Mechanisms facilitating the uptake of carboxyl–polythene glycol-functionalized gold nanoparticles into multicellular spheroids

Author:

Fobian Seth-Frerich1ORCID,Petzer Melissa1ORCID,Vetten Melissa2ORCID,Steenkamp Vanessa1ORCID,Gulumian Mary234ORCID,Cordier Werner1ORCID

Affiliation:

1. Department of Pharmacology, Faculty of Health Sciences, University of Pretoria , Pretoria , South Africa

2. Toxicology Section, National Institute for Occupational Health, National Health Laboratory Service , Johannesburg , South Africa

3. Molecular Medicine and Haematology, School of Pathology, University of Witwatersrand , Johannesburg , South Africa

4. Water Research Group, Unit for Environmental Sciences and Management, North-West University , Potchefstroom , South Africa

Abstract

Abstract Objectives Nanomedicines represent theragnostic alternatives to traditional candidate drugs, with increased targeting and delivery potential due to their size and functional tailorability. Biological activity typically relies on nanomaterials permeating into the intracellular environment, necessitating characterization of uptake and intracellular trafficking pathways. Spheroids’ three-dimensional architecture and heterogenous cellular distribution offer an in-vivo-representative platform to assess the biological activity of nanoparticles (NPs). This study aimed to develop an A549 alveolar carcinoma spheroid model as a NP uptake assessment platform for carboxyl–polythene glycol-functionalized gold NPs affording further biological characterization opportunities in nanomedicine. Methods A549 spheroids were generated via the liquid overlay method, and their morphology and viability were assessed for 21 days. Cytotoxicity was assessed via lactate dehydrogenase release. NP uptake was elucidated using uptake pathway inhibition, combined with CytoViva hyperspectral imaging of sectioned spheroids to count internalized NPs. Key findings Cytotoxicity was absent for all exposure groups. Clathrin-mediated endocytosis was the primary endocytic mechanism (33.5–54.8% of uptake), which may precede lysosomal degradation. Lysosomal membrane permeabilization appears to be a potential downstream application. Low penetration into spheroids (4.5 μm) suggests the failure of NPs to traverse cellular layers in the spheroid. Conclusions Although poor uptake was observed, a multicellular spheroid model of A549 alveolar carcinoma cells was established, allowing for similar future uptake assessment of various NPs.

Funder

National Research Foundation

Publisher

Oxford University Press (OUP)

Subject

Pharmaceutical Science,Pharmacology

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