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Gold nanoparticles protected by mixed hydrogenated/fluorinated monolayers: controlling and exploring the surface features

  • Maria Şologan
  • Cristina Gentilini
  • Silvia Bidoggia
  • Mariangela Boccalon
  • Alice Pace
  • Paolo Pengo
  • Lucia Pasquato
Perspectives
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  1. 20th Anniversary Issue: From the editors

Abstract

Harnessing the reciprocal phobicity of hydrogenated and fluorinated thiolates proved to be a valuable strategy in preparing gold nanoparticles displaying mixed monolayers with a well-defined and pre-determined morphology. Our studies display that the organisation of the fluorinated ligands in phase-separated domains takes place even when these represent a small fraction of the ligands grafted on the gold surface. Using simple model ligands and by combining 19F NMR or ESR spectroscopies, and multiscale molecular simulations, we could demonstrate how the monolayer morphology responds in a predictable manner to structural differences between the thiolates. This enables a straightforward preparation of gold nanoparticles with monolayers displaying stripe-like, Janus, patchy, and random morphologies. Additionally, solubility properties may be tuned as function of the nature of the ligands and of the monolayer morphology obtaining gold nanoparticles soluble in organic solvents or in aqueous solutions. Most importantly, this rich diversity can be achieved not by resorting to ad hoc developed fabrication techniques, but rather relying on the spontaneous self-sorting of the ligands upon assembly on the nanoparticle surface. Besides enabling control over the monolayer morphology, fluorinated ligands endow the nanoparticles with several properties that can be exploited in the development of novel materials with applications, for instance in drug delivery and diagnostic imaging.

Keywords

Gold nanoparticles Self-assembly Fluorinated thiolates Monolayer morphology Phase segregation Janus nanoparticles 

Introduction

Introducing simple functional groups in the monolayer of gold nanoparticles represents a viable strategy to develop functional nanomaterials; most of them are mixed monolayer nanoparticles. This seemingly minimalist approach led to many remarkable examples of gold nanoparticles mimicking, for instance the complexity of cooperative catalysis (Mancin et al. 2016; Pengo et al. 2005; Pengo et al. 2006; Manea et al. 2004; Diez-Castellnou et al. 2014) or the multivalent recognition events commonly found in naturally evolved systems (Fantuzzi et al. 2003). The efficiency of this mimicry is strictly related to the correct positioning of the functional groups on the nanoparticle surface and this requires control over the monolayer morphology. Indeed, an increasing body of evidence gained in recent years points out that the morphology of mixed monolayers itself is central in determining many of the fundamental properties of these gold nanoparticles, such as solubility, surface wettability and interfacial energy (Centrone et al. 2008; Kuna et al. 2009). These, in turn, affect their assembly behaviour (DeVries et al. 2007), molecular recognition properties (Huang et al. 2013; Huang et al. 2014; Hung et al. 2011; Cho et al. 2012) and catalytic performance (Ghosh et al. 2011). Several examples highlight that monolayer morphology is also a factor responsible of the nanoparticle interaction with cell membranes (Verma et al. 2008; Van Lehn and Alexander-Katz 2011) and of the mechanism the cells exploit for the nanoparticles uptake. This, in turn, determines the fate of the nanoparticles and their toxicity (Sabella et al. 2014) and therefore their applicability in nanomedicine (Pengo et al. 2017). The increasing evidence that the monolayer features are of primary importance in such a broad span of nanoparticle applications pinpoints a challenging research target in nanoparticle science: the control by design of the monolayer morphology.

