Pharmacological Characterization of the RPMI 2650 Model as a Relevant Tool for Assessing the Permeability of Intranasal Drugs

Mercier, Clément; Hodin, Sophie; Hé, Zhiguo; Perek, Nathalie; Delavenne, Xavier

doi:10.1021/acs.molpharmaceut.8b00087

Cited by 18 publications

(18 citation statements)

References 58 publications

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“…In former studies, especially the glycosylation status of IgGs affects the binding to Fc receptors [ 31 , 41 ]. Several models have been developed so far to test the permeation of drugs through the olfactory epithelium with ex vivo tissue explants, primary nasal cells and tumor cell lines such as RPMI 2650 [ 13 , 36 , 39 , 42 , 43 ]. Here, the IgG permeation was evaluated in these models as well as the relevance of using allo- or xenogenic IgGs and their glycosylation.…”

Section: Resultsmentioning

confidence: 99%

“…To exclude interspecies effects due to the use of human IgG in porcine tissue and cells, the permeation experiments were repeated using the nasal mucosa standard cell line RPMI 2650 [ 37 , 39 , 49 ]. The results from the OEPC model could be confirmed in the RPMI 2650 model, indicating again a cross-species mechanism for IgG trafficking.…”

Section: Discussionmentioning

confidence: 99%

“…Porcine mucosa was used for modeling the human nasal mucosa as its high similarity was described before in other studies and the cross-species transport of human IgG by the porcine FcRn has been already shown by Stirling et al [ 13 , 14 , 33 , 34 , 35 ]. In addition, the permeation experiments were also performed in porcine olfactory epithelial primary cells (OEPC) and in the human cell line RPMI 2650 (ACC 287, DSMZ, Braunschweig, Germany) [ 36 , 37 , 38 , 39 ]. The most important factor limiting the nasal absorption of high molecular weight molecules is the low epithelial membrane permeability and the mucociliary clearance [ 40 ].…”

Section: Introductionmentioning

confidence: 99%

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Impact of Glycosylation and Species Origin on the Uptake and Permeation of IgGs through the Nasal Airway Mucosa

et al. 2020

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Although we have recently reported the involvement of neonatal Fc receptor (FcRn) in intranasal transport, the transport mechanisms are far from being elucidated. Ex vivo porcine olfactory tissue, primary cells from porcine olfactory epithelium (OEPC) and the human cell line RPMI 2650 were used to evaluate the permeation of porcine and human IgG antibodies through the nasal mucosa. IgGs were used in their wild type and deglycosylated form to investigate the impact of glycosylation. Further, the expression of FcRn and Fc-gamma receptor (FCGR) and their interaction with IgG were analyzed. Comparable permeation rates for human and porcine IgG were observed in OEPC, which display the highest expression of FcRn. Only traces of porcine IgGs could be recovered at the basolateral compartment in ex vivo olfactory tissue, while human IgGs reached far higher levels. Deglycosylated human IgG showed significantly higher permeation in comparison to the wild type in RPMI 2650 and OEPC, but insignificantly elevated in the ex vivo model. An immunoprecipitation with porcine primary cells and tissue identified FCGR2 as a potential interaction partner in the nasal mucosa. Glycosylation sensitive receptors appear to be involved in the uptake, transport, but also degradation of therapeutic IgGs in the airway epithelial layer.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Impact of Glycosylation and Species Origin on the Uptake and Permeation of IgGs through the Nasal Airway Mucosa

et al. 2020

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“…Here, we defined the most important parameters as the growth in defined monolayers, the formation of cilia (drug clearance), tightly connected cell layers and the physico-chemical environment (mucus). The actual state of the art model for nasal epithelial cells is the tumour cell line RPMI 2650 [21,39]. As an alternative to tumour cells lines, primary cell models are moving more and more into focus in many fields.…”

Section: Resultsmentioning

confidence: 99%

“…Epithelial cell features such as the presence of cilia, mucus secretion and tight junction formation are important factors that influence the bioavailability of nasally applied drugs [7]. Generally, a heterogenic mixture of different cell types is preferred for a valid model, since this better represents the mucosal epithelial assembly in respect to the permeation profile of drugs through the cellular barrier [37,39]. Furthermore, cultured tumour cells tend to build multilayers, as their growth is mostly not limited by contact inhibition after reaching confluency, whereas primary cells remain in monolayers.…”

