Magnetic Dendritic Halloysite Nanotube for Highly Selective Recovery

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Magnetic Dendritic Halloysite Nanotube for Highly Selective Recovery of Heparin Digested from Porcine Intestinal Mucosa Hamed Eskandarloo, Mohammad Arshadi, and Alireza Abbaspourrad ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/ acssuschemeng.8b03188 • Publication Date (Web): 29 Aug 2018 Downloaded from http://pubs.acs.org on August 30, 2018

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ACS Sustainable Chemistry & Engineering

Magnetic Dendritic Halloysite Nanotube for Highly Selective Recovery of Heparin Digested from Porcine Intestinal Mucosa

Hamed Eskandarloo,† Mohammad Arshadi,† Alireza Abbaspourrad* Department of Food Science, College of Agriculture & Life Sciences, Cornell University, 243 Stocking Hall, Ithaca, NY 14853, USA *Corresponding author: E-mail address: [email protected] Tel.: (607) 255-2923 †

These authors contributed equally to this work.

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ABSTRACT Heparin, as a sulfated polysaccharide found in animal tissues, is a commonly employed clinical anticoagulant. However, the heparin concentration in digested raw materials is very low and difficult to recover at high concentrations. To address this issue and enrich the heparin content that can be purified, we have fabricated novel polyamidoamine (PAMAM) dendrimers functionalized on halloysite nanotubes (HNTs), which were also decorated and magnetized with iron oxide (Fe3O4) nanoparticles to enable magnetic separation for selective, scalable recovery of heparin. Using absorption spectroscopy, the heparin recovery efficiency of HNTs and PAMAM-Fe3O4/HNTs was evaluated and compared the results to Amberlite FPA98 Cl, a commercially accessible resin used in heparin extraction. Our results showed that the PAMAM-Fe3O4/HNTs demonstrated higher efficiency of heparin recovery, both in terms of the capacity and rate of adsorption. We also studied the adsorption mechanism of heparin onto the functional amino groups of PAMAM-Fe3O4/HNTs using X-ray photoelectron spectroscopy and zeta potential techniques, and the results confirmed the strong electrostatic interaction between the functional groups on the surface of PAMAMFe3O4/HNTs and the sulfate groups of heparin. Additionally, we demonstrated that a saturated NaCl solution could be effectively used for the recovery of the PAMAMFe3O4/HNTs and heparin adsorption process could be repeated without considerable loss in adsorption capacity. In addition, PAMAM-Fe3O4/HNTs selectively recovered heparin from a real sample, consisting of heparin digested from porcine intestinal mucosa. These results confirm that PAMAM-Fe3O4/HNTs have the potential to be employed as a low-cost, green, and efficient adsorbent for heparin recovery.

Keywords: Heparin, Heparin Digestion, Heparin Recovery, Halloysite Nanotubes, Polyamidoamine Dendrimer, Scale-up Purification.


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INTRODUCTION Heparin is a polysaccharide composed of glucosamine and either D-glucuronic acid or Liduronic acid, featuring a high density of negative charges due to the presence of carboxylate and sulfate groups.1,2 It is a widely used anticoagulant for pre-operative inhibition of blood clotting and the treatment of systemic embolism syndrome and deep vein thrombosis.3,4 Heparin is commercially produced by extraction from porcine intestinal mucosa.5 The preliminary extraction of heparin in initial steps results in a crude heparin.6 Through chemical or autolysis isolation the crude heparin can then be digested from proteoglycans and mast cells.7 However, the resulting heparin concentration is very low (~0.01% w/w). As a result, an additional purification step should be applied to selectively recover and purify the heparin from the autolyzed starting material. Recovery of heparin from digestion mixtures by ammonium cations is currently the most broadly used method. Under slightly acidic conditions, hydrophobic primary amines will form insoluble complexes with heparin through the electrostatic interaction between the positively charged amine groups and heparin’s negatively charged sulfate and carboxylate groups.7 Nevertheless, lately techniques use quaternized ammonium cations, in the form of quaternary ammonium salts to form insoluble complexes with heparin8,9 or functionalized on a resin.10,11 Both techniques exploit the unique high charge density (~3.7 negative charges/disaccharide) and polymeric nature of heparin, which distinguishes heparin from other biopolymers available in the isolation mixture,12 thