title: Effect of mucoadhesive polymers on the in vitro performance of insulin-loaded silica nanoparticles: Interactions with mucin and biomembrane models.
abstract: The present paper focuses on the development and characterization of silica nanoparticles (SiNP) coated with hydrophilic polymers as mucoadhesive carriers for oral administration of insulin. SiNP were prepared by sol-gel technology under mild conditions and coated with different hydrophilic polymers, namely, chitosan, sodium alginate or poly(ethylene glycol) (PEG) with low and high molecular weight (PEG 6000 and PEG 20000) to increase the residence time at intestinal mucosa. The mean size and size distribution, association efficiency, insulin structure and insulin thermal denaturation have been determined. The mean nanoparticle diameter ranged from 289 nm to 625 nm with a PI between 0.251 and 0.580. The insulin association efficiency in SiNP was recorded above 70%. After coating, the association efficiency of insulin increased up to 90%, showing the high affinity of the protein to the hydrophilic polymer chains. Circular dichroism (CD) indicated that no conformation changes of insulin structure occurred after loading the peptide into SiNP. Nano-differential scanning calorimetry (nDSC) showed that SiNP shifted the insulin endothermic peak to higher temperatures. The influence of coating on the interaction of nanoparticles with dipalmitoylphosphatidylcholine (DPPC) biomembrane models was also evaluated by nDSC. The increase of ΔH values suggested a strong association of non-coated SiNP and those PEGylated nanoparticles coated with DPPC polar heads by forming hydrogen bonds and/or by electrostatic interaction. The mucoadhesive properties of nanoparticles were examined by studying the interaction with mucin in aqueous solution. SiNP coated with alginate or chitosan showed high contact with mucin. On the other hand, non-coated SiNP and PEGylated SiNP showed lower interaction with mucin, indicating that these nanoparticles can interdiffuse across mucus network. The results of the present work provide valuable data in assessing the in vitro performance of insulin-loaded SiNP coated with mucoadhesive polymers.
authors.affiliation: Department of Biology and Environment, University of Tras-os Montes e Alto Douro, UTAD, Quinta de Prados, P-5001-801 Vila Real, Portugal; Centre for Research and Technology of Agro-Environmental and Biological Sciences, CITAB, UTAD, Quinta de Prados, P-5001-801 Vila Real, Portugal.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Andreani
authors.affiliation: Department of Pharmaceutical Sciences, UNESP-Universidade Estadual Paulista, Rodovia Araraquara-Jau, Km. 01, Araraquara, São Paulo, Brazil.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Miziara
authors.affiliation: Department of Biochemistry and Chemical Technology, Institute of Chemistry, UNESP, Araraquara, São Paulo, Brazil.
authors.forename: Esteban N
authors.initials: EN
authors.lastname: Lorenzón
authors.affiliation: Department of Pharmaceutical Sciences, UNESP-Universidade Estadual Paulista, Rodovia Araraquara-Jau, Km. 01, Araraquara, São Paulo, Brazil.
authors.forename: Ana Luiza R
authors.initials: AL
authors.lastname: de Souza
authors.affiliation: Department of Pharmaceutical Sciences, UNESP-Universidade Estadual Paulista, Rodovia Araraquara-Jau, Km. 01, Araraquara, São Paulo, Brazil.
authors.forename: Charlene P
authors.initials: CP
authors.lastname: Kiill
authors.affiliation: Research Centre for Biomedicine (CEBIMED), Fernando Pessoa University (UFP), Praça 9 de Abril, 349, P-4249-004 Porto, Portugal.
authors.forename: Joana F
authors.initials: JF
authors.lastname: Fangueiro
authors.affiliation: Department of Physical Chemistry, Faculty of Pharmacy, Barcelona University, Av. Joan XXIII s/n, 08028 Barcelona, Spain.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Garcia
authors.affiliation: Department of Pharmaceutical Sciences, UNESP-Universidade Estadual Paulista, Rodovia Araraquara-Jau, Km. 01, Araraquara, São Paulo, Brazil.
authors.forename: Palmira D
authors.initials: PD
authors.lastname: Gremião
authors.affiliation: Department of Biology and Environment, University of Tras-os Montes e Alto Douro, UTAD, Quinta de Prados, P-5001-801 Vila Real, Portugal; Centre for Research and Technology of Agro-Environmental and Biological Sciences, CITAB, UTAD, Quinta de Prados, P-5001-801 Vila Real, Portugal.
authors.forename: Amélia M
authors.initials: AM
authors.lastname: Silva
authors.affiliation: Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra (FFUC), Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal; Center for Neuroscience and Cell Biology & Institute for Biomedical Imaging and Life Sciences (CNC-IBILI), University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal. Electronic address: ebsouto@ff.uc.pt.
authors.forename: Eliana B
authors.initials: EB
authors.lastname: Souto
mesh_terms: D015060:1,2-Dipalmitoylphosphatidylcholine / Q000737:chemistry; D000268:Adhesiveness; D000284:Administration, Oral; D000464:Alginates / Q000737:chemistry; D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical; D048271:Chitosan / Q000737:chemistry; D002942:Circular Dichroism; D004337:Drug Carriers; D020723:Glucuronic Acid / Q000737:chemistry; D006603:Hexuronic Acids / Q000737:chemistry; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000737:chemistry*; D007328:Insulin / Q000008:administration & dosage / Q000737:chemistry*; D008567:Membranes, Artificial; D008970:Molecular Weight; D009077:Mucins / Q000737:chemistry*; D050997:Nanomedicine; D053758:Nanoparticles; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D012822:Silicon Dioxide / Q000737:chemistry*; D013499:Surface Properties; D013678:Technology, Pharmaceutical / Q000379:methods; D013696:Temperature
chemical_list: D000464:Alginates; D004337:Drug Carriers; D006603:Hexuronic Acids; D007004:Hypoglycemic Agents; D007328:Insulin; D008567:Membranes, Artificial; D009077:Mucins; D011108:Polymers; D015060:1,2-Dipalmitoylphosphatidylcholine; D011092:Polyethylene Glycols; D012822:Silicon Dioxide; D020723:Glucuronic Acid; D048271:Chitosan
keywords: Biomembranes; Insulin; Mucoadhesion; Oral delivery; Silica nanoparticles; Thermal denaturation