As far as binary mixtures of ligands are used—which is indeed the most common case—three main types of monolayer morphologies can arise: (i) ligands can be randomly arranged or (ii) they may form isolated patches of various shapes or (iii) they may be phase separated in bulk domains forming a Janus nanoparticle. It is worth stressing here that since the formation of a mixed monolayer on the surface of gold nanoparticles is a self-assembly process, the monolayer morphologies are already “encoded” in the structure of the ligands. The driving forces that operate during self-assembly and are responsible for the morphology of the monolayer stem from structural mismatches or, broadly speaking, from “dissimilarities” between the ligands. The preference for one or another morphology depends on several factors, and among others, the difference in length and steric bulk between the ligands and the nanoparticle size were disclosed by theoretical analyses of Glotzer and collaborators (Singh et al. 2007; Carney et al. 2008; Ghorai and Glotzer 2010). At present, a relatively narrow range of ligand mixtures encompassing, e.g. mercaptopropionic acid and octane- or dodecanethiol (Jackson et al. 2004; Jackson et al. 2006); mercaptopropanesulfonate and phenylmethanethiol (Stewart et al. 2012); thiopronin and mercaptoundecyltetraethyleneglycol (Harkness et al. 2011); 11-mercapto-1-undecanesulfonate and octanethiol (Verma et al. 2008); octanethiol and N-1-{2-[2-(2-methoxyethoxy)ethoxy]ethyl}-8-sulfanyloctanamide (HC8TEG) (Guarino et al. 2012); dodecanethiol and diphenyl thiol (Liu et al. 2012), proved to be already sufficient to generate several different monolayer morphologies. However, in perspective and with applications in mind, it is deemed necessary to broaden as much as possible the span of ligands enabling to achieve patterned monolayers with predictable morphologies. This requires, in particular, understanding the role of the ligands’ molecular structure and properties, in addition to geometrical mismatch, in determining the likelihood of domains’ formation, and eventually their size and shape. Building on “molecular dissimilarity” as leading concept, some years ago, we realised that a relatively simple way to bring this dissimilarity to an extreme was to use mixtures of hydrogenated (H-) and fluorinated (F-) ligands, given the well-known immiscibility of hydrocarbons and fluorocarbons. This seemed a viable strategy because the immiscibility of H- and F-building blocks is not restricted to bulk phases but also takes place at smaller length scale such as in the cases of self-assembled monolayer of thiolates on flat surfaces and vesicular aggregates of H- and F-amphiphiles (Krafft and Riess 2009; Bernardini et al. 2013; Elbert et al. 1984; Kunitake et al. 1983; Şologan et al. 2017). Using fluorinated ligands for the preparation of gold nanoparticles could also be beneficial to their stability, owing to the strength of the C–F bond. This is particularly relevant for bio-medical applications, where long circulation times are often required for therapeutic purposes. In addition, the magnetic properties of the 19F nuclei could be exploited in 19F magnetic resonance imaging (19F MRI) which is an emerging and very sensitive diagnostic technique. It may be argued, however, that this approach, benefits aside, could lead to poorly soluble systems, another face of the incompatibility between fluorocarbons and hydrocarbons or aqueous media. Indeed, the early attempts of preparing silver or gold nanoparticles featuring F-ligands in their monolayer, dating back to 2000 (Shah et al. 2000; Yonezawa et al. 2001a, b; Dass et al. 2008), were frustrated by very low nanoparticle solubility. However, H-/F-mixed monolayers suffer this limitation only to a minor extent, vide infra, and these systems can be conveniently studied in common organic solvents of low polarity. We displayed that the solubility limit can be largely overcome by a proper design of the ligands (Gentilini et al. 2008a, b; Pengo and Pasquato 2015), recognising that the immiscibility of H- and F-units, required to achieve a desired morphology of the monolayer, only needs to be operative in its inner part. The outermost part of the monolayer, the one in contact with the environment, may be endowed with whatever solubilising moieties suitable for bringing the nanoparticles in polar solvent or even in water. Furthermore, tuning the difference in length between the solubilising moieties appended to the H- and F-units may strengthen the self-sorting process according to the rational outlined by Glotzer, and represent an additional degree of freedom in monolayer design. By pursuing this approach, we developed nanoparticles with excellent solubility, paving the way to a series of studies inaccessible to perfluoroalkanethiolate-protected gold nanoparticles. As important as the development of synthetic strategies for the preparation of nanoparticles with monolayers displaying well-defined morphologies is the need of developing reliable strategies to characterise these morphologies unambiguously (Ong et al. 2017). These characterisation strategies mostly rely on well-established techniques, such as nuclear magnetic resonance (NMR) (Liu et al. 2012; Pradhan et al. 2009; Şologan et al. 2016b), electron spin resonance (ESR) (Posocco et al. 2012; Lucarini and Pasquato 2010), scanning tunnelling microscopy (STM) (Ong et al. 2013, 2014; Biscarini et al. 2013), small angle neutron scattering (SANS) (Moglianetti et al. 2014) and matrix-assisted laser desorption/ionisation mass spectrometry (MALDI-MS) (Farrell et al. 2015; Harkness et al. 2010; Merz et al. 2016), to name a few. However, strong integration with computational methods and predictive models is often required to achieve correct interpretation of the experimental data.

In this account, we shall describe the development of H-/F-mixed monolayer nanoparticles and the characterisation of their monolayer morphologies. First, we shall discuss some fundamental studies involving unfunctionalised H- and F-thiols. Afterwards, we present our development of H-/F-mixed monolayer nanoparticles soluble in polar and aqueous media. In this context, the properties of homoligand fluorinated monolayers will be discussed in comparison to the properties of homoligand hydrogenated monolayers.

Model systems and fundamental studies

In designing mixed monolayers, we are concerned with systems that converge spontaneously to well-defined and controlled morphologies. To this end, the ligands should be encoded in order to self-recognise one another upon assembly and the monolayer, as a supramolecular object, should be formed under thermodynamic control (Luo et al. 2017). In the development of our studies, we surmised that, in keeping with the background provided by the studies of Glotzer and Stellacci, the onset of domains formation, the shape of the domains and the resulting monolayer morphology should depend on the structural differences, or mismatch, between the H- and F-ligands. Furthermore, for mixtures of H- and F-ligands, their reciprocal immiscibility should provide an additional driving force to self-sorting and/or influence the shape of the domains. In closer details, we expected that even at very low loading of the F-ligands, these should cluster together eventually forming larger patches as the percentage of the F-ligands in the monolayer increases.

