Abstract
The concept of nanomaterials that can be designed and administered into the human body to improve health is of great interest. During the past years there has been an increasing amount of research on the uses of nanomaterials in diverse areas of biomedical research including biological sensing, labelling, imaging, cell separation and therapy. In this chapter, the first evaluation of titanate nanotubes (TiONts) as potential carriers of therapeutic molecules is presented. TiONts with controlled parameters have been developed from a hydrothermal synthesis and their biomedical applications have been explored over the last decade. These nanotubes are elaborated as stable suspensions of nanocarriers by surface chemistry engineering. They can be used as transfection agents for cardiomyocytes and we have shown that TiONts can increase the ionizing effect of radiation therapy in the case of glioblastoma. Furthermore, TiONts’ biodistribution has been evaluated by SPECT/CT in male Swiss nude mice and TiONts are quickly cleared. More recently, we have demonstrated that TiONts-docetaxel (DTX) nanohybrids are versatile nanocarriers to limit the systemic toxicity of taxanes and to improve the selectivity of radiotherapy (RT). Our strategy is based on the intraprostatic injection of the TiONts-DTX nanohybrids both in place of brachytherapy and in combination with RT. This is achieved by taking advantage of the TiONts’ morphology as well as their radiosensitization effect and by associating them with docetaxel molecules, also recognized for their radiosensitizing potential. We also grafted the surface of TiONts with gold nanoparticles, for a resulting combined radiosensitizing effect. The elaboration of nanohybrid materials, intended for drug delivery systems and based on TiONts coated with chitosan polymer has also been evaluated. Such nanotubes are combined with transresveratrol derivatives for their anti-oxidizing and antitumor effects. All the aspects of a potential toxicity are also considered.
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1 Introduction
The shape of nanoparticles is an essential element to take into account for the internalization, cytotoxicity, biodistribution and intracellular exchanges of nano-objects in the organism (Ernsting et al. 2013).
Diffusion phenomena, through the cells’ membrane, have already been observed by anisotropic nanoparticles, allowing the internalization of these biomaterials in the cytoplasm in addition to endocytosis (Kostarelos et al. 2007). Besides, it was demonstrated that anisotropic nanoparticles were characterized by a higher blood circulation time and prolonged retention at tumor sites compared to spherical nanoparticles (Agarwal et al. 2015). Z. J. Deng et al. have shown that the shape of TiO2 nanoparticles (nanosphere, nanorod and nanotube) plays an important role in the absorption of proteins on their surface, thus dictating their biokinetics and their behavior in vivo (Deng et al. 2009).
Intrinsic properties of nanoparticles are also influenced by their shape. It has been shown that magnetic nanoparticles of elongated shape exhibit higher magnetic hyperthermia heating capacities than their spherical equivalents (Das et al. 2016). Similarly, gold nanorods have interesting optical properties due to the resonance effects of the surface plasmon. Finally, excellent properties associated with guided geometry nanoparticles have opened up exciting opportunities for new material designs and will potentially revolutionize the current practice in Biology and Medicine (Decuzzi et al. 2017). Nanoparticles can be built from different materials and can host a wide range of active components for various biomedical applications, including chemotherapeutics, proteins, contrast agents, and nucleic acids.
The major elongated nanoparticles used in nanomedicine are: carbon nanotubes (Bianco et al. 2005), gold nanorods (Awan et al. 2018), ZnO nanorods (Jeong et al. 2020), silver nanorods (Suganya and Devasena 2015), silica nanotubes (Ma et al. 2009), iron oxide nanorods (Singh et al. 2020), apatite nanorods (Ge et al. 2019), alumina nanotubes (Campos et al. 2016), titanium oxide nanorods (Sun et al. 2016) and titanate nanotubes (Bavykin and Walsh 2009). Gold nanorods, for instance, have been developed for biomedical applications focus on detection, biocatalysis, imaging, drug delivery, and gene delivery (Wang et al. 2013). ZnO nanorods, as for them, are suitable in biosensing and biodetection (Hahm 2016).
Titanate nanotubes (TiONts) have been used in hip prostheses and dental implants (Bavykin and Walsh 2009) and for dopamine detection (Niu et al. 2008). Our group is a pioneer in the development of TiONt-based nanocarriers (Mirjolet et al. 2013; Papa et al. 2013). This chapter aims to summarize the chemical challenges and biomedical opportunities around these fascinating titanate nanotubes.
2 The Preparation of Titanate Nanotubes and their Characterization
2.1 Hydrothermal Synthesis of Titanate Nanotubes
TiONts have historically been synthesized by two methods: (i) via hydrothermal synthesis starting from nanometric and spherical TiO2 precursor (Kasuga et al. 1998; Papa et al. 2009), which will be described in this chapter, and (ii) via electrochemical anodization of a Ti metal foil substrate (Gong et al. 2001). The parameters of these reactions (such as temperature, time, pH, agitation, washings, etc.) enable a precise control of the physicochemical characteristics of the resulting TiONts such as shapes (Bellat et al. 2015) (tubes, sheets, ribbons), dimensions (inner/outer diameters; length), size distribution, specific surface and chemical composition. These parameters can be specifically tuned and optimized to best fit the targeted bioapplications.
