Augmentin loaded functionalized halloysite nanotubes: A sustainable emerging nanocarriers for biomedical applications

Rubber composites based on halloysite nanotubes (HNT) have attracted tremendous attention during the last decades owing to the improved mechanical, dynamic mechanical, and thermal properties [1–3]. Before exploring the various aspects of HNT/rubber composite systems, we first briefly describe the HNT. It was first introduced by Berthier long back in the year of 1826 [4]. HNTs are a type of naturally occurring silicates with rolled nanotubular or spiral morphology, which have an analogous chemical structure of kaolinite [5]. They are naturally occurring and economically viable, and many countries such as China, France, Belgium, and New Zealand have deposits of these clay minerals. The major origin of HNT is a clay mineral obtained from a weathering product of granitic and rhyolitic volcanic rocks. The chemical composition of HNT is reported as Al2(OH)4Si2O5∙nH2O with n 1⁄4 0 or 2 for the anhydrous and the fully hydrated halloysite, respectively. The nanotubular structure was evolved from kaolinite by rolling up the layers under natural conditions. Most of the HNTs are multiwall or double-wall nanotubes [6]. Usually, the inner diameter of HNT is in the range of 50–80 nm and length of about 1,000 nm. Based on the state of hydration, HNTs are classified in two categories: hydrated HNTs with a crystalline structure of 10 A (d001) spacing and dehydrated ones with 7 A (d001) spacing [7]. HNTcontains two different types of hydroxyl groups, inner and outer hydroxyl groups, which are positioned in between the layers and on the surface, respectively. Attributed to the multilayer structure, most of the hydroxyl groups are inner groups, and only a few hydroxyl groups are located on the surface of HNT. The surface of HNT is mainly composed of outer O–Si–O (silanol) groups and O–Al–O (aluminol) groups situated inside the lumen. It is interesting to note that the density of surface hydroxyl groups in HNT is rather lower compared to other silicates clay minerals, for instance, kaolinite and montmorillonites (Fig. 1).

At present, petrochemical-based plastics are commonly used in many industries. Yet, environmental concerns over these materials have led to the search for biodegradable alternatives in several industries including packaging. In this regard, the renewable resource-based polymer, poly (lactic acid) (PLA), holds a greater demand due to its unique properties (such as biodegradability and biocompatibility). Despite the merits of PLA, limitations in mechanical, thermal and gas barrier properties have restricted the usage of PLA in a wider range of applications in the packaging industry. Therefore, it has become a necessity to reinforce PLA to overcome these drawbacks. The main objective of this research is to investigate the feasibility of halloysite nanotubes (HNTs) as a nanofiller to reinforce PLA. PLA/HNTs nanocomposite films were prepared using the solution casting method by varying the HNTs loading (from 2.5 – 10 (w/w %)). Evaluation of the physico-chemical properties of the films revealed that the mechanical and thermal properties of PLA films were enhanced with the addition of HNTs. The interfacial interaction was further investigated with Fourier transform infrared (FTIR) spectroscopy and the end-hydroxyl groups of PLA were found to chemically interact with outer surface siloxane groups of HNTs. Furthermore, a comparison study was conducted to investigate the influence of the nanocomposite processing methods, namely melt compounding and solution casting, on the thermo-mechanical properties of PLA/HNTs nanocomposite films. Moreover, the ductility of PLA/HNTs films was improved by incorporating a plasticiser, poly (ethylene) glycol (PEG), while the dispersion of HNTs in PLA at high filler loadings was further improved by modifying the outer surface of HNTs with a silane modifier, γ-aminopropyltriethoxysilane (APTES). In addition, after evaluating the effect of three different types of HNTs (which are structurally different) on the tensile properties, this study suggests the best type of HNTs that can be incorporated into the PLA matrix in order to obtain the optimum tensile properties. In this dissertation, an alternative finite element (FE) approach to accurately predict the elastic modulus of polymer/HNTs nanocomposites is proposed. A real-structure-based 3-D computational model with randomly oriented HNTs was developed and compared with the conventional, idealized modelling approach. The developed idealized model consists of nanotubes with fixed aspect ratio and the proposed alternative real-structure-based model takes the experimentally observed variations in HNTs sizes, impurities and aspect ratios into account. According to the parametric studies, a unit cell model with cylindrical reinforcements (representing HNTs) and at least 30 inclusions gave promising results, provided the model included actual information about HNT's size ranges and aspect ratios. Numerical studies were validated with experimental findings and the developed real-structure-based model gave more accurate results than idealized and analytical models. Furthermore, the reinforcing mechanism was carefully studied in terms of the stress distribution. As the final stage of this research, the PLA/HNTs nanocomposite films were further developed for better end user application by creating high performance, multifunctional, active packaging films. ZnO nanoparticles have been successfully investigated to remarkably enhance the antimicrobial properties of poly (lactic acid) (PLA) composite films for active packaging, where they can enhance the shelf life of goods, but the addition of ZnO into PLA decreases its thermo-mechanical properties. In this study, ZnO nanoparticles were deposited on the outer and inner surfaces of halloysite nanotubes (HNTs) using a novel solvothermal method and these ZnO deposited HNTs (ZnO-HNTs) were incorporated into the PLA matrix as a reinforcing filler. PLA nanocomposite films with ZnO had inferior mechanical properties compared to PLA films with ZnO-HNTs which showed significant improvements, with an increase in the tensile strength and modulus by 33% and 74%, respectively, with the addition of 5 (w/w %). Antimicrobial tests revealed that ZnO-HNTs can act as a promising antimicrobial agent against bacteria such as Escherichia coli and Staphylococcus aureus where the bacteria count reduced by more than 99%.