Section: Introductionmentioning

confidence: 99%

Improved In Vitro Model for Intranasal Mucosal Drug Delivery: Primary Olfactory and Respiratory Epithelial Cells Compared with the Permanent Nasal Cell Line RPMI 2650

et al. 2019

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Background: The epithelial layer of the nasal mucosa is the first barrier for drug permeation during intranasal drug delivery. With increasing interest for intranasal pathways, adequate in vitro models are required. Here, porcine olfactory (OEPC) and respiratory (REPC) primary cells were characterised against the nasal tumour cell line RPMI 2650. Methods: Culture conditions for primary cells from porcine nasal mucosa were optimized and the cells characterised via light microscope, RT-PCR and immunofluorescence. Epithelial barrier function was analysed via transepithelial electrical resistance (TEER), and FITC-dextran was used as model substance for transepithelial permeation. Beating cilia necessary for mucociliary clearance were studied by immunoreactivity against acetylated tubulin. Results: OEPC and REPC barrier models differ in TEER, transepithelial permeation and MUC5AC levels. In contrast, RPMI 2650 displayed lower levels of MUC5AC, cilia markers and TEER, and higher FITC-dextran flux rates. Conclusion: To screen pharmaceutical formulations for intranasal delivery in vitro, translational mucosal models are needed. Here, a novel and comprehensive characterisation of OEPC and REPC against RPMI 2650 is presented. The established primary models display an appropriate model for nasal mucosa with secreted MUC5AC, beating cilia and a functional epithelial barrier, which is suitable for long-term evaluation of sustained release dosage forms.

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Transferrin-modified chitosan nanoparticles for targeted nose-to-brain delivery of proteins

Gabold

Adams

Brameyer

et al. 2022

Drug Deliv. and Transl. Res.

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Nose-to-brain delivery presents a promising alternative route compared to classical blood–brain barrier passage, especially for the delivery of high molecular weight drugs. In general, macromolecules are rapidly degraded in physiological environment. Therefore, nanoparticulate systems can be used to protect biomolecules from premature degradation. Furthermore, targeting ligands on the surface of nanoparticles are able to improve bioavailability by enhancing cellular uptake due to specific binding and longer residence time. In this work, transferrin-decorated chitosan nanoparticles are used to evaluate the passage of a model protein through the nasal epithelial barrier in vitro. It was demonstrated that strain-promoted azide–alkyne cycloaddition reaction can be utilized to attach a functional group to both transferrin and chitosan enabling a rapid covalent surface-conjugation under mild reaction conditions after chitosan nanoparticle preparation. The intactness of transferrin and its binding efficiency were confirmed via SDS-PAGE and SPR measurements. Resulting transferrin-decorated nanoparticles exhibited a size of about 110–150 nm with a positive surface potential. Nanoparticles with the highest amount of surface bound targeting ligand also displayed the highest cellular uptake into a human nasal epithelial cell line (RPMI 2650). In an air–liquid interface co-culture model with glioblastoma cells (U87), transferrin-decorated nanoparticles showed a faster passage through the epithelial cell layer as well as increased cellular uptake into glioblastoma cells. These findings demonstrate the beneficial characteristics of a specific targeting ligand. With this chemical and technological formulation concept, a variety of targeting ligands can be attached to the surface after nanoparticle formation while maintaining cargo integrity. Graphical abstract

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Pharmacological Characterization of the RPMI 2650 Model as a Relevant Tool for Assessing the Permeability of Intranasal Drugs

Cited by 18 publications

References 58 publications

Impact of Glycosylation and Species Origin on the Uptake and Permeation of IgGs through the Nasal Airway Mucosa

Impact of Glycosylation and Species Origin on the Uptake and Permeation of IgGs through the Nasal Airway Mucosa

Improved In Vitro Model for Intranasal Mucosal Drug Delivery: Primary Olfactory and Respiratory Epithelial Cells Compared with the Permanent Nasal Cell Line RPMI 2650

Transferrin-modified chitosan nanoparticles for targeted nose-to-brain delivery of proteins

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