The hydrothermal synthesis of TiONts is a single step process starting from TiO2 spherical nanoparticles (i.e. rutile, anatase or P25) under highly basic conditions such as 10 M NaOH (Fig. 1). The hydrothermal treatment (3–4 bar) is maintained over 12 to 72 h and 100 to 180 °C. The formation mechanism of titanate nanotubes is still a matter of debate. Several phenomena are discussed in literature: the dissolution of the precursor crystallites in bulk followed by the formation of nanosheets which then curl into nanotubes (Sun and Li 2003; Bavykin et al. 2006). After this, the reaction mixture is washed by centrifugation cycles, dialyzed or ultrafiltered until the suspension reaches neutral pH. Finally, the TiONts’ suspension is freeze-dried and the resulting lyophilized particles are stable for months at room temperature.
2.2 Titanate Nanotubes’ Features and Characterizations
Titanate nanotubes display a large specific surface area (higher than 200 m2/g) due to their hollow and multilayered assembly (Sallem et al. 2017b) (Fig. 2a). Unlike carbon nanotubes, their multilayered morphology is not concentric, rather it is arranged in a spiral fashion. A large number of surface hydroxyls have been estimated by TGA (thermogravimetric analysis) and verified by XPS (X-ray photoemission spectroscopy) surface analyses. The zeta (ζ) potential measurements made on TiONts indicate a maximum zeta potential value around 20 mV and an isoelectric point (IEP) around pH 3 (Fig. 2b). The TiONts’ surface charge varies with the pH according to the following equilibria:
3 The Surface Modification of Titanate Nanotubes (Synthesis and Characterizations)
Bare TiONts are not stable enough in physiological conditions (ca. 50% of TiONts settled after 20 min and about 80% after one hour, Fig. 3a and b) and require surface modifications to improve their colloidal stability: to do so alkoxysilanes, phosphonates and catechols can be interestingly used to obtain surface-modified TiONts (Fig. 3c), the description of which will be described in the following paragraphs.
3.1 TiONts’ Modification by Silane Derivatives
TiONts can easily be modified by silane derivatives to yield silica-coated TiONts with a view to i) stabilize TiONts for further applications and ii) possibly bring new chemical functions provided that the silane used is terminated with an amine or a carboxylic acid group for example.
The mostly used alkoxysilane is 3-aminopropyltriethoxysilane (APTES) for which the silane function reacts with the surface hydroxyls of the TiONts and the amine function makes it possible in particular to have an electrostatic-type repulsion at the surface of the TiONts. APTES formula is \({\text{(}{\text{CH}}_{3}{{\text{CH}}}_{2}\text{O)}}_{3}\text{-Si-}{\left({\text{CH}}\right)}_{3}-{\text{NH}}_{2}\) (M = 221 g.mol−1) (Fig. 4). It is commonly used to obtain biocompatible surfaces. This molecule is mainly used to promote protein adhesion and cell growth on biological implants (Balasundaram et al. 2006) as well as for biosensing or DNA extraction (Howarter and Youngblood 2006).
Several steps are necessary when grafting APTES on TiONts and any consideration in the following lines could be theoretically applied to any silane derivative: other hydrolyzable groups (3-aminopropyltrimethoxysilane or 3-aminopropyltrichlorosilane); other end groups (3-R-propylalkoxysilane with R = epoxide, Cl–, N3–, etc.); and various lengths of alkyl chains bearing the chemical function of interest (ω-R-alkylalkoxysilane). First, a reaction of APTES in aqueous solution forms a silanol with the hydrolysis of three ethanol molecules (Fig. 5a). Then, oligomerization of silanols (intermolecular condensation) leads to the formation of oligosiloxanols with different chain sizes (Fig. 5b). Then, hydrogen bonds appear between oligosiloxanols and the hydroxyls of the TiONts’ surface (Fig. 5c). Finally, the last step is the condensation of oligosiloxanols on TiONts with the formation of covalent bonds (Fig. 5d).
It is important to control the different stages of silanization to obtain a monolayer of APTES and to be able to optimize the number of amine functions on the surface of TiONts for subsequent grafting. Indeed, it is possible to create multilayers of APTES during condensation (Fig. 6) and to affect the final structure of the layer of aminosilane on the surface of the inorganic substrate. This is notably due to several parameters such as water content, reaction temperature, concentration, and nature of the silane (White and Tripp 2000). Among these, temperature, and proportion of solvent (ratio water/ethanol) are the main parameters which play on the structure and on the grafting rate of APTES. In fact, an increase in temperature favors the condensation of the polysiloxane on the TiONts’ surface as well as the reaction speed, while the proportion of the solvent can affect the competitive reactions between hydrolysis and oligomerization (Liu et al. 2013).
Recently, N. Millot et al. have developed advanced surface-modified TiONts for biomedical applications including a first coating of silane derivatives (APTES in the following examples) prior to further functionalization(s): polymer-coated TiONts (Papa et al. 2015), TiONts as optical probe thanks to phthalocyanines (Boudon et al. 2014; Paris et al. 2015), docetaxel nanocarriers (Mirjolet et al. 2017; Loiseau et al. 2017), chitosan-coated TiONts (Sallem et al. 2017a), or also TiONts as potential candidate for drug delivery applications across the brain (Sruthi et al. 2018).
