Key for crossing the BBB with nanoparticles: the rational design

• Sonia M. Lombardo,
• Marc Schneider,
• Akif E. Türeli and
• Nazende Günday Türeli

Beilstein J. Nanotechnol. 2020, 11, 866–883, doi:10.3762/bjnano.11.72

• endocytic vesicles have been identified and described in the brain endothelial cells: clathrin-coated pits, caveolae and macropinocytosis vesicles. Clathrin-coated pits are involved in most of the internalization processes mediated by receptors such as TfR or insulin receptors [39][40]. After endocytosis

• [39]. The intracellular pathway taken by the vesicles depends on the receptor, on the internalization pathway (clathrin-mediated or caveolae) and also on the type of ligand binding to the receptors [39]. Furthermore, it has been shown that bEND3 cells (mouse brain microvascular cell line) had less

• , resulting in an overall net positive charge [108][126]. CPPs are able to enhance membrane penetration and cell internalization of their conjugated cargo in a large variety of cells, through pathways not always well known [126][127]. In the case of BBB crossing, their positive charge might induce their

Luminescent gold nanoclusters for bioimaging applications

• Nonappa

Beilstein J. Nanotechnol. 2020, 11, 533–546, doi:10.3762/bjnano.11.42

• . Review Luminescent gold nanoclusters Luminescent AuNCs show high photostability and biocompatibility and are nontoxic [41]. Their size is highly precise and small compared to QDs, offering a better internalization in cells and tissues [42][43][44][45][46][47]. The presence of surface ligands allows for a

• of streptavidin with biotin was exploited for imaging human hepatoma cells (HepG2, Figure 4C). HepG2 are cancerous cells that contain excess biotin. Retnakumari et al. studied the surface functionalization of Au-BSA NCs with folic acid (FA) for selective binding, internalization and imaging of folate

• , HeLa, HepG2 and A375, as well as a normal HEK cell line (Figure 5B). Confocal imaging confirmed the internalization of the nanocarriers. After incubating the cell lines with sodium azide, there was a decrease by 82% of uptake of the nanocarriers, suggesting that the internalization is through

Multilayer capsules made of weak polyelectrolytes: a review on the preparation, functionalization and applications in drug delivery

• Varsha Sharma and
• Anandhakumar Sundaramurthy

Beilstein J. Nanotechnol. 2020, 11, 508–532, doi:10.3762/bjnano.11.41

Brome mosaic virus-like particles as siRNA nanocarriers for biomedical purposes

• Alfredo Nuñez-Rivera,
• Pierrick G. J. Fournier,
• Danna L. Arellano,
• Ana G. Rodriguez-Hernandez,
• Rafael Vazquez-Duhalt and
• Ruben D. Cadena-Nava

Beilstein J. Nanotechnol. 2020, 11, 372–382, doi:10.3762/bjnano.11.28

• distribution [6], limitations in the blood flow of tumor vessels [7], pressure gradients, cellular internalization [8], and the escape of endosomal and lysosomal compartments and drug efflux pumps [9]. The use of nanoparticles as nanovehicles has been proposed to overcome some of these limitations

• properties of biomedical interest are demonstrated, such as biocompatibility, tumor cell internalization, and their efficiency as nanocarriers for siRNA delivery. In addition, the capacity of the BMV and CCMV viruses to modulate the immune response in vitro was also analyzed. Results and Discussion Cell

• internalization of VLPs In order to test the cell internalization of VLPs, BMV and CCMV VLPs were loaded with NanoOrange, a hydrophobic fluorescent dye. Both BMV and CCMV viruses have hydrophobic residues in their capsid protein in which hydrophobic molecules, such as NanoOrange, are bound. Due to the high

Poly(1-vinylimidazole) polyplexes as novel therapeutic gene carriers for lung cancer therapy

• Gayathri Kandasamy,
• Elena N. Danilovtseva,
• Vadim V. Annenkov and
• Uma Maheswari Krishnan

Beilstein J. Nanotechnol. 2020, 11, 354–369, doi:10.3762/bjnano.11.26

• internalization and escaped the endosome effectively. The polyplex was more effective than free siRNA in silencing VEGF in lung cancer cells. The silencing of VEGF was quantified using Western blot and was also reflected in the depletion of HIF-1α levels in the cells treated with the polyplex. VEGF silencing by

• incubated for 48 h. The cell viability was then assessed using the MTS reagent as described above. Internalization studies: Internalization of the polyplex in A549 cells was studied with Cy3 fluorophore-tagged siRNA. A549 cells at a seeding density of 105 cells/well were cultured on a cover slip in a 6-well