Aiming at addressing these points at the fundamental level, a sensible choice was to use alkanethiols and fluorinated alkanethiols devoid of any specific functionalisation, which could have provided additional contributions, difficult to rationalise, to the thermodynamics of self-assembly (Ghorai and Glotzer 2010).

Accordingly, we took into consideration the fluorinated and hydrogenated ligands displayed in Fig. 1.1 This series encompasses straight-chain thiols with a length of 8, 12 and 16 carbon atoms plus a branched thiol with the branching point very close to the sulfur atom. This was used, in analogy to literature reports (Liu et al. 2012), to introduce local disorder in the nanoparticle monolayer impairing the formation of domains of the fluorinated ligands. As fluorinated ligands, we considered two 1H,1H,2H,2H-perfluoroalkanethiols with a chain length of 8 and 12 carbon atoms; the former carries a fluorous unit of 6 carbon atoms while the latter of 10 carbon atoms. As far as the difference in length is concerned, these thiols can be combined in several different ways and we analysed in details the nanoparticles obtained by the combinations of thiols with a difference in length, Δl, of 8, 4 and 0 atoms (see Table 1).
Fig. 1

Model alkanethiols used for assessing the dependence of the monolayer morphology on the structural differences between the hydrogenated ad fluorinated ligands

Table 1

Nanoparticle systems prepared by combination of the fluorinated and hydrogenated alkanethiols reported in Fig. 1

Nanoparticle system

Δla

Expected morphology

Found morphology

NP-C16/F6

8

Stripe-like

Stripe-like

NP-C12/F6

4

Stripe-like

Stripe-like, patchy

NP-brC12/F6

4

Random

Random

NP-C8/F6

0

Janus

Random/patchy

NP-C12/F10

0

Janus

Janus

aDifference in length between the hydrogenated and fluorinated thiols expressed as number of carbon atoms

For the ligands’ combination with the higher Δl, the monolayer was expected to display a stripe-like morphology. Instead, the Janus morphology of the monolayer was expected to become more likely at Δl = 0. In fact, when the difference in length between the ligands is significant, the formation of extended interfaces between different domains allows the long ligands to experience a high conformational freedom. This results in a favourable entropic contribution to the assembly of the ligands in narrow, stripe-like domains with a large interfacial area between domains to surface ratio. On the other hand, when the difference in length between the ligands is nil, the formation of compact domains with a small interfacial area between the domains to surface ratio allows increasing the number of H/H and F/F van der Waals interactions minimising the less favourable H/F contacts. Thus, when Δl = 0, the thermodynamic drive to phase segregation is enthalpic in nature. Since for nanoparticles with high curvature radius (small nanoparticles) the effect of the difference in length between the ligands levels off, we restricted our analyses to nanoparticles with a core of 2–4 nm in diameter. These were prepared either by the Brust-Schiffrin reaction employing blends of thiols or by place exchange starting from narrowly dispersed NP-C12 prepared using the Miyake procedure (Shimizu et al. 2003).

Characterising the morphology of mixed monolayers is a very challenging task; direct methods such as STM although allowing true visualisation of the monolayer features require very delicate instrumental set-up and may not be completely general. This, for instance, is the case of nanoparticles displaying flexible PEG chains on their outer surface or of fluorinated nanoparticles because of their “slippery” nature. However, mixed monolayers with well-defined morphologies are objects inherently heterogeneous in terms of their local composition, i.e. this is different in different loci and differs from the overall composition of the monolayer. Indeed, only in the case of randomly distributed thiolates, the local composition of the monolayer is expected to be the same in different regions and coincides with its overall composition. This heterogeneity offers an entry to indirect methods of characterisation. In the case of H-/F-mixed monolayer nanoparticles, a technique that is particularly suited to this end is 19F NMR spectroscopy because the 19F chemical shift is very sensitive to the environment experienced by the observed nuclei and hence to the local composition of the monolayer (Şologan et al. 2016b).

Furthermore, since different morphologies result from the growth of patches with different shapes, the 19F chemical shift is expected to vary with the composition of the monolayer in a way that is strictly morphology dependant. A few years ago, this characterisation strategy was validated by Stellacci and co-workers who reported a compelling assessment of the monolayer morphology of Janus, striped and random nanoparticles by means of 1H NMR and bidimensional NOE NMR experiments (Liu et al. 2012). These authors also provided interpretive models that represent a useful guide to determine the morphology of the monolayer from a series of NMR chemical shift data as a function of the monolayer composition. The simpler system we considered is the one of NP-brC12/F6l = 4); because of the branched nature of the hydrogenated thiolate, we expected the ligands to be distributed at random. In this case, the chemical shift of the terminal trifluoromethyl group of thiolate F6 was expected to depend linearly on the composition of the monolayer. This behaviour could be experimentally observed for the terminal trifluoromethyl group (Fig. 2a) but also that of the adjacent fluoromethylene group (data not shown).
Fig. 2

a Dependence of the 19F chemical shift of the terminal CF3 group of the thiolate F6 as a function of its percentage in the monolayer of NP-brC12/F6. b Equilibrium morphologies of two samples of mixed monolayer NP-brC12/F6 from multiscale molecular simulations. Adapted with permission from reference Şologan et al. (2016b). Copyright of the American Chemical Society