3.2 TiONts’ Modification by Phosphonate Derivatives
Phosphonic acids and their derivatives (R-PO(OR′)2; R,R′ = hydrogen, alkyl) have become increasingly attractive due to their strong affinity for hydroxylated surfaces (Ries and Cook 1954). They have already proven themselves in biological fields for biosensors or for medical implants (Mutin et al. 2005). The chemisorption mechanisms of phosphonate agents on inorganic substrates are greatly affected by reaction conditions such as temperature, pH of the medium, concentration, solvent and type of oxide (Pujari et al. 2014). The type of interaction between the phosphorus atom and the hydroxyl oxygen can differ depending on the Lewis strength of the atoms on the surface of the metal oxide (Fig. 7a). Indeed, in the case of a surface with high Lewis acidity, the bonds (P-O-M) are even more stable and stronger as the P atom becomes more electrophilic and induces consecutive heterocondensations with hydroxyls. Otherwise, hydrogen bonds can form due to a higher affinity with phosphonate and hydroxyls on the surface of the metal oxide. In addition, the presence of three oxygen atoms on the phosphonates makes it possible to induce three modes of chelation (mono-, bi- and tridentate). The oxygen can then be linked to the same metal site or to different atoms present on the surface (Fig. 7b) (Guerrero et al. 2013).
The phosphonates are then interesting, in comparison with the alkoxysilanes, because they form stable monolayers. In addition, they are less likely to become detached from the surface of the oxide by self-condensation reactions which can break the bonds formed. However, this can happen under high temperature dehydration conditions (Mutin et al. 2005). Also, the handling conditions (phosphonate coupling reactions are often optimized in water) and storage (in air at 20 °C) make them more accessible and less restrictive than aminosilanes or catechols. In addition, phosphonic acids have remarkable affinities with metal oxides having a high degree of oxidation such as titanium (Ti4+) (Guerrero et al. 2001). The hydrolytic stabilities of monolayers during the formation of P-O-M bonds are then better than in the case of alkoxysilanes and are comparable to those of catechols (Daou et al. 2007; Pujari et al. 2014).
Finally, phosphonates can also be bifunctional molecules. On the one hand, the phosphonate group should have a strong affinity with the surface of TiONts and on the other hand, a reactive function is present to generate an electrostatic effect capable of improving the colloidal stability of the nanotubes and then to graft other molecules. An example of phosphonates is the monophosphonate 6-phosphonohexanoic acid (PHA, Fig. 8): the phosphonic side interacts with the metal oxide surface and the opposite side of the molecule is ended by a carboxylic acid function for further functionalization.
N. Millot et al. have investigated three different types of phosphonate grafting to improve the colloidal stability of TiONts: the 6-phosphonohexanoic acid monophosphonate (PHA, Fig. 8), the alendronic acid bisphosphonate (ALD, Fig. 9a) or a PEGylated monophosphonate (Fig. 9b). These agents are all heterobifunctional molecules and PHA has already been studied in our laboratory on iron oxide nanoparticles but also during initial investigations on TiONts (Paris et al. 2015; Thomas et al. 2016). PHA has a carboxylic function at one end, while the alendronate and the PEG (polyethylene glycol) derivative have an amine function in addition to the phosphonate function.
The influence of a monophosphonate and a bisphosphonate on colloidal stability under physiological conditions have been compared. The alendronic acid is particularly interesting because it is already used as an anticancer drug (anti-tumor properties), for the treatment of osteoporosis and for other bone diseases (Benyettou et al. 2011; Motte et al. 2011). Finally, the presence of a long carbon chain, with a phosphonate group on one end and an amine function on the other, allows a steric effect and an electrostatic effect to occur thus improving the colloidal stability with the phosphonate-type polymer.
As depicted in Fig. 10, it should be noted that alendronic acid has five pKa (pKa1 = 0.8, pKa2 = 2.2, pKa3 = 6.3, pKa4 = 10.9 as regards the pairs of the two phosphonates POOH/POO– and pKa5 = 12.2 for the NH3+/NH2 pair, Fig. 9a). In a previous study, alendronate was grafted to the surface of maghemite nanoparticles at pH 2 via two Fe–O-P bonds (corresponding to pKa1 and pKa2) (Benyettou et al. 2011). In the same study, it is shown that at pH 7.4, the negative charge of the obtained nanohybrid is due to the deprotonation of the OH function of the couple relative to pKa3. In theory, to promote the grafting of the alendronate via two Fe–O-P bonds, it is preferable to have pH between 2.2 and 6.3. However, the TiONts’ IEP is ca. 3 (Fig. 2b) (Papa et al. 2015). Thus, to form Ti–O-P bonds, it is preferable have pH below 3 (Fig. 10). Note that at pH 7.4, the agglomeration of TiONts is weaker than at acidic pH (the ζ-potential is −35 mV due to deprotonated hydroxyl groups). It is the same with PHA and (HO)2–(O = )P–PEG–NH2 for which the pKa of phosphonate are between 2 and 8.5. Finally, the choice of pH must consider the pKa of these three molecules, their solubility but also, the IEP and the colloidal stability of the TiONts.
