Limits and Challenges in Using Transport Inhibitors to Characterize How nano-sized Drug Carriers Enter Cells

Francia, Valentina; Reker‐Smit, Catharina; Boel, Guido; Salvati, Anna

doi:10.2217/nnm-2018-0446

Cited by 49 publications

(77 citation statements)

References 70 publications

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“…We previously performed an extensive study on these aspects and carefully optimized their use on HeLa cells, in order to demonstrate their efficacy and minimize their toxicity. 49 The same conditions were applied for this study. There, we also found that the presence of serum can strongly limit the efficacy of some of these compounds.…”

Section: Resultsmentioning

confidence: 99%

Corona Composition Can Affect the Mechanisms Cells Use to Internalize Nanoparticles

et al. 2019

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Nanosized objects, such as nanoparticles and other drug carriers used in nanomedicine, once in contact with biological environments are modified by adsorption of biomolecules on their surface. The presence of this corona strongly affects the following interactions at cell and organism levels. It has been shown that corona proteins can be recognized by cell receptors. However, it is not known whether the composition of this acquired layer can also affect the mechanisms nanoparticles use to enter cells. This is of particular importance when considering that the same nanoparticles can form different coronas for instance in vitro when exposed to cells in different serum amounts or in vivo depending on the exposure or administration route. Thus, in this work, different coronas were formed on 50 nm silica by exposing them to different serum concentrations. The uptake efficiency in HeLa cells was compared, and the uptake mechanisms were characterized using transport inhibitors and RNA interference. The results showed that the nanoparticles were internalized by cells via different mechanisms when different coronas were formed, and only for one corona condition was uptake mediated by the LDL receptor. This suggested that coronas of different composition can be recognized differently by cell receptors, and this in turn leads to internalization via different mechanisms. Similar studies were performed using other cells, including A549 cells and primary HUVEC, and different nanoparticles, namely 100 nm liposomes and 200 nm silica. Overall, the results confirmed that the corona composition can affect the mechanisms of nanoparticle uptake by cells.

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Section: Resultsmentioning

confidence: 99%

Corona Composition Can Affect the Mechanisms Cells Use to Internalize Nanoparticles

et al. 2019

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“…However, it is well established that perturbation of a cellular mechanism might as well lead to the alteration of other mechanisms. Therefore, when performing such studies, it is important to have appropriate controls to verify the effect of the selected treatment on the pathway of interest and exclude potential artefacts of this kind [22,133,158].…”

Section: Methods To Characterize Uptake Mechanismsmentioning

confidence: 99%

“…Apart from RNAi, so far, many studies on the uptake of nanosized materials make use of transport inhibitors, whose action on cells is instead very fast. However, some of these inhibitors lack specificity, they might interfere with multiple pathways, and they can cause cellular toxicity [22,133,158,213]. In contrast to these approaches to block uptake pathways, other strategies can be found in which proteins are instead overexpressed, in order to eventually detect an increase in nanoparticle uptake [17].…”

Section: Methods To Characterize Uptake Mechanismsmentioning

confidence: 99%

“…Overall, it is clear that none of these different methods, alone, can provide a full picture of the mechanisms that nano-sized materials use to interact with cells since they all display different advantages and pitfalls [22,133,158]. The combination of different techniques and the application of proper controls could help us to gain a better knowledge of the endocytic processes involved in the uptake of nano-sized materials.…”

Section: Methods To Characterize Uptake Mechanismsmentioning

confidence: 99%

“…A reason of this ambiguity and complexity might be that multiple mechanisms are triggered at the same time, as suggested by several studies [18,115,132,[156][157][158][159]. It could also be that, besides the generally studied classical routes such as clathrin-and caveolae-mediated endocytosis, other less wellknown pathways of internalization are involved in the uptake of nanomedicines, such as those briefly described in Section 2.1.…”

Section: Endocytosis Of Nanoparticles: Effects Of Materials Propertiesmentioning

confidence: 99%

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Interactions at the cell membrane and pathways of internalization of nano-sized materials for nanomedicine

Francia¹,

Montizaan²,

Salvati³

2020

Beilstein J. Nanotechnol.

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101

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Nano-sized materials have great potential as drug carriers for nanomedicine applications. Thanks to their size, they can exploit the cellular machinery to enter cells and be trafficked intracellularly, thus they can be used to overcome some of the cellular barriers to drug delivery. Nano-sized drug carriers of very different properties can be prepared, and their surface can be modified by the addition of targeting moieties to recognize specific cells. However, it is still difficult to understand how the material properties affect the subsequent interactions and outcomes at cellular level. As a consequence of this, designing targeted drugs remains a major challenge in drug delivery. Within this context, we discuss the current understanding of the initial steps in the interactions of nano-sized materials with cells in relation to nanomedicine applications. In particular, we focus on the difficult interplay between the initial adhesion of nano-sized materials to the cell surface, the potential recognition by cell receptors, and the subsequent mechanisms cells use to internalize them. The factors affecting these initial events are discussed. Then, we briefly describe the different pathways of endocytosis in cells and illustrate with some examples the challenges in understanding how nanomaterial properties, such as size, charge, and shape, affect the mechanisms cells use for their internalization. Technical difficulties in characterizing these mechanisms are presented. A better understanding of the first interactions of nano-sized materials with cells will help to design nanomedicines with improved targeting.

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Strategies for Delivering Nanoparticles across Tumor Blood Vessels

Sheth

Wang

Bhattacharya

et al. 2020

Adv Funct Materials

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Nanoparticle transport across tumor blood vessels is a key step in nanoparticle delivery to solid tumors. However, the specific pathways and mechanisms of this nanoparticle delivery process are not fully understood. Here, the biological and physical characteristics of the tumor vasculature and the tumor microenvironment are explored and how these features affect nanoparticle transport across tumor blood vessels is discussed. The biological and physical methods to deliver nanoparticles into tumors are reviewed and paracellular and transcellular nanoparticle transport pathways are explored. Understanding the underlying pathways and mechanisms of nanoparticle tumor delivery will inform the engineering of safer and more effective nanomedicines for clinical translation.

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Limits and Challenges in Using Transport Inhibitors to Characterize How nano-sized Drug Carriers Enter Cells

Cited by 49 publications

References 70 publications

Corona Composition Can Affect the Mechanisms Cells Use to Internalize Nanoparticles

Corona Composition Can Affect the Mechanisms Cells Use to Internalize Nanoparticles

Interactions at the cell membrane and pathways of internalization of nano-sized materials for nanomedicine

Strategies for Delivering Nanoparticles across Tumor Blood Vessels

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