To gain complimentary information on the monolayer morphology of this nanoparticle system, we performed multiscale molecular simulations to predict the equilibrium distribution of the thiolates on the gold surface. These are consistent with the lack of specific organisation of the ligands that appear, indeed, to be randomly distributed on the nanoparticle surface in all of the molar fraction range explored (Fig. 2b). The second case that is amenable of simple interpretation is the one of NP-C12/F10l = 0), for which we expected a Janus morphology. In this case, the chemical shift of the CF3 group should depend on the composition of the monolayer in a completely different manner with respect to the previous case. In particular, if we consider the formation of a single patch of fluorinated ligands that grows in size as the fraction of the fluorinated ligands is increased, the number of fluorinated ligands that experience an interaction with the hydrogenated chains, with respect to those that do not, has to be proportional to the interfacial area/surface ratio of the patch. This means that the chemical shift should drop very fast and conform to a 1 ∕ x allometric function where x represents the percentage of the fluorinated ligands in the monolayer.

Experimentally, this was clearly observed for the nanoparticle system NP-C12/F10 (Fig. 3a) and molecular simulations suggest an organisation of the fluorinated ligands that is consistent with their clustering in a single domain (Fig. 3b). On the other hand, for the nanoparticle system NP-C8/F6l = 0) which was also a candidate to display a Janus morphology, this was not as clear (Fig. 3c). Molecular simulations shed light into this discrepancy displaying that in the case of NP-C8/F6, the ligands assumed a random distribution, while formation of patches, mainly isolated, could be observed only at relatively high molar fractions of the F-ligands (Fig. 3d). Although, as described above, the only case in which we do not expect—a priori—the formation of domains is the one in which the branched thiol is employed, it has to be mentioned that using mixtures of fluorinated and hydrogenated ligands results in an inherent imbalance in steric bulk because the cross section of a fluorinated chain is 1.5 times larger than that of a hydrogenated one (Dalvi and Rossky 2010) and this certainly biases the formation of the observed random morphology. If cases of random and Janus nanoparticles are those for which is relatively easy to find an interpretative model of the chemical shift variation versus the monolayer composition, the chemical shift behaviour of other morphologies is not so easy to analyse. However, departure from the models above may still be an indication of a morphology different from random or Janus. For nanoparticles NP-C12/F6l = 4), we expected a stripe-like arrangement of the ligands and the chemical shift profile as a function of the monolayer composition reveals a neat biphasic behaviour which is very different from those obtained for NP-brC12/F6, NP-C12/F10 and NP-C8/F6. When the amount of the fluorinated ligand in the monolayer is below 20%, the CF3 chemical shift remains fairly constant, then it changes rapidly, indicating the onset of a sudden evolution of the monolayer morphology (Fig. 4a). Indeed, molecular simulations displayed that at low loading, the F-ligands tend to form small isolated patches but already at the 40% level, these merge in elongated domains (Fig. 4b). This behaviour nicely illustrates the thermodynamic trade-off involved in the phase segregation of H-/F-thiolates assembled on the nanoparticle surface. When the amount of F-ligands is small, the minimisation of the unfavourable H/F interfaces, while maximising the conformational freedom of the long hydrogenated thiolates and the number of F/F contacts, can be achieved by confining the fluorinated ligands in (small) isolated patches.
Fig. 3

a Dependence of the 19F chemical shift of the terminal CF3 group of the thiolate F10 as a function of its percentage in the monolayer of NP-C12/F10. b Equilibrium morphologies of two selected samples of mixed monolayer NP-C12/F10 from multiscale molecular simulations. c Dependence of the 19F chemical shift of the terminal CF3 group of the thiolate F6 as a function of its percentage in the monolayer of NP-C8/F6. d Equilibrium morphologies of two selected samples of mixed monolayer NP-C8/F6 from multiscale molecular simulations. Adapted with permission from reference Şologan et al. (2016b). Copyright of the American Chemical Society

Fig. 4

a Dependence of the chemical shift of the terminal CF3 group of the thiolate F6 as a function of its percentage in the monolayer of NP-C12/F6. b Selected equilibrium morphologies of the mixed monolayer NP-C12/F6. Adapted with permission from reference Şologan et al. (2016b). Copyright of the American Chemical Society

Clustering in a single narrow—stripe-like—domain would certainly have increased the favourable entropic contribution derived from the conformational freedom of the hydrogenated thiolates at the boundary of the patch but minimised the F/F contacts creating an exceedingly large and energetically unfavourable H/F interface. This morphology becomes favoured when the amount of F-ligand is increased to about 40%.

For the nanoparticle system NP-C16/F6l = 8), which is the one that more markedly should give rise to a stripe-like morphology of the monolayer, the chemical shift profile resembles, indeed, the profile reported by Stellacci for this morphology. Already at the 20% of the fluorinated ligand in the monolayer, molecular simulations fully support that the equilibrium morphology of the monolayer of NP-C16/F6 is stripe-like.

