Folic acid-capped PEGylated magnetic nanoparticles enter cancer cells mostly via clathrin-dependent endocytosis

Allard-Vannier, Émilie; Hervé-Aubert, Katel; Kaaki, Karine; Blondy, Thibaut; Shebanova, A. S.; Шайтан, К. В.; Ignatova, Anastasia A.; Saboungi, Marie‐Louise; Feofanov, Аlexey V.; Chourpa, Igor

doi:10.1016/j.bbagen.2016.11.045

Cited by 38 publications

(25 citation statements)

References 32 publications

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“…The uptake of the nanoparticles by the MCF-7 cells not expressing the folate receptor indicates that the FR-receptor-mediated endocytosis (RME) was not the only endocytic pathway of the magnetic nanoparticles uptake, as was also reported recently by Allard-Vannier et al for folic acid-functionalized SPIONs. 32 The uptake of the Mag-Alg-PEG-FA nanoparticles by the cancer cells was visualized with confocal microscopy (Figures 7 and S5–S7). In the absence of a magnetic field, the nanoparticles are co-localized with the lysosomes in both cell lines at prolonged time of incubation (24 h, Supporting Information Figures S6 and S7).…”

Section: Discussionmentioning

confidence: 99%

Folic Acid-Functionalized, Condensed Magnetic Nanoparticles for Targeted Delivery of Doxorubicin to Tumor Cancer Cells Overexpressing the Folate Receptor

et al. 2019

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This study concerns the development of folic acid (FA)-functionalized iron oxide condensed colloidal magnetic clusters for a more selective delivery of doxorubicin (DOX) to tumor cancer cells overexpressing the folate receptor. Alginate-coated condensed magnetic nanoparticles (co-MIONs) were synthesized via an alkaline precipitation method of an iron precursor in the presence of sodium alginate. Poly(ethylene glycol) (OH-PEG-NH2) was conjugated to the carboxylic acid end group of alginate and folic acid (FA) was conjugated to the hydroxyl terminal group of PEG to produce folate-functionalized, pegylated co-MIONS (Mag-Alg-PEG-FA). The physicochemical properties of nanoparticles were fully characterized. DOX was loaded on the nanoparticles, and the cellular uptake and anticancer efficacy of the nanoparticles were examined in cancer cell lines expressing and not expressing the folate receptor. The biocompatibility of the carrier (blank nanoparticles) was also evaluated by cytocompatibility and hemocompatibility experiments. The nanoparticles exhibited sustained DOX release in aqueous buffers and biorelevant media, which was responsive to pH and external alternating current magnetic fields. The effect of the magnetic field on DOX percentage release appeared to be independent of the timing (onset time) of magnetic field application, providing flexibility to the magnetic control of drug release from the nanoparticles. The blank nanoparticles were not cytotoxic and did not cause hemolysis. The DOX-loaded and FA-functionalized nanoparticles exhibited increased uptake and caused increased apoptosis and cytotoxicity against the MDA-MB-231 cell line, expressing the folate receptor, compared to the MCF-7 cell line, not expressing the folate receptor. The application of a 0.5 T magnetic field during incubation of the nanoparticles with the cancer cells increased the cellular uptake and cytotoxicity of the nanoparticles. The obtained results indicate the potential of the folate-functionalized, pegylated co-MIONS for a more efficacious DOX delivery to cancer cells of solid tumors.

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Section: Discussionmentioning

confidence: 99%

Folic Acid-Functionalized, Condensed Magnetic Nanoparticles for Targeted Delivery of Doxorubicin to Tumor Cancer Cells Overexpressing the Folate Receptor

et al. 2019

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“…Ligands for the FR (e.g., folate) and CD44 (e.g., hyaluronic acid, CD44 antibodies) have been, therefore, widely used along with IONs for tumor targeting both in vitro and in vivo [ 200 , 201 , 202 , 203 ]. Although these receptors are commonly internalized through lipid raft-dependent mechanisms (e.g., CLIC/GEEC pathway), recent reports have also described the contribution of CME [ 204 , 205 ]. This is presumed to occur due to the high abundance of CME in all cell types, which can make them passive cargoes of CCPs [ 44 ], especially when nanoparticle multivalency increases [ 206 ].…”