• good serum stability of the polyplex. In vitro studies The internalization of the polyplex in A549 cells was determined and the results are presented in Figure 3. It is observed that the PVI polyplexes accumulate on the membrane surface after 15 min and are starting to be internalized into the cells

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

• Valentina Francia,
• Daphne Montizaan and
• Anna Salvati

Beilstein J. Nanotechnol. 2020, 11, 338–353, doi:10.3762/bjnano.11.25

• 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

• drugs currently present on the market [5]. This enables nanomedicines to potentially overcome problems associated with the passive diffusion of small molecular drugs through cell membranes, such as their indiscriminate internalization in different cell types and organs, which is often associated with

• system, blood circulation time, biodistribution, and cellular recognition and internalization can be tailored [1][2][3][7][8]. Moreover, the surface of nanomedicines can be engineered by introducing functional groups to reduce clearance and increase biodistribution, as well as for active targeting

Facile biogenic fabrication of hydroxyapatite nanorods using cuttlefish bone and their bactericidal and biocompatibility study

• Satheeshkumar Balu,
• Manisha Vidyavathy Sundaradoss,
• Swetha Andra and
• Jaison Jeevanandam

Beilstein J. Nanotechnol. 2020, 11, 285–295, doi:10.3762/bjnano.11.21

• porosity and high surface-to-volume ratio when compared to spherical nanometer-sized Hap particles, which facilitates interconnectivity and improves targeted cell internalization efficiency [22]. Thus, the aim of the present work is to use a simple, facile, unique, safe and cost-effective precipitation

Rational design of block copolymer self-assemblies in photodynamic therapy

• Maxime Demazeau,
• Laure Gibot,
• Anne-Françoise Mingotaud,
• Patricia Vicendo,
• Clément Roux and
• Barbara Lonetti

Beilstein J. Nanotechnol. 2020, 11, 180–212, doi:10.3762/bjnano.11.15

• ones such as polyesters or polyacrylates. A second part focuses on important parameters for their design and the improvement of their efficiency. Finally, particular attention has been paid to the question of nanocarrier internalization and interaction with membranes (both biomimetic and cellular), and

• use of irradiation to promote drug delivery (photochemical internalization). Block copolymers used for vectorization of photosensitizers Most of the used photosensitizers are highly hydrophobic and have the tendency to aggregate in aqueous environments, which is detrimental for their effectiveness in

• diameter and ζ-potential values switch from negative to positive thus accelerating cellular internalization [36]. Poly ion complexes formed thanks to electrostatic interactions between positively charged weak bases and negatively charged weak acids are ideal pH-responsive nanocarriers. PICs formed by

Internalization mechanisms of cell-penetrating peptides

• Ivana Ruseska and
• Andreas Zimmer

Beilstein J. Nanotechnol. 2020, 11, 101–123, doi:10.3762/bjnano.11.10

• the cell interior. Nevertheless, the mechanism they use to enter cells still remains an unsolved piece of the puzzle. Endocytosis and direct penetration have been suggested as the two major mechanisms used for internalization, however, it is not all black and white in the nanoworld. Studies have shown

• that several CPPs are able to induce and shift between different uptake mechanisms depending on their concentration, cargo or the cell line used. This review will focus on the major internalization pathways CPPs exploit, their characteristics and regulation, as well as some of the factors that

• influence the cellular uptake mechanism. Keywords: cell-penetrating peptides; direct translocation; drug delivery; endocytosis; internalization; Introduction The cell membrane is a semipermeable barrier, serving as a protective layer for the cells. It is an essential organelle for cell survival and

The different ways to chitosan/hyaluronic acid nanoparticles: templated vs direct complexation. Influence of particle preparation on morphology, cell uptake and silencing efficiency

• Arianna Gennari,
• Julio M. Rios de la Rosa,
• Erwin Hohn,
• Maria Pelliccia,
• Enrique Lallana,
• Roberto Donno,
• Annalisa Tirella and
• Nicola Tirelli

Beilstein J. Nanotechnol. 2019, 10, 2594–2608, doi:10.3762/bjnano.10.250

• protein adsorption on chitosan-containing nanoparticles [14] and a receptor-mediated mechanism of internalization [15]. A larger size of the anionic component corresponds to a higher avidity toward chitosan, thus polyelectrolyte complexes are more stable but also difficult to reverse; this irreversibility

• presentation of HA [18], which affected the nanoparticle internalization in both RAW 264.7 macrophages [19][20] and XS106 dendritic cells [21]. In both cases, nanoparticles based on chitosan of low molecular weight appeared to be surrounded by a corona of loosely bound HA, which on one hand lowered the maximum