There is another indirect method that enables gaining qualitative information on the clustering of ligands on the nanoparticle surface that received only little attention so far. This is a simple comparison of the composition of the monolayer with respect to the composition of the mixture of thiols used for the preparation of the nanoparticles (Şologan et al. 2016a). Indeed, in the case of mixtures of F- and H-ligands, it is reasonable to expect that the fluorinated ones would tend to be excluded from the monolayer because of the unfavourable interaction with the hydrogenated chains; this is to say that the composition of the resulting monolayer will be imbalanced towards the hydrogenated component. However, if the F-ligands cluster on the nanoparticle surface, this disfavoured process could be mitigated to an extent.

To illustrate this concept, we shall consider, as a limiting example, the case of NP-brC12/F6, for which 19F NMR supports a random organisation of the ligands. In Fig. 5a, we report the correlation of the monolayer composition expressed as the molar fraction of the fluorinated ligand (Xfin) versus the composition of the mixture of thiols used in the synthesis (Xin). In all of the cases, the monolayer composition data lay beneath the diagonal of the plot, indicating that the introduction of the fluorinated ligands remains unfavourable in the whole composition range and no evidence of F-ligand clustering was observed in the calculated equilibrium morphologies (Fig. 5b).
Fig. 5

Dependence of the final composition of the nanoparticles monolayer as a function of the composition of the thiol mixture used in the synthesis of the nanoparticles and some representative equilibrium morphologies of their monolayer. a, b NP-brC12/F6; c, d NP-C12/F10; e, f NP-C16/F6. Adapted with permission from reference Şologan et al. (2016a) (copyright of the Royal Society of Chemistry) and reference Şologan et al. (2016b) (copyright of the American Chemical Society)

Another limiting case is that of NP-C12/F10, for which the 19F NMR analyses support the Janus morphology of the monolayer and multiscale molecular simulations suggest the formation of a single patch even at very low loading of the fluorinated component. The composition analysis of the monolayer indicates that in this case, the introduction of the fluorinated ligands is favoured and the composition of the monolayer is very close to the composition of the reaction mixture used for the preparation of the nanoparticles (Fig. 5c); as mentioned earlier, the equilibrium morphology is consistent with F-ligand clustering (Fig. 5d). A similar behaviour could be observed in the case of NP-C12/F6 in which the ligands display a length mismatch of 4 carbon atoms; even in this case, the introduction of the fluorinated ligand is relatively easy.

A different picture emerges instead for the NP-C16/F6 made of thiols featuring an 8-atom mismatch (Fig. 5e). In this case, the introduction of the first few fluorinated ligands is very difficult; more than 20% of the fluorinated ligand is required to achieve a mixed monolayer containing about 10% of this ligand. However, after that point, the experimental data abruptly approach the diagonal, suggesting the onset of conditions enabling an easier introduction of the F-ligands in the nanoparticle monolayer in a way closely reminiscent to a cooperative process. Indeed, molecular simulations suggest the formation of domains of fluorinated ligands in this composition range (Fig. 5f). Therefore, despite the simplicity, these analyses provide useful information which nicely matches with those provided by independent techniques. Moreover, a similar approach has been recently devised as a general way to quantify the ability of a ligand to displace dodecanethiolates in place exchange reactions (Goldmann et al. 2017).

Other useful indicators of existence of preferential morphologies arising from the self-organisation of thiols on the nanoparticle surfaces are the solubility properties of the nanoparticles.

The nanoparticles displaying large fluorinated domains tend to be less soluble than those in which the ligands are arranged in narrower domains. It is remarkable that in the case of nanoparticles NP-C16/F6, the system is still soluble in chloroform even if it contains the 80% of fluorinated ligand.

Properties of mixed monolayer and homoligand fluorinated nanoparticles in polar media

Although it is evident that modulating the monolayer morphology achieves regulation of the nanoparticles solubility, the systems described so far are inherently insoluble in polar organic or aqueous media. However, the design of more soluble nanoparticle systems may easily rely on the introduction of solubilising end groups appended at either the fluorinated or hydrogenated units. The first fluorinated nanoparticle system fully soluble in a wide range of polar media including water was developed some years ago by using the amphiphilic fluorinated thiol HF8PEG, reported in Fig. 6. This allowed the synthesis of the homoligand nanoparticles NP-F8PEG employing a single-phase methodology which has the benefit of limiting the use of any compound potentially interfering in the purification process. The solubilising PEG unit of thiol HF8PEG consists of 12–13 repeating oxoethylene moieties. Shorter PEG chains, although increasing the solubility in polar media, did not prove sufficient to achieve water-soluble materials. With respect to the 1H,1H,2H,2H-perfluoroalkanethiol reported in the preceding section, the thiol group of HF8PEG is one methylene unit closer to the fluorinated chain. This has a significant impact on its reactivity, at variance with other alkanethiols; this species could not be used as such in the synthesis of nanoparticles, because of its markedly reduced nucleophilicity. Instead, conversion to the thiolate anion allowed obtaining nanoparticles, whose stability is comparable to that of nanoparticles prepared by using hydrogenated alkanethiolates or superior due to the larger cross section and rigidity of the fluorinated chain with respect to the hydrogenated one giving rise to a very efficient coverage of the gold surface.
Fig. 6