Zinc sulfide (ZnS) nanoparticles are successfully deposited on the surface of natural halloysite nanotubes (HNTs) to produce ZnS /HNTs nanocomposites. The samples are characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), Fourier transform infrared (FTIR) spectroscopy, ultraviolet-visible (UV-vis) spectroscopy and photoluminescence (PL) analysis. The results indicate that ZnS nanoparticles are uniformly attached on the surface of HNTs with narrow particle size distribution center at ~10 nm, and are prevented from aggregation by HNTs and expose more active sites. ZnS /HNTs show excellent photocatalytic activity for the degradation of eosin B under UV light, better than pure ZnS and HNTs, indicating its potential application in the field of environmental protection. The mechanism for photocatalytic activity enhancement is also investigated.

The development of stimuli-responsive drug nanocarriers is an increasingly important area in nanomedicine because efficient delivery of toxic drugs to targeted tissues minimizes side effects. The specific objective of this study was to synthesize and characterize a novel pH-responsive drug carrier based on halloysite nanotubes for the controlled release of the anticancer drug doxorubicin. Poly(N,N-dimethylaminoethyl methacrylate) brushes were grafted from the surface of halloysite nanotubes using the combination of mussel-inspired polydopamine surface modification and activators regenerated by electron transfer in atom transfer radical polymerization. The chemical structure and morphology of the modified halloysite nanotubes were investigated by Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, thermal gravimetric analysis as well as scanning and transmission electron microscopies. Dynamic light scattering and zeta potential analysis were carried out to evaluate the pH-responsivity of the functionalized halloysite nanotubes. The results of the drug loading and release study of pristine and functionalized halloysite nanotubes showed that grafting of poly(N,N-dimethylaminoethyl methacrylate) brushes on the polydopamine-modified halloysite nanotubes surface leads to a drastic increase in doxorubicin loading capacity and a highly pH-sensitive release behaviour. Less than 10 % of the loaded doxorubicin was released from poly (N,N-dimethylaminoethyl methacrylate)-grafted halloysite nanotubes at pH 7.4 after 24 h; in contrast, at pH 5.5 there was a continuous release of doxorubicin totalling 13 % in the first 30 min, i.e. lower than for the pristine halloysite nanotubes (32 %), but reaching 48 % after 24 h. Poly (N,N-dimethylaminoethyl methacrylate)-grafted halloysite nanotubes can hence be considered as a potential candidate for delivering highly toxic drug molecules to the acidic target sites.