• -116 cells massively express CD44, both in its standard and variant forms [42]. Their “HA receptor cocktail” may trigger internalization processes with conditions that favour the endosomolytic properties of high-MW chitosan. High-MW polycations should, in principle, be better at membrane disruption

Small protein sequences can induce cellular uptake of complex nanohybrids

• Jan-Philip Merkl,
• Malak Safi,
• Christian Schmidtke,
• Fadi Aldeek,
• Johannes Ostermann,
• Tatiana Domitrovic,
• Sebastian Gärtner,
• John E. Johnson,
• Horst Weller and
• Hedi Mattoussi

Beilstein J. Nanotechnol. 2019, 10, 2477–2482, doi:10.3762/bjnano.10.238

• [20][21]. This peptide is produced during viral capsid maturation and is thought to enable cellular internalization of the virus. It has been shown that the MBP-fused γ-peptide is able to disrupt artificial liposomes [20][21]. Recently, we have used this His6-MBP-γ to promote the uptake of QDs by

Toxicity and safety study of silver and gold nanoparticles functionalized with cysteine and glutathione

• Barbara Pem,
• Igor M. Pongrac,
• Lea Ulm,
• Ivan Pavičić,
• Valerije Vrček,
• Darija Domazet Jurašin,
• Marija Ljubojević,
• Adela Krivohlavek and
• Ivana Vinković Vrček

Beilstein J. Nanotechnol. 2019, 10, 1802–1817, doi:10.3762/bjnano.10.175

• concentration of 25 mg Ag L−1 would release only 0.2 mg Ag+ L−1 in the cell culture media, the concentration of ionic Ag that is non-toxic to L929 cells. Thus, the toxicity mechanism is much more complicated than a simple metal ion release in cell culture media. The cellular internalization of NPs by active

• Figure S7 in Supporting Information File 1). This is in accordance with recently published in vivo data on GSH-coated gold nanoclusters with promising theranostic properties [55][56]. Our GSH-AuNPs bypassed internalization by L929 cells similar to the interaction of GSH-protected Au nanoclusters with the

• with regard to cell viability, the number of cells in late apoptosis, and DNA damage, which can be explained by efficient internalization of these type of AuNPs (Figure 5, Figures S6 and S7 in Supporting Information File 1). The GSH-AuNPs proved to be not only less toxic than CYS-AuNPs, but even

Scavenging of reactive oxygen species by phenolic compound-modified maghemite nanoparticles

• Małgorzata Świętek,
• Yi-Chin Lu,
• Rafał Konefał,
• Liliana P. Ferreira,
• M. Margarida Cruz,
• Yunn-Hwa Ma and
• Daniel Horák

Beilstein J. Nanotechnol. 2019, 10, 1073–1088, doi:10.3762/bjnano.10.108

• augment particle internalization compared to heparin modification alone. Previous studies have suggested that electrostatic interactions, oxidation-dependent conjugation, and hydrogen bonds between the phenolic OH groups and polysaccharide moieties and/or amino acid residues of the cell membrane may

• enhance nanoparticle internalization [34]. The application of a magnetic field during incubation with γ-Fe2O3 increased the MNPcell level by 2.7-fold compared with that without the magnet in L-929 cells. The γ-Fe2O3@Hep uptake in LN-229 cells was increased by 1.8-fold compared with that without magnetic

• phenolic compound-modified nanoparticles (100 μg/mL), they were incubated with L-929 and LN-229 cells for 3 h, and 2 mM H2O2 was added for 30 min, followed by staining with CM-H2DCFDA for 1 h. Figure 6 shows the representative flow cytometry results of nanoparticle internalization and the intracellular ROS

Serum type and concentration both affect the protein-corona composition of PLGA nanoparticles

• Katrin Partikel,
• Robin Korte,
• Dennis Mulac,
• Hans-Ulrich Humpf and
• Klaus Langer

Beilstein J. Nanotechnol. 2019, 10, 1002–1015, doi:10.3762/bjnano.10.101

• enrichment in the membrane. This step is usually considered as a prerequisite for a successive internalization by cells [38]. Besides, some of the proteins in the corona could mediate the interaction with cells by the recognition of specific receptor binding sites localized on the cell surface and thus

Heating ability of magnetic nanoparticles with cubic and combined anisotropy

• Nikolai A. Usov,
• Mikhail S. Nesmeyanov,
• Elizaveta M. Gubanova and
• Natalia B. Epshtein