Structures of the fluorinated amphiphilic thiols HF8PEG and HC8TEG used for the preparation of the homoligand fluorinated nanoparticles NP-F8PEG and the mixed monolayer NP-C8TEG/F8PEG. The structure of the nitroxide radical probe RP-1 used for the characterisation of the self-sorting behaviour of the thiolates in the monolayer of NP-C8TEG/F8PEG is also displayed

This low nucleophilicity effect was never observed with 1H,1H,2H,2H-perfluoroalkanethiols, indicating that two methylene groups are sufficient to reduce the electron-withdrawing effect of the F-chain to negligible. Aiming at assessing whether or not the electron-withdrawing fluorinated chains altered the properties of the gold core, these nanoparticles were characterised by X-ray photoelectron spectroscopy (XPS). The XPS spectral data of NP-F8PEG were in keeping with those of nanoparticles protected by hydrogenated alkanethiolates. In closed details, the Au 4f core level of the NP-F8PEG appears as the metallic doublet with a 4f7/2 binding energy of 83.95 eV, therefore excluding a significant amount of oxidised gold atoms, (Au(I)), that is usually observed at 1 eV higher binding energies (Gentilini et al. 2008b). Thiol HF8PEG could be used in combination with thiol HC8TEG (Fig. 6) for the preparation of mixed monolayer nanoparticles in single-phase reactions, obtaining truly mixed monolayer systems and not a mixture of homoligand nanoparticles (Posocco et al. 2012). Most importantly from the application point of view, NP-F8PEG proved to be reactive in place exchange reaction allowing an entry to functionalised mixed monolayer nanoparticles. This reactivity was exploited in the preparation of a series of mixed monolayer nanoparticles NP-C8TEG/F8PEG (Fig. 6) of varying compositions (Table 2).
Table 2

Composition of mixed monolayer nanoparticles NP-C8TEG/F8PEG, average gold core diameter and equilibrium constants (298 K) for the partitioning of the radical probe RP-1 to the fluorinated domains of the nanoparticles. Data from references Gentilini et al. (2009) and Posocco et al. (2012)

H/F ratio

X H

Core diameter (nm)

KF (M−1)

Composition

0.51

0.50

2.2 ± 0.4

200

Au400(C8TEG)54(F8PEG)54

2.5

0.71

2.5 ± 0.4

350

Au540(C8TEG)108(F8PEG)43

4

0.80

1.9 ± 0.2

762

Au230(C8TEG)66(F8PEG)16

20

0.95

1.9 ± 0.3

600

Au240(C8TEG)68(F8PEG)3

The assessment of the phase segregation of the H- and F-ligands in the monolayer of these mixed monolayer nanoparticles was performed by means of electron spin resonance (ESR) using the nitroxide radical probe RP-1 reported in Fig. 6 (Gentilini et al. 2009; Posocco et al. 2012). ESR is an ideal technique in this respect because the sensitivity of the ESR spectral parameters (hyperfine coupling constants) on the polarity of environment experienced by the probe allows locating its recognition site within the monolayer. In addition, ESR is a fast technique allowing the simultaneous assessment of both the concentrations of free and bound radical probe in the presence of the nanoparticles, enabling the reliable determination of its binding constant to the monolayer. With these nanoparticles, we could observe that when the spectral parameters of the nitroxide probe (ΔG)2 are reported against the composition of the monolayers, these are the same as those obtained with homoligand fluorinated nanoparticles even if the amount of fluorinated ligand in the mixed monolayer is only 29%. Ligand clustering could be observed even when 5% of fluorinated alkanethiolates were present in the monolayer. The probe starts experiencing the hydrogenated environment only when the C8TEG thiolates are 80% of the total (Fig. 7a), suggesting phase segregation of the two ligands. As striking as the previous observation is that the logarithm of the binding constants of the probe for the fluorinated region of nanoparticles monolayer plotted against the monolayer composition, expressed as the molar fraction of the H-ligand, displays a steady increase, up to a maximum obtained when the monolayer contains 20–30% of fluorinated ligands (Fig. 7b). Hence, the binding to the fluorinated region of the monolayer is stronger in a relatively narrow composition of the monolayer. This, at first, seems counterintuitive because fluorinated surfaces are known to be “non sticky”. Nonetheless, it is also known that fluorination of small-molecule drugs increases their affinity towards receptors. There is therefore a discrepancy between the common perception of macroscopic nonsticky fluorinated surfaces and their nanoscale counterparts. Multiscale molecular simulation by coarse grain methods performed on NP-C8TEG/F8PEG gave a rather detailed picture of the monolayer organisation (Fig. 7c) and it confirmed that fluorinated and hydrogenated ligands do tend to self-sort forming small patches or elongated domains depending on their relative amount with respect to the hydrogenated ligands. Molecular simulation shed light also on the reason why nanoparticles featuring fluorinated domains display the increased binding constant observed for radical probe RP-1 in mixed monolayers. In fact in the mixed monolayer nanoparticles, the phase segregation between the H- and F-thiolates and the different lengths of the hydrophilic chains cause the longer PEG moieties to bend towards the shorter ones. This hinders the access of the probe to the hydrogenated regions while favouring the access to the fluorinated patches.
Fig. 7

a Dependence of ΔG (in gauss) as a function of monolayer composition of nanoparticles NP-C8TEG/F8PEG. b Log KF for the binding of radical probe RP-1 to the fluorinated region of the monolayer of nanoparticles NP-C8TEG/F8PEG as a function of their composition expressed as molar fraction of the hydrogenated ligand. c Equilibrium morphologies of the monolayer of NP-C8TEG/F8PEG. Reproduced with permission from reference Posocco et al. (2012). Copyright of the American Chemical Society