The superior physical and mechanical performances of halloysite nanotubes (HNTs) make them ideal fillers for rubber reinforcement. However, due to the abundant hydroxyl groups on their surface, they are highly polar and have poor compatibility with polymers, making it difficult for them to disperse uniformly in polymers, thus limiting their application in rubber composites to a certain extent. In this paper, noncovalently modified HNTs filled with a natural rubber/chloroprene rubber/chloro-isobutylene-isoprene rubber (NR/CR/CIIR) blend system, using polydopamine(PDA) as a surface modifier, was investigated. and a green and high-performance PDA/HNTs/NR/CR/CIIR composite was prepared by mechanical blending. Transmission electron microscopy (TEM) showed that the original HNTs had a hollow, multi-walled nanotube structure, and the outer surface of the PDA-modified halloysite nanotubes(PDA/HNTs)showed an obvious cladding layer. X-ray diffraction indicated that the modification experiments did not damage the halloysite crystal structure; the modifier only interacted on the outer surface of the HNTs. Zeta potential and thermogravimetric analysis (TGA) further indicated the presence of interfacial interactions between PDA and HNTs, suggesting that PDA was successfully grafted to the surface of HNTs. In addition, the effects of PDA/HNTs on the mechanical properties, vulcanization properties and Rubber Process Analyzer (RPA analysis) of the NR/CR/CIIR blend were also investigated. The dispersion of HNTs in the NR/CR/CIIR blend was enhanced by the adsorption of PDA on the HNTs surface by non-covalent bonds, and the comprehensive properties of the composites were improved.

The adsorption and retention of phosphates in soil systems is of wide environmental importance, and understanding the surface chemistry of halloysite (a common soil clay mineral) is also of prime importance in many emerging technological applications of halloysite nanotubes (HNTs). The adsorption of phosphate anions on tubular halloysite (7 Å) has been studied to gain a greater understanding of the mechanism and kinetics of adsorption on the surface of HNTs. Two well-characterized tubular halloysites with differing morphologies have been studied: one polygonal prismatic and one cylindrical, where the cylindrical form has a greater surface area and shorter tube length. Greater phosphate adsorption of up to 42 μmol g–1 is observed on the cylindrical halloysite when compared to the polygonal prismatic sample, where adsorption reached a maximum of just 15 μmol g–1 compared to a value for platy kaolinite (KGa-2) of 8 μmol g–1. Phosphate adsorption shows strong pH dependence, and the differences in phosphate sorption between the prismatic and cylindrical morphologies suggest that phosphate absorption does not occur at the same pH-dependent alumina edge sites and that the lumen may have a greater influence on uptake for the cylindrical form.

Addition of natural inorganic nanotubes to epoxy acrylate resin can significantly improve their mechanical properties. Halloysite nanotubes are one kind of novel reinforcing and toughening materials for polymers. In the present work, halloysite nanotubes were compounded to epoxy acrylate resin to improve the wear resistance and toughness of the composites. To improve the embedding of halloysite nanotubes within the epoxy acrylate resin matrix, the halloysite nanotubes surface was grafted by poly (methyl methacrylate). The morphology of the grafted halloysite nanotubes particles demonstrates a core-shell structure with halloysite nanotubes as the core and the grafted polymer as the shell. Poly (methyl methacrylate) was chemically attached to the halloysite nanotubes particles as indicated by the Fourier transform infrared and X-ray photoelectron spectroscopy results. The poly (methyl methacrylate) grafted halloysite nanotubes (poly (methyl methacrylate)- g-halloysite nanotubes) then compounded with epoxy acrylate resin and composites are formed via ultraviolet-curing method. The hardness, flexibility, impact resistance and wear resistance of epoxy acrylate/poly (methyl methacrylate)- g-halloysite nanotubes composites were markedly improved in comparison with that of neat epoxy acrylate. The improvement was correlated to the well-dispersed halloysite nanotubes and the interfacial bonding between epoxy acrylate resin and poly (methyl methacrylate)- g-halloysite nanotubes. The well dispersion of halloysite nanotubes in the matrix is attributed to the modification on the surface of halloysite nanotubes.

Halloysite nanotubes (HNTs) surface-grafting poly(D,L-lactide) (g-HNTs) were synthesized by bulk ring-opening polymerization of D,L-lactide using stannous octoate as catalyst and HNTs as co-initiator. Fourier transform infrared (FTIR), thermal gravimetric analysis (TGA), X-ray diffraction (XRD) and zeta potential measurement were employed to elucidate the structure and properties of HNTs before and after grafting with D,L-lactide. FTIR spectrum certified the existence of poly(D,L-lactide) chains on the surface of g-HNTs. The amount of surface-grafted poly(D,L-lactide) measured by TGA was 4.6% in weight. The grafted poly(D,L-lactide) chains on the surfaces of HNTs can relieve the clustering effect of HNTs to some extents.