The dispersion state of TiONts, after the different graftings of PHA, ALD and of polymer (HO)2-(O = )P-PEG-NH2 has been analyzed by TEM (Fig. 11). In these pictures, the grafts for the TiONts-ALD and the TiONts-PHA seem to favor the individualization of the nanohybrids, unlike naked nanotubes which are organized in bundles (Papa et al. 2009; Boudon et al. 2014) even if they sometimes form a few small agglomerates. This attests that the surface modification of TiONts by ALD and PHA greatly improves their dispersion. However, it is the TiONts-PEG-NH2 which show better dispersion on the observation grid while they have been found to be less stable by UV–visible spectroscopy. They exhibit a homogeneous dispersion over the entire surface, without agglomerate: it is therefore the polymer chains which contribute sterically to this individualization. This remarkable state of dispersion (better than with the TiONts/APTES/PEG system) allows synthetic by-products to be visualized, such as nanoribbons, but in negligible amount compared to the number of nanotubes.
3.3 TiONts’ Modification by Catechols
The applications of nanopowders in suspension are often limited by the insufficient colloidal stability of nanoparticles. Catechols have good properties as stabilizers (Amstad et al. 2009, 2011a) to remedy this; they also exhibit antioxidant activity (Lee et al. 2003). Catechols generally form a charged monolayer on the surface of metal oxide, which stabilizes nanoparticles to absorb light or to lead to reversible redox reactions and they present as well an interesting potential barrier for photovoltaic and biomedical applications (Pujari et al. 2014). Catechol derivatives are used as dispersants for various oxides, in particular with titanium and iron oxides (Amstad et al. 2011a; Bahri et al. 2011). Despite similar chemical properties between different catechols, the affinities on these oxides vary considerably. Catechols can form weakly reversible or strong bonds, depending on their affinity with the cations of the oxides (Amstad et al. 2011b). The grafting mechanism of catechols on oxides is relatively close to that of phosphonates (Sect. 3.2). Briefly, a mono- or bidentate complex can form with one or two oxygen from the catechols and the metal atoms from the oxide, as is the case with titanium.
Moreover, pH is a key parameter in the grafting and conformation of catechols on the surface of metal oxide. In addition to being the main oxidation factor for catechols, the protonation state of the different groups depends on pH (Fig. 12a). Thus, concentration and pH of the reaction medium influence the grafting capacity of catechols (pKa of the catechols’ hydroxyls have a value of between 8.5 and 10), as well as the conformation of the molecule on the surface of the oxide (Fig. 12b).
A study related to the grafting of L-3,4-dihydroxyphenylalanine (LDOPA) on TiO2, has shown that pH 6 favors a stretched conformation and an orientation perpendicular to the surface of nanoparticles (which has also been observed with a high concentration of catechol during grafting) unlike pH 2 for which the molecule seems to be lying on the surface of TiO2 (Fig. 12b) (Lee et al. 2012). It is therefore preferable to have a pH around 6 on a TiO2 surface to optimize the grafting of catechols and lead to available reactive functions. Furthermore, excessive basic pH promotes the oxidation of catechols (Bahri et al. 2011): the choice of pH is therefore essential to obtain an optimal conformation of the molecule while limiting its oxidation for future grafting. The grafting of three hydrophilic catechols has been carried out to modify the surface of TiONts: L-3,4-dihydroxyphenylalanine (LDOPA), 3,4-dihydroxyhydrocinnamic acid (DHCA) and nitrodopamine (NDOPA) (Fig. 13). These molecules have one or many reactive functions in addition to the catechol group so that colloidal stability is improved by electrostatic repulsion (-COOH, -NH2, -NO2). These same functions allow subsequent grafting of molecules such as polymers, therapeutic or chelating agents. In addition, the hydroxyls of catechols have a very strong affinity with titanium oxides (Amstad et al. 2009).
The grafting of DHCA and LDOPA catechols can be carried out under pH 6 because it leads to a fairly good dispersion of TiONts in water (value far from the IEP of bare TiONts), a pH close to the pKa of both catechol hydroxyls (to promote grafting) and allows the oxidation of catechols to be limited as it occurs at strongly acidic or basic pH (LDOPA: pKaCOOH = 2.3, pKaNH2 = 9.7, pKaOH = 8.7 and 13.4; DHCA: pKaCOOH = 4.2, pKaOH = 9.2 and 11.7; NDOPA: pKaNH2 = 8.7, pKaNO2 = 6.7, pKaOH = 6.5 and 10.3) (Amstad et al. 2011a; Togashi et al. 2012; Thomas et al. 2015) (Fig. 14).