We also proved that homoligand NP-F8PEG (Keq = 176 M−1) are slightly better hosting systems than NP-C8TEG (Keq = 104 M−1).

The increased binding constants scored by the homoligand nanoparticles NP-F8PEG for the hydrogenated guest RP-1 with respect to the hydrogenated analogue NP-C8TEG drove our attention on exploring other water-soluble fluorinated nanoparticle systems and some fluorinated radical probes (Boccalon et al. 2015). To this end, we designed the amphiphilic nanoparticles NP-C6OFPEG (Fig. 8a), in which the fluorinated moiety instead of being close to the gold surface is far for it and is more flexible than that of NP-F8PEG. In the case of NP-C6OFPEG, the binding constant of the probe RP-1 was Keq = 593 M−1 and the binding site was identified as the oxyfluorinated region of the monolayer by ESR spectroscopy. This binding constant is 3.3 times larger than that measured for NP-F8PEG (Keq = 176 M−1) and about 6 times larger than the binding constant scored by NP-C8TEG. Moreover, with NP-C6OFPEG, the binding constant increases with the increasing of the gold core size with clear indication that reducing the inter-ligand available room tightens the binding of the guest.
Fig. 8

a Cartoon representation of the structure of the homoligand nanoparticles obtained by using thiols HC8PEG or HC6OFPEG. The structure of the thiols is reported in panel b. The figure depicts also the partition of the radical probes RP-2 to RP-6 whose structures are reported in panel c

Nanoparticles NP-C6OFPEG were also screened against the panel of radical probes reported in Fig. 8b; NP-F8PEG (Fig. 6) and NP-C8PEG (Fig. 8a) were used as reference systems. The structure of radical probes RP-2 to RP-6 was decided upon in order to assess the role of increasing fluorination in affecting the binding constants.

Changing the nature of the group at the para position of the phenyl ring with groups of lower lipophilicity and surface area gave, in general, smaller binding constants with respect to that of probe RP-1, but in all of the cases, the binding constants increased going from the hydrogenated nanoparticles to the fluorinated systems, with the NP-C6OFPEG acting as better host with respect to NP-F8PEG. The binding properties of NP-C6OFPEG were also analysed in terms of its ability to complex different probes with different fluorine loading by analysing the probe RP-2 with a hydrogenated phenyl group compared to RP-5. In this case, the binding constant for the fluorinated probe is 13 times larger than that for the hydrogenated analogue. Quite interestingly, if we calculate the contribution to the binding constant of each H/F replacement, it turns out that the gain in binding constants can be estimated in a factor of about 2.5 for fluorine atom, and a similar figure was obtained when this contribution was computed for the methyl/trifluoromethyl systems RP-3/RP-6.

The quasi equivalence of the fluorine nuclei of the ligands in the monolayer of NP-C6OFPEG and the 100% natural abundance of the 19F nucleus were exploited in a preliminary evaluation of these nanoparticles as contrast agents in 19F magnetic resonance imaging (19F MRI). This is an extremely interesting diagnostic technique because it does not suffer of interferences from the background signal, given the absence of endogenous fluorine, and allows quantitative determinations. With these systems, and in phantom experiments, we could obtain a signal to noise ratio of 5.7 using a clinical set-up and a concentration of nanoparticles of 1.9 mg/ml (Boccalon et al. 2013) which is still not optimal and requires further structural refinement of the ligands but is very promising. This nanoparticle system holds promise of applications because of their low toxicity that was quantitatively evaluated against HeLa cells using fluorescence-tagged nanoparticles. The nanoparticles were easily internalised and after uptake, 95% of the cells remained viable. These examples highlight the range of properties and scope of applications of fluorinated nanoparticles soluble in aqueous media.

Decorating the outermost surface of these systems with PEG units proved successful in this respect, but it would be desirable developing complimentary strategies. Recently, we started exploring the feasibility of forming mixed monolayer nanoparticles by using blends of thiols in which one of the components is a charged amphiphilic thiol and the other component is a 1H,1H,2H,2H-perfluoroalkanethiol (Bidoggia et al. 2017). Although not optimised, these systems display promising solubility in polar media, including water, and this allowed a preliminary assessment of their toxicity in HeLa cells that was found to be generally low and comparable to that of nanoparticles prepared using amphiphilic—charge neutral—thiols.