Halloysite nanotubes as carriers for irinotecan: Synthesis and characterization by experimental and molecular simulation methods

Nanometer ferriferrous oxide (Fe3O4) with about 10–30 nm diameter were deposited on the inner and outer surfaces of natural halloysite nanotubes (HNTs) via the reduction co-precipitation process. The aggregation of Fe3O4 nanoparticles will be significantly reduced as they are distributed on the surfaces of HNTs with higher specific surface areas. Powder X-ray diffraction (XRD) and Fourier transform infrared (FT-IR) spectrometer showed that Fe3O4/HTNs composites had a good thermal stability at 373 K and 523 K. Furthermore, Vibrating-sample magnetometer (VSM) confirmed the superparamagnetism of Fe3O4/HTNs composites could be preserved at different heat treatment of 373 K and 523 K.

Halloysite nanotube (HNT) is a natural clay mineral with a hollow and tubular structure, which can be a potential reinforcement for biodegradable polymers such as poly(vinyl alcohol) (PVA). This study investigates the improvement of interfacial adhesion between HNT and PVA by means of controlled acid etching on HNT surfaces. Such an improvement is attributed to a porous structure with rough HNT surfaces in that acid favors the dissolution of AlO6. The strength of PVA/HNT nanocomposites increased up to 10% when HNT were subjected to 1 h acid treatment. However, the reinforcement effect could have been more pronounced if HNT aspect ratio were maintained during the composite fabrication process.

In this paper, new porous pH-responsive microspheres based on functionalized halloysite nanotubes (HNTs) with poly-lactic-co-glycolic acid (PLGA) are investigated as the phenytoin sodium (PHT-Na) carrier. For this purpose, the surfaces of HNTs were modified by a silane coupling agent, (3-aminopropyl)triethoxysilane (APTES) and then the desired microsphere was synthesized through PLGA coating on modified HNTs. Formation of these hybrid particles are confirmed using various characterization methods like Fourier transform infrared (FT-IR), transmission electron microscope (TEM), scanning electron microscope (SEM), EDX, zeta-potential, and X-ray diffraction. The results of the FT-IR spectrum show the presence of APTES, PHT-Na and PLGA peaks, which supported the modification of HNTs and drug capsulation. TEM images confirm the presence of APTES on HNTs, due to the increase in outer diameter. SEM images displayed that by grafting PLGA polymer to modified HNTs, the shape of nanotubes has changed from rod-like to microsphere. Hence, the prospering connection of APTES and PLGA on HNTs was emphasized by zeta-potential results. Moreover, the profile of drug release is recorded via HPLC. In vitro drug release tests show that both the presence of polymer chains around drug containers and the pH value of the release medium play an important role in controlled release. Eventually, the kinetics of drug release was evaluated based on Korsmeyer–Peppas kinetic model.

In this study, we demonstrate the use of poly (ethylene oxide) (PEO) for in-situ modification of the inner surface of halloysite nanotubes (HNTs) with water molecules as the hydrogen bond forming medium, as well as the nano-confinement of PEO molecular chains within the nanotube. Before testing, the Soxhlet experiment of PEO/HNTs powder is applied in order to remove the physical adsorption of PEO molecules onto the outmost surface of HNTs. The crystal temperature of PEO changes sharply from 36.9 °C of neat PEO to −25 °C of PEO in the PEO/HNTs powder and the decomposed temperature of PEO in the PEO/HNTs powder is about 13.1 °C higher than that of neat PEO, which is mainly owing to the nano-confinement effect of PEO within the HNTs with a diameter of about 10 nm. From thermo-gravimetric (TG) analysis, about 7.71 % by weight of PEO has been chemically bonded to HNTs. The hydrogen bonds among PEO, HNTs, and water molecules are evidenced by FTIR and XPS performances. Meanwhile, the binding energy of Al2p in the innermost surface of HNTs shifts from 74.7 eV in the neat HNTs to 74.5 eV in the PEO/HNTs powder, while that of Si2p on the outmost surface of HNTs keeps almost constant, indicating that the hydrogen bonds only exists inner the nanotube and PEO molecular chains have been trapped in nano-scale within HNTs, which is in accordance with the DSC and TG observation.