Catechol-based stabilizers can be grafted on TiONts: their presence can be proven by several characterization techniques such as FTIR (Fourier Transform InfraRed spectroscopy), XPS, TGA. However, DHCA and LDOPA can transform into quinone at high pH and via oxidation or reduction reactions, limiting their grafting. pH 6 seems the most suitable to avoid these phenomena, but to the detriment of a high grafting yield, due to a lower deprotonation of the hydroxyls of the catechol (Fig. 14). For all these reasons, NDOPA has aroused interest (Patil et al. 2018; Albu et al. 2019) as the use of this molecule allowed the oxidation process to be limited thanks to the close location of NO2 and NH2 groups. Furthermore, the grafting rate of NDOPA on TiONts can be improved in selecting the synthesis pH close to the pKa of both hydroxyls of LDOPA and DHCA. These can be proven by TGA with a more significant weight loss for TiONts-NDOPA. In addition, the characterizations carried out by IR and XPS showed a greater rate of formation of the Ti–O-catechol bond. Although, N. Millot et al. (Loiseau 2017) showed that grafting the NDOPA molecules on TiONts did not significantly improve the colloidal stability of TiONts-NDOPA under physiological conditions. It should be noted that TiONts with their elongated morphology and rather large size are often more difficult to stabilize than small spherical nanoparticles. Regardless, catechol-based coatings have proven their effectiveness in many cases such as substrates (Saiz‐Poseu et al. 2019; Cheng et al. 2019) and nanoparticles (TiO2, Fe3O4, etc.) (Benyettou et al. 2009; Motte et al. 2011; Guenin et al. 2014; Thapa et al. 2018; Mohammadi et al. 2020).
To conclude, catechol derivatives are great stabilizers in most situations and offer new possibilities of further graftings thanks to their amine or carboxylic acid moieties on them. When the criteria of colloidal stability are eventually not met, silanes and phosphonate pathways are excellent alternatives. Other options consist of additional polymer graftings such as polyethyleneglycol (PEG) or polysaccharide (chitosan for instance) derivatives as described in the following section.
3.4 Other TiONts’ Surface Modifications
PEGylated chains grafted on nanoparticle (NP) surfaces lead to a charge shielding phenomenon (Maurizi et al. 2015), which enables to reduce the hepatic capture. Only a few studies are reporting the effect of PEGylated chain density and length on the biological behavior of TiONts and not much more on other metal oxide NPs (Gref et al. 2000; Gratton et al. 2008; Jokerst et al. 2011; Wu et al. 2020). It has been reported that higher PEG density and chain lengths improve the colloidal stability, reduce nonspecific adsorption of proteins and hence minimize the NP detection by the immune system, as well as their uptake by cells (Mosqueira et al. 2001; Cruje and Chithrani 2014). That is why the influence of different PEGylated chain lengths (HS-PEGn-COOH; n = 3,000; 5,000; 10,000) on the colloidal stability of TiONts and on the PEGn density and conformation has been investigated by N. Millot et al. (Loiseau et al. 2021).
ζ-potential measurements prove (Fig. 15) the presence of PEGn on the TiONts-APTES-surface via an important charge shielding for the different PEGylated chain lengths (the longer the chain, the most important the shielding). Colloidal stability was also investigated under physiological conditions (PBS 0.1 M; pH 7.4) by turbidimetric analyses (inset in Fig. 15) and correlated with TEM observations (Loiseau et al. 2021). The absorbance measurements as a function of time demonstrated a better colloidal stability for TiONts-APTES-PEGn suspensions than in bare TiONts and TiONts-APTES without PEG. TGA results correlated with FT-IR and XPS analyses, prove the effective synthesis of TiONts-APTES-PEGn nanohybrids. In particular, TGA analyses lead to 0.09 PEG3,000/nm2; 0.05 PEG5,000/nm2 and 0.03 PEG10,000/nm2. These results reflect a relatively dense PEGn brush conformation.
Chitosan (CT) has been also used to enhance the biocompatibility of hydrothermally synthesized nanotubes in a biological medium as a substitute for polyethylene glycol that is generally used for biocompatibility. CT grafting was carried out using two different approaches; the first one was made by forming covalent bonds using two intermediate molecules, and the second one is based on electrostatic interactions between CT and TiONts (Fig. 16) (Sallem et al. 2017a). The type of linkage on the surface of TiONts was proven to influence the colloidal stability of the elaborated nanohybrids, which were studied in different media (Sallem et al. 2017a).
4 Theranostic Applications of Titanate Nanotubes
Regarding theranostic applications, a key feature of TiONts is their shape. Indeed, beyond composition and surface chemistry (a custom-engineered one according to the application), nanomaterial shape has a tremendous impact on nanoparticle-plasma protein interaction (Nel et al. 2009), margination (Blanco et al. 2015), biodistribution (Blanco et al. 2015) and cellular internalization pathways (Gratton et al. 2008). Thus, one can benefit from these unique tubular nanobiomaterials (i) to increase drug, nucleic acid, protein or imaging agent delivery, as well as (ii) to improve the retention of the therapeutic or imaging modality at pathological site (Loiseau et al. 2017). This section explores the use of TiONts in the context of transfection, drug delivery, and radiotherapy monitored with medical imaging (theranostic).
4.1 TiONts as New Transfection Agents
The rationale behind using TiONts as a transfection agent was that neonatal cardiomyocytes (CM) are a highly challenging target for nucleic acid delivery (Papa et al. 2013). High transfection efficiencies are only achieved with the use of viral vectors as a mean of nucleic acid delivery (i.e. transduction). Conventional non-viral methods include liposomal delivery (Hunton et al. 2002; Lan et al. 2009) (such as Lipofectamine) and electroporation (Louch et al. 2011). However, liposomal delivery only achieves limited expression in this challenging CM model and electroporation represents a technical challenge in vivo. Because the internalization of tubular nanomaterials is often greater than their spherical counterparts (Gratton et al. 2008), there is thus potential to utilize this superior internalization of TiONts within CM. This could fill the current technological gap in non-viral nucleic acid delivery vehicles that achieve safe delivery but lack efficiency. Such a solution could provide non-viral methods that potentially address safety risks with viral techniques, in the context of clinical translation.