Beilstein J. Nanotechnol. 2019, 10, 305–314, doi:10.3762/bjnano.10.29

• SAR in the alternating magnetic field [3][16]. On the contrary, in biological media, nanoparticles have a tendency to aggregate because of active biological processes, such as cellular internalization in endocytic compartments [10][13]. As a result, the nanoparticles in biological media may form

Targeting strategies for improving the efficacy of nanomedicine in oncology

• Gonzalo Villaverde and
• Alejandro Baeza

Beilstein J. Nanotechnol. 2019, 10, 168–181, doi:10.3762/bjnano.10.16

• selective delivery to these organelles [49]. The peptide Lys–Asp–Glu–Leu (KDEL) has been anchored on gold nanoparticles loaded with siRNA for the selective delivery of the genetic material into the endoplasmic reticulum [50]. The main mechanism for the internalization of nanoparticles within mammalian cells

• solutions, a real alternative? Active targeting is already one of the most used strategies for bringing nanoformulations into tumoral cells. Although usually great results were achieved in vitro, the in vivo assays have shown smaller effects regarding cell internalization. There has been no real enhancement

• and affinity to glioma cells for LPR interaction. The exposed dual peptide cation enables the possible accumulation into gliomas via the combination of EPR effect and active targeting for an antiangiogenic and apoptotic treatment. In vitro assays showed improved internalization only when the liposomes

The nanoscaled metal-organic framework ICR-2 as a carrier of porphyrins for photodynamic therapy

• Jan Hynek,
• Sebastian Jurík,
• Martina Koncošová,
• Jaroslav Zelenka,
• Ivana Křížová,
• Tomáš Ruml,
• Kaplan Kirakci,
• Ivo Jakubec,
• František Kovanda,
• Kamil Lang and
• Jan Demel

Beilstein J. Nanotechnol. 2018, 9, 2960–2967, doi:10.3762/bjnano.9.275

• rate of internalization of the photosensitizers into the cells with different modifications of nanoICR-2. The highest cellular uptake was observed for nanoICR-2/TPPPi(Ph), followed by nanoICR-2/TPPPi(iPr) and nanoICR-2/TPPPi(Me). The most efficiently accumulating sample nanoICR-2/TPPPi(Ph) was

Cytotoxicity of doxorubicin-conjugated poly[N-(2-hydroxypropyl)methacrylamide]-modified γ-Fe₂O₃ nanoparticles towards human tumor cells

• Zdeněk Plichta,
• Yulia Kozak,
• Rostyslav Panchuk,
• Viktoria Sokolova,
• Matthias Epple,
• Lesya Kobylinska,
• Pavla Jendelová and
• Daniel Horák

Beilstein J. Nanotechnol. 2018, 9, 2533–2545, doi:10.3762/bjnano.9.236

• stability in aqueous media and limited internalization by the cells, however, enabled adhesion to the cell surface. While the neat PHPMA-coated particles proved to be non-toxic, doxorubicin-conjugated particles exhibited enhanced cytotoxicity in both drug-sensitive and drug-resistant tumor cells compared to

• , internalization of PHPMA-modified γ-Fe2O3 particles by the cells was restricted and the particles were localized mostly on the cell surface and in the perimembranous space, where Dox retained its activity. To get comparable dose-dependent data, the amount of Dox in P(HPMA-MMAA)-Dox added to the γ-Fe2O3@PHPMA

Involvement of two uptake mechanisms of gold and iron oxide nanoparticles in a co-exposure scenario using mouse macrophages

• Dimitri Vanhecke,
• Dagmar A. Kuhn,
• Dorleta Jimenez de Aberasturi,
• Sandor Balog,
• Ana Milosevic,
• Dominic Urban,
• Diana Peckys,
• Niels de Jonge,
• Wolfgang J. Parak,
• Alke Petri-Fink and
• Barbara Rothen-Rutishauser

Beilstein J. Nanotechnol. 2017, 8, 2396–2409, doi:10.3762/bjnano.8.239

• single-exposure experiment. This may initially appear paradoxical can be easily explained by the activation of two parallel uptake pathways. After internalization, the fluorescent signals from AuNPs and FeOxNPs never completely colocalise, which may again be a reflection of different uptake mechanisms

• [39]. Furthermore, it was shown that exosomes moved along the extracellular side of filopodia prior to internalization [40]. The transport along filopodia has been suggested to be mediated by the underlying actin–myosin cytoskeleton [41]. The distance between linearly arranged AuNPs averaged 37 nm