Proton binding (i.e., charging) isotherms of halloysite nanotubes (HNT) were determined from cycled acid-base potentiometric titrations in KCl solution at constant ionic strengths (0.01, 0.10, 1.00 mol dm−3). The isotherms measured in the pH cycle from 3 to 11 and back exhibit a pronounced hysteresis with respect to the direction of pH change, which is accurately reproducible when the cycle is repeated. The hysteresis is absent if the cycled titration is performed within a narrow pH range between 5 and 9. These results align with the dissolution rates of alumina and silica, which form the two surfaces of the rolled kaolinite sheet in HNT, and clearly point to reversible partial dissolution-deposition processes in the HNT interior during a titration cycle, outside the above pH range (alumina dissolution below pH ≈ 5 and silica dissolution above pH ≈ 8.5). In the studied titration experiments, these processes produce partially dissolved surface-bound, rather than completely dissolved species (reversible surface etching). Under the applied conditions, reversible surface etching is less pronounced in the acidic part of the titration cycle. Charging isotherms recorded in the decreasing pH titrations at varied ionic strength exhibit a common intersection point very close to zero charge (point of zero charge) around pH ≈ 8.1, characteristic for an amphoteric solid surface. These isotherms were reasonably well fitted by applying the surface protonation model in the HNT interior, which invokes the Stern model of the electric double layer (EDL), by summing the surface charges calculated for alumina and silica as separate components (surfaces). The model surface charge isotherms for alumina surface in the HNT interior exhibit a point of zero charge at pH = 9.0, while the silica surface has a negative charge above pH > 8.5, which is in very good agreement with the values reported in the literature: as for these two surfaces, thus for kaolinite nanoparticles. The best-fit protonation site density for both surfaces is equal to 8.0 nm−2, while the best-fit intrinsic pKa for alumina and silica surfaces of HNT are equal to 9.0 and 8.5, respectively. The pH-dependence of electrophoretic mobility, measured by means of electrophoretic light scattering, reveals a more acidic behavior of the outermost silica surface than within the inner HNT phase, which is consistent with the literature result reported for kaolinite. The results reported herein confirm that the inner and outer surfaces of the HNT are oppositely charged below pH < 8.0 and negatively charged above that value, and importantly, they reveal new details about the protonation affinities and EDL parameters at active surfaces of HNT, important for the colloidal stability of HNT suspensions and the functionalization of HNT through the electrostatic binding of active molecules.

Recent developments in nanotechnology have identified clay minerals, characterised by a low cost and earthwide abundance, as candidates for high-end applications. Among them, halloysite nanotubes with their unique morphology and high biocompatibility have emerged as a promising material for use in water remediation and drug delivery. The void at the centre of each tube and the fact that aggregation of halloysite nanotube generates a hierarchical porous structure with meso- and macropores qualifies them for the adsorption of various molecules including therapeutic agents and water pollutants. In this context, however, the absence of surface functional groups that can interact with the guest molecules is the main challenge and developing surface modification methods to create such functional groups on the halloysite nanotubes is crucial for enhancing their performance. The aim of this dissertation was to investigate the potential of surface-modified halloysite nanotubes for applications in water remediation and drug delivery. For this purpose, the halloysite surface was functionalized with a thin layer of polydopamine through a nature-inspired and convenient deposition method. A detailed structural analysis of polydopamine formation on halloysite surface is described in Chapter 3 and the performance of halloysite nanotubes modified with polydopamine for removing of methylene blue from the aqueous solutions is detailed in Chapter 4. Chapters 5 and 6 explain how stimuli-responsive polymer brushes were successfully grown from the surface of halloysite nanotubes, and how the potential use of these hybrid materials as novel smart nanocarriers for doxorubicin was studied. Chapter 6 also describes how the nanotubes, labelled with a fluorescent dye, enter inside HeLa cells, as revealed by a combination of confocal microscopy and stimulated emission depletion nanoscopy. Our study demonstrated that the nanotubes penetrate into the cells without affecting cell viability; clusters larger than 1 µm accumulate in lysosomes, while clusters below 1 µm can be located either in the cytosol or enclosed by lysosomes.