For this application, the negative charge of TiONts following their synthesis and purification to pH 6 (\(\upzeta \) = −34.5 mV) was reversed using polyethyleneimine (PEI, Mn ~ 1,800 g.mol−1) in order to complex the negatively charged plasmid DNA (linear pmaxGFP™) at the tube surface, as well as provide the TiONts’ suspension with greater stability and dispersion (\(\upzeta \) = +39.0 mV for both 1:1 and 1:10 TiONt:PEI w:w ratios) (Papa et al. 2013). TiONt-PEI-DNA complexes were formed in serum-free cell media to ensure no interference with plasma protein adsorption on the tube surface (i.e. protein corona) and the resulting net charge at the complex surface was −21.0 mV and +25.0 mV for 1:1 and 1:10 TiONt:PEI, respectively. These zeta potential values, coupled with a study of nanohybrid saturation of DNA via gel electrophoresis, confirmed that the two carriers had opposite net charge and that the 1:1 TiONt-PEI-DNA was saturated in nucleic acids, compared to the 1:10 TiONt-PEI-DNA complex (that could potentially still increase its loading capacity). The positively charged 1:10 TiONt-PEI-DNA complex failed to achieve transfection, presumably due to a transient cytotoxicity observed solely for the high PEI load formulation as seen with LDH assays. In contrast and interestingly, the negatively charged complex lead to a successful transfection (i.e. 33% of CM population was GFP positive) 24-h following a 5-h incubation/transfection of the purified complexes with CM.
Compared to classical non-viral spherical nanoparticles, TiONts offer a new opportunity to mitigate the risks and challenges associated with the use of viral carriers for clinical translation.
4.2 TiONts as New Radiosensitizers
One of the major challenges in radiation oncology is to get therapeutic effects in increasing the ionizing one while minimizing the administered doses whereas the dramatic side effects on healthy surrounding tissue should be minimized. TiONts are good candidates to induce a radiosensitizing effect (Mirjolet et al. 2013, 2017; Loiseau et al. 2019) – even though titanium has a low atomic number (Z = 22) (Maezawa et al. 1996; Takakura 1996) – along with an absence of cytotoxicity (see Sect. 5) (Mirjolet et al. 2013; Papa et al. 2013; Loiseau et al. 2017). N. Millot et al. studied the incubation of glioblastoma cell lines (SNB-19 and U87MG) with TiONts and under irradiation (Fig. 17). The resulting clonogenic assays showed that radiosensitization is effective by TiONts at both low and high doses with a decrease in the SF2 parameter for both SNB-19 and U87MG cells. The latter is confirmed by an increase and decrease of α and β parameters, respectively. Biological consequences could be explained by a decrease of DNA repair efficiency after irradiation and amplification of G2/M cell-cycle arrest (Boudon et al. 2014). Due to their shape, TiONts have the capability to be internalized in cells better than their spherical counterparts TiO2 (Papa et al. 2013). Moreover, after intratumoral injection, the oblong-shaped TiONts are maintained several days inside the tumor (more than 80% after 96 h by SPECT/CT imaging (Mirjolet et al. 2017) and more than 40% after 20 days by gamma counting (Loiseau et al. 2019)).
Thus, these nanomaterials are very interesting as therapeutic platform (intrinsic radiosensitizing properties, delivery of chemotherapeutic and radiotherapeutic agents in tumor sites). To promote TiONts to the theranostic level, superparamagnetic nanoparticles (iron oxide nanoparticles for example) can be associated to get detectable via MRI (magnetic resonance imaging) (Papa et al. 2011) while still benefiting from their radiosensitizing and shape properties.
4.2.1 TiONts-DTX for the Treatment of Primary Tumor
Combining the ability of radiosensitization and concurrent chemotherapy is of great interest in an effort to improve current management of advanced prostate cancer. Thus, the combination between docetaxel (DTX), an anti-mitotic chemotherapy taxane-type drug, and TiONts has been investigated (Mirjolet et al. 2017; Loiseau et al. 2017, 2019). The idea is to increase the drug intracellular concentration by maintaining the tubes within the tumor, avoiding repeated injections that can result in chemotherapy resistance, several side effects for patients (Larsen et al. 2000; Parhi et al. 2012). A grafting strategy of TiONts carrying DTX has been developed by A. Loiseau et al. (Loiseau et al. 2017) and biological assays showed a satisfactory cytotoxic activity of the TiONt-DTX nanohydrid against two prostate cancer cell lines (PC-3 (Mirjolet et al. 2017) (Fig. 18a) and 22RV1 (Loiseau et al. 2017) for which IC50 is around 360–390 nM) when compared to that of free DTX (IC50: 2–4 nM). Thereafter, the RT efficacy of these nanohybrids was also evaluated in vivo after intratumoral injection in PC-3 xenografted prostate tumors into Swiss nude mice (Mirjolet et al. 2017; Loiseau et al. 2017). The treatment with TiONts-DTX was significantly more effective than that with free DTX. Interestingly, mice treated with TiONts-DTX, without RT, exhibited a trend toward tumor growth delay compared with mice receiving free DTX (40 days vs. 30 days). Finally, tumor growth was significantly slowed down by TiONts-DTX associated with RT (three daily fractions of 4 Gy), compared with free DTX in the same conditions (73 days vs. 56 days to reach a tumor volume of 1,000 mm3, respectively) (Fig. 18b). These results suggest that TiONts-DTX noticeably improved RT efficacy and might enhance treatments of high-risk localized prostate cancers.