Carbon nano-onions as fluorescent on/off modulated nanoprobes for diagnostics

• Stefania Lettieri,
• Marta d’Amora,
• Adalberto Camisasca,
• Alberto Diaspro and
• Silvia Giordani

Beilstein J. Nanotechnol. 2017, 8, 1878–1888, doi:10.3762/bjnano.8.188

• development of a nanosensor which can be “turned on” in an acidic environment. Remarkably, the fluo-CNOs maintained the switching properties upon cell internalization, as they were “switched-on” in response to acidic pH. In vitro experiments on HeLa cells showed excellent cellular uptake and low toxicity of

• application as intracellular sensors. Confocal imaging Confocal imaging was performed on human cervical carcinoma (HeLa) cells treated with fluo-CNOs, in order to confirm the preservation of the PET and ICT characteristics of the dye attached to CNOs after cell internalization, hence the possible use of fluo

Synthesis and functionalization of NaGdF₄:Yb,Er@NaGdF₄ core–shell nanoparticles for possible application as multimodal contrast agents

• Dovile Baziulyte-Paulaviciene,
• Vitalijus Karabanovas,
• Marius Stasys,
• Greta Jarockyte,
• Vilius Poderys,
• Simas Sakirzanovas and
• Ricardas Rotomskis

Beilstein J. Nanotechnol. 2017, 8, 1815–1824, doi:10.3762/bjnano.8.183

• , Tween 80-coated core–shell nanoparticles presented enhanced optical and MR signal intensity, good colloidal stability, low cytotoxicity and nonspecific internalization into two different breast cancer cell lines, which indicates that these nanoparticles could be applied as an efficient, dual-modal

Uptake and intracellular accumulation of diamond nanoparticles – a metabolic and cytotoxic study

• Antonín Brož,
• Lucie Bačáková,
• Pavla Štenclová,
• Alexander Kromka and
• Štěpán Potocký

Beilstein J. Nanotechnol. 2017, 8, 1649–1657, doi:10.3762/bjnano.8.165

• in cultures exposed and unexposed to photoluminescent nanodiamonds. This positive effect can be attributed to the fact that the mechanism of the ND uptake was clathrin-mediated endocytosis, that is, a physiological cellular mechanism for internalization of various bioactive substances from the

Cationic PEGylated polycaprolactone nanoparticles carrying post-operation docetaxel for glioma treatment

• Cem Varan and
• Erem Bilensoy

Beilstein J. Nanotechnol. 2017, 8, 1446–1456, doi:10.3762/bjnano.8.144

• than 100 nm and a net positive surface charge to facilitate cellular internalization of drug-loaded nanoparticles. Hydroxypropyl cellulose films were prepared to incorporate these nanoparticle dispersions to complete the implantable drug delivery system. Results: The diameter of core–shell

• effective on growth inhibition of breast and prostate cancer cells when compared to free docetaxel [23]. Core–shell nanoparticles are also used as non-viral vectors for the treatment of glioma. Zamora et al. prepared photochemical internalization mediated polyamine core–shell nanoparticles for tumor

Nano-engineered skin mesenchymal stem cells: potential vehicles for tumour-targeted quantum-dot delivery

• Liga Saulite,
• Dominyka Dapkute,
• Karlis Pleiko,
• Ineta Popena,
• Simona Steponkiene,
• Ricardas Rotomskis and
• Una Riekstina

Beilstein J. Nanotechnol. 2017, 8, 1218–1230, doi:10.3762/bjnano.8.123

• QDs possessing a protein corona are differently recognized by NIH3T3 cells and internalized by different pathways [23], consistent with the data from the present study. Interestingly, MSCs showed more effective internalization of QDs under serum-free conditions, as the protein corona interferes with

• observed internalization of QDs in early endosomes after 6 h of incubation, followed by re-localization to late endosomes/lysosomes after 24 and 48 h of incubation (Figure 8). Cell division, excretion and degradation are the main mechanisms reported for QD signal elimination over time [50][51]. It has been

Uptake of the proteins HTRA1 and HTRA2 by cells mediated by calcium phosphate nanoparticles

• Olga Rotan,
• Katharina N. Severin,
• Simon Pöpsel,
• Alexander Peetsch,
• Melisa Merdanovic,
• Michael Ehrmann and
• Matthias Epple

Beilstein J. Nanotechnol. 2017, 8, 381–393, doi:10.3762/bjnano.8.40

• that the main internalization pathway for anionic calcium phosphate nanoparticles into HeLa cells was macropinocytosis. In that case, cationic nanoparticles were also taken up much better than anionic nanoparticles [47]. This is also supported by earlier studies on the uptake of nanoparticles with