Section: Enhancing Ion Internalizationmentioning

confidence: 99%

Tailoring Iron Oxide Nanoparticles for Efficient Cellular Internalization and Endosomal Escape

et al. 2020

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Iron oxide nanoparticles (IONs) have been widely explored for biomedical applications due to their high biocompatibility, surface-coating versatility, and superparamagnetic properties. Upon exposure to an external magnetic field, IONs can be precisely directed to a region of interest and serve as exceptional delivery vehicles and cellular markers. However, the design of nanocarriers that achieve an efficient endocytic uptake, escape lysosomal degradation, and perform precise intracellular functions is still a challenge for their application in translational medicine. This review highlights several aspects that mediate the activation of the endosomal pathways, as well as the different properties that govern endosomal escape and nuclear transfection of magnetic IONs. In particular, we review a variety of ION surface modification alternatives that have emerged for facilitating their endocytic uptake and their timely escape from endosomes, with special emphasis on how these can be manipulated for the rational design of cell-penetrating vehicles. Moreover, additional modifications for enhancing nuclear transfection are also included in the design of therapeutic vehicles that must overcome this barrier. Understanding these mechanisms opens new perspectives in the strategic development of vehicles for cell tracking, cell imaging and the targeted intracellular delivery of drugs and gene therapy sequences and vectors.

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“…FA can be actively transported into cells by the reduced folate carrier (RFC) or via the folate receptors (FRs) either by photocytosis or endocytosis [ 19 , 20 ]. The affinity of FA to bind FRα is 100–200 times greater than to RFC [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

Heterocyclic Substitutions Greatly Improve Affinity and Stability of Folic Acid towards FRα. an In Silico Insight

et al. 2021

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Folate receptor alpha (FRα) is known as a biological marker for many cancers due to its overexpression in cancerous epithelial tissue. The folic acid (FA) binding affinity to the FRα active site provides a basis for designing more specific targets for FRα. Heterocyclic rings have been shown to interact with many receptors and are important to the metabolism and biological processes within the body. Nineteen FA analogs with substitution with various heterocyclic rings were designed to have higher affinity toward FRα. Molecular docking was used to study the binding affinity of designed analogs compared to FA, methotrexate (MTX), and pemetrexed (PTX). Out of 19 FA analogs, analogs with a tetrazole ring (FOL03) and benzothiophene ring (FOL08) showed the most negative binding energy and were able to interact with ASP81 and SER174 through hydrogen bonds and hydrophobic interactions with amino acids of the active site. Hence, 100 ns molecular dynamics (MD) simulations were carried out for FOL03, FOL08 compared to FA, MTX, and PTX. The root mean square deviation (RMSD) and root mean square fluctuation (RMSF) of FOL03 and FOL08 showed an apparent convergence similar to that of FA, and both of them entered the binding pocket (active site) from the pteridine part, while the glutamic part was stuck at the FRα pocket entrance during the MD simulations. Molecular mechanics Poisson-Boltzmann surface accessible (MM-PBSA) and H-bond analysis revealed that FOL03 and FOL08 created more negative free binding and electrostatic energy compared to FA and PTX, and both formed stronger H-bond interactions with ASP81 than FA with excellent H-bond profiles that led them to become bound tightly in the pocket. In addition, pocket volume calculations showed that the volumes of active site for FOL03 and FOL08 inside the FRα pocket were smaller than the FA–FRα system, indicating strong interactions between the protein active site residues with these new FA analogs compared to FA during the MD simulations.

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Folic acid-capped PEGylated magnetic nanoparticles enter cancer cells mostly via clathrin-dependent endocytosis

Cited by 38 publications

References 32 publications

Folic Acid-Functionalized, Condensed Magnetic Nanoparticles for Targeted Delivery of Doxorubicin to Tumor Cancer Cells Overexpressing the Folate Receptor

Folic Acid-Functionalized, Condensed Magnetic Nanoparticles for Targeted Delivery of Doxorubicin to Tumor Cancer Cells Overexpressing the Folate Receptor

Tailoring Iron Oxide Nanoparticles for Efficient Cellular Internalization and Endosomal Escape

Heterocyclic Substitutions Greatly Improve Affinity and Stability of Folic Acid towards FRα. an In Silico Insight

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