4.2.2 TiONts-AuNPs-DTX as Radiosensitizing Agents
The radiosensitizing effect of these nanohybrids has been further improved (when compared to the results presented in Sect. 4.2.1) by grafting gold nanoparticles (Au@DTDTPA NPs) on TiONts. These Au@DTDTPA NPs are biologically well-tolerated and present a low toxicity (Miladi et al. 2014; Schuemann et al. 2016), they can improve the efficiency of radiation therapy by two-fold after intratumoral injection in animals (Miladi et al. 2014; Butterworth et al. 2016). However, their potential is probably under-exploited because of their fast renal clearance (Alric et al. 2013). Consequently, the association of Au@DTDTPA NPs with TiONts-DTX is expected to overcome this limitation by maintaining them on tumor sites after injection: the resulting TiONts-AuNPs-DTX nanohybrids were elaborated step-by-step by A. Loiseau et al. (Loiseau et al. 2019). In vitro assays on a PC-3 human prostate cancer cell lines were performed (Fig. 19a) (Loiseau et al. 2019): Au@DTDTPA NPs and TiONts-AuNPs-PEG3000 did not present any cytotoxicity while TiONts-AuNPs-PEG3000-DTX exhibited a greater cytotoxic activity compared to that observed for TiONts-DTX (IC50: 82 nM vs. 360 nM, respectively).
Finally, the synergistic combination between TiONts, DTX and AuNPs in the same entity with RT showed a better therapeutic efficacy by fulfilling their role as carriers and concentrating the radiotherapeutic and chemotherapeutic agents (Fig. 19b). Indeed, tumor growth was significantly slowed down (p = 0.035) by the treatment of TiONts-AuNPs-PEG3000-DTX + RT (55 days to reach a tumor volume of 1,000 mm3), compared with TiONts-DTX + RT (50 days) in the same conditions. The elaborated design asserts TiONt-based nanohybrids to be an attractive, and versatile platform for the treatment of prostate cancer.
4.3 TiONts as New Nanocarriers
In 2016, T. Baati et al. have shown the effectiveness of a TiONt-based nanocarrier against glioblastoma multiform with a controlled administration of genistein (biologically active flavonoid) in glioblastoma cells (Baati et al. 2016). This study showed that these TiONts have a drug loading efficiency of 51.2 wt.% and allows a controlled release of the therapeutic agent. F. Sallem et al. have developed the nanocarrier of a therapeutic molecule: a stilbene phenol, 4′-hydroxy-4-(3-aminopropoxy)-trans-stilbene (HAPtS), which is a trans-resveratrol derivative. Trans-resveratrol is a natural stilbenic polyphenol, known to prevent or slow down number of diseases including cardiovascular ones (Hung et al. 2000) and cancer (Baur and Sinclair 2006) because of its anti-inflammatory (Xiao et al. 2013), antiviral, antitumor and antifungal properties (Pirola and Froejdoe 2008). Despite all the interesting biological properties of trans-resveratrol, its low bioavailability and solubility (Lu et al. 2009), its rapid metabolism and its rapid elimination in the urine remain its major limitations. The grafting of this molecule on TiONts’ surface can circumvent these limitations.
After pre-functionalization with 3-chloropropyltriethoxysilane (CPTES), the stilbenic phenol (HAPtS) was successfully grafted onto TiONts-CPTES surface using a condensation reaction between HAPtS and CPTES through nucleophilic substitution. The resulting grafting rate was of about 72.5 mg/g of TiONts (Sallem 2017).
5 Biosafety and Nanotoxicity of TiONts
This section intends to discuss the internalization pathways of TiONts, as well as summarize some of the subsequent key aspects of TiONts’ cytotoxicity profile that have been discovered thus far (Maurizi et al. 2018).
