Physics and Astronomy, University of Turku, FI-20014, Finland.
Jarno
J
Salonen
Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, FI-00014, Finland.
Jouni
J
Hirvonen
i3S - Instituto de Investigação e Inovação em Saúde and INEB - Instituto Nacional de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; CESPU, Instituto de Investigacão e Formacão Avançada em Ciências e Tecnologias da Saúde, 4585-116 Gandra, Portugal.
Bruno
B
Sarmento
Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, FI-00014, Finland. Electronic address: helder.santos@helsinki.fi.
Hélder A
HA
Santos
D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D048271:Chitosan / Q000737:chemistry; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D007421:Intestine, Small / Q000378:metabolism; D008747:Methylcellulose / Q000031:analogs & derivatives / Q000737:chemistry; D053761:Nanocomposites / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D053758:Nanoparticles / Q000737:chemistry; D017208:Rats, Wistar; D012825:Silicon / Q000737:chemistry
D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; C048331:hydroxypropylmethylcellulose acetate succinate; D052216:Glucagon-Like Peptide 1; D008747:Methylcellulose; D048271:Chitosan; D012825:Silicon
Chitosan; Dipeptidyl peptidase-4; Ex vivo; Glucagon-like peptide-1; In vivo; Oral delivery; Porous silicon nanoparticles