Conclusions

Our studies demonstrate that the self-sorting of fluorinated and hydrogenated alkanethiols is operative on mixed monolayers grafted on the surface of gold nanoparticles in analogy to what is observed in other supramolecular assemblies comprising mixtures of fluorinated and hydrogenated molecules. This phase segregation process takes place even if the amount of fluorinated ligands introduced in the monolayer is very small. Experimentally, the introduction of a mere 5% of fluorinated alkanethiolates in the nanoparticle monolayer proved to be sufficient to achieve ligand clustering. In model systems, we could prove that obtaining H-/F-mixed monolayer nanoparticles displaying, by design, a pre-determined morphology is possible. This requires acting on a set of structural parameters of the H- and F-ligands such as length and steric bulk that are relatively easy to control.

The characterisation of these monolayer morphologies has been accomplished, indirectly, by combining 19F NMR or ESR and multiscale molecular simulations that display a high predictive value. The success of this integrated approach is particularly relevant because these spectroscopic analyses are easy to perform and are possible in most research labs. In particular, integrating NMR and molecular simulation can be considered complimentary to direct methods of morphology assessment such as STM or SANS and we feel confident in anticipating that this approach will enjoy a strong development. Unavoidably, this requires the development of interpretive models mapping the chemical shift dependence on the monolayer composition to a specific morphology. At present, such interpretive models are available for random and Janus particles only. As far as mixtures of fluorinated and hydrogenated ligands are concerned, evidence supporting the clustering of the F-ligands can be obtained comparing the composition of the monolayer with that of the mixture of thiols used for the nanoparticle synthesis. The solubility properties of H-/F-mixed monolayer nanoparticles are other indirect reporters of the monolayer morphology.

Moreover, the common perception of fluorinated nanoparticles as insoluble materials has to be revisited, at least in part, when considering mixed monolayer nanoparticles. Indeed, mixed monolayer nanoparticles with stripe-like morphology are freely soluble in conventional organic solvents even though the monolayer consists at 80% of fluorinated species. Appending charged end groups to the hydrogenated thiols was envisaged as a viable strategy to further enlarge the solubility range of these systems; preliminary results are encouraging, but there is room for further improvements. This will enable an accurate analysis of the role of surface features of H-/F-mixed monolayer nanoparticles in their interaction with the complex machinery of living cells and other complex biological structures. This is feasible because fluorinated nanoparticles are well tolerated by model cell lines and display toxicities similar to those of hydrogenated analogues.

Nanoparticles displaying fluorinated monolayers proved to act as hosting systems for small, drug-like molecules; they invariably locate in the fluorinated regions of the monolayer. As far as homoligand nanoparticles are concerned, fluorinated systems are better hosts than hydrogenated analogues, and in the case of mixed monolayer, the nanoparticle patchiness affects the strength of binding.

We could exploit the magnetic properties of the 19F nuclei developing a putative contrast agent for 19F MRI; this is particularly relevant because by combining the complexing ability of these systems with a diagnostic technique, it would be possible to design drug delivery vehicles that can be monitored in their action, representing an approach to gold nanoparticle-based theranostics.

In summary, fluorinated nanoparticles and H-/F-mixed monolayer nanoparticles hold promise in many respects. The fundamental reason for that stems from the spontaneous separation of hydrogenated and fluorinated domains which proved to be a valuable strategy to achieve nanosized patterning of curved surfaces in a controlled manner. This nanoscale heterogeneity in polarity and functional activity mimics several naturally evolved structures and in the opinion of the authors will foster future development in several areas, from the interaction with complex biological media to the bottom-up development of novel self-assembled materials.

Footnotes

  1. 1.

    All the thiols and thiolates in the text are named according to the following example: HC8 stands for octanethiol with explicit reference to the sulfhydryl proton, the corresponding thiolate is reported as C8.

  2. 2.

    ΔG is the field separation between the low-field lines due to radical RP-1 partitioned in water (which resonates always at the same field value and can be considered as a field marker) and in the monolayer.

Notes

Acknowledgements

We also wish to thank all the collaborators of our group that with their enthusiasm and hard research work contributed to the results cited here: Paolo Ronchese, Elena Pellizzoni and Stefano Valente and the collaborators of other research groups/institutions; Marco Lucarini and his research group at the University of Bologna; Maurizio Fermeglia, Sabrina Pricl and Paola Posocco of the MOSE lab at the University of Trieste; Francesco Stellacci and Silke Krol and their research groups in Milano; Stefano Polizzi and the electron microscopy group of the University of Venezia; Petra Rudolf and her group of the University of Gröningen; Paolo Scrimin of the University of Padova for the support and the very helpful discussions and Fabrizio Mancin, University of Padova, for several analyses and the continuous fruitful discussions. We are very grateful to Claudio Gamboz and Paolo Bertoncin of the Electron Microscopy facilities lab of the University of Trieste for TEM images and Chiara Schmid, DIA, University of Trieste for TGA measurements.

Funding information

This research received support from the University of Trieste (FRA 2015, FRA 2016).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

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© Springer Science+Business Media B.V., part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Chemical and Pharmaceutical Sciences, and INSTM Trieste UnitUniversity of TriesteTriesteItaly

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