In early studies, TiONts have been detected inside vacuoles of SNB-19 and U87MG cells suggesting an internalization via endocytosis/macropinocytosis. In parallel, TiONts were also seen penetrating the plasma membrane, suggesting their diffusion through the lipidic bilayer (Mirjolet et al. 2013). Further studies have confirmed this diffusion phenomena as TiONts were still detected within murine microglial BV-2 cells despite their incubation with the endocytosis inhibitor amiloride (Sruthi et al. 2018). These observations are in agreement with what has been described regarding the internalization pathways of carbon nanotubes (Raffa et al. 2009). Once they cross the plasma membrane, nanoparticles can potentially induce cellular stress, or even cell death, depending on multiple physicochemical factors that modulate their (cyto)toxicity or safety profile (i.e. chemical composition, nanoparticle surface engineering, intracellular concentration). Thus, each TiONts’ formulation (depending on the specific synthesis parameters, see Sect. 2) needs to be assessed within the relevant physiological in vitro or in vivo models. For example, Magrez et al. demonstrated that titanate-based nanofilaments have different levels of cytotoxicity in regards to H596 lung carcinoma cells, depending on their chemical composition (Magrez et al. 2009). Specifically, the post-synthesis acidic treatment used (to substitute Na+ by H+) generated a composition that was more cytotoxic to H596 cells when compared to non-acid treated filament counterparts (Magrez et al. 2009). This illustrates the complexity and multifaceted behavior of these biomaterials. As previously said, Papa et al. evaluated the cytotoxicity of bare (and non-acid treated) TiONts, TiONts-PEI as well as their spherical counterpart P25 TiO2 in regards to neonatal cardiomyocytes via MTT assay (Papa et al. 2013). No apparent cytotoxicity was detected within the range of concentrations tested (up to 10 μg/mL) at 24 h (Papa et al. 2013). In addition, up to 100 μg/mL TiONts did not induce significant cytotoxicity towards SNB-19 and U87MG cell lines at 72 h, as measured by cell proliferation assay (Mirjolet et al. 2013). Overall, the mechanism of diffusion of the TiONts across the cell membrane does not appear to affect cell viability in multiple cell lines, despite inducing transient lipid bilayer disruption.
Microglial activation and associated oxidative burst are major challenges in drug delivery applications across the brain (Bussy et al. 2015). In this context, TiONts-APTES have been evaluated in vitro using murine microglial BV-2 cells (Sruthi et al. 2018). TiONts-APTES exposure (from 5 μg/mL up to 80 μg/mL of TiONts-APTES up to 24 h) lead to an increased ROS (Reactive Oxygen Species) production and transient mitochondrial hyperpolarization. Furthermore, the TiONts-APTES showed good biocompatibility on BV-2 cells as revealed by the plasma membrane integrity, lysosomal membrane integrity, morphology, and viability analysis.
The toxicity assessment on the zebrafish embryo model is a very recent and interesting method for the in vivo screening of nanoparticles. This test analyzes toxicity in a much more complex system than cultured cells. It is a less expensive test than large-scale biocompatibility studies in mice or rats (Rizzo et al. 2013). Zebrafish embryos are transparent and develop outside their mother, making it easy to follow and understand the cellular mechanism using a simple light microscope. TiONts-chitosan nanohybrid developed in Sect. 3.4 have been evaluated with concentrations varying from 1 to 100 µg/mL. The survival, hatching and development of zebrafish were monitored for 96 h. The survival of zebrafish must be close to 100%, hatching greater than 90% (between 24 and 48 h) and the larval malformations close to 0% conclude on the non-toxicity of nanohybrids. The survival and hatching of zebrafish are not affected by the presence of nanohybrids for the entire concentration range studied from 1 to 100 µg/mL (Fig. 21). No lethality or morphological change was observed even for the highest concentrations. This confirms the non-toxicity of TiONts modified by chitosan.
In these models, TiONts show a good safety profile within the relevant concentrations and doses tested. Nonetheless, further studies including the interaction of TiONts with immune cells, blood cells and plasma proteins, will allow a better understanding of the biological behavior and fate of these bioengineered materials.
6 Conclusions
The aim of this chapter was to illustrate the potential of titanate nanotubes as new potent tools for nanomedicine. The difficulties encountered during their synthesis as well as the different strategies for their necessary surface modification have been illustrated, always via a step-by-step approach. Several bioapplications of these engineered TiONts have been outlined: nanocarriers of plasmid DNA or of trans-resveratrol derivatives, radiosensitizers etc. TiONts have also shown a good safety profile in all the bioassays developed to evaluate their potential toxicity. Finally, these functionalized TiONts appear as promising versatile tools in the biomedical field to fight some diseases such as cancer. In this context and for these elongated inorganic nanoparticles, intratumoral injection seems to be a relevant way of administration.
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Acknowledgements
JB, AL, FS, LM and NM acknowledge the funding support from French Government through the CNRS, the “Université de Bourgogne”, the “Conseil Régional Bourgogne Franche-Comté, the European Union (PO FEDER-FSE Bourgogne 2014/2020 programs), the Cancéropôle Est and the EIPHI Graduate School (ANR-17-EURE-0002). ALP acknowledges the support from the George Washington University start-up funds. All the people who contributed in the results presented in this chapter are greatly acknowledged: Sudhakaran Sruthi, Gérard Lizard, Thomas Courant, Johanna Chluba, Laurence Motte, Erwan Guénin, Frédéric Geinguenaud, Laure Dumond, David Vandroux, Céline Mirjolet, Véronique Morgand, Olivier Heintz and Rémi Chassagnon, as well as all the people from the PharmImage® consortium, the 3MIM agreement and the IMAPPI program who are involved but not mentioned in the presented results.
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Boudon, J., Sallem, F., Loiseau, A., Maurizi, L., Papa, AL., Millot, N. (2021). Development of Novel Versatile Theranostic Platforms Based on Titanate Nanotubes: Towards Safe Nanocarriers for Biomedical Applications. In: J.M. Abadie, M., Pinteala, M., Rotaru, A. (eds) New Trends in Macromolecular and Supramolecular Chemistry for Biological Applications. Springer, Cham. https://doi.org/10.1007/978-3-030-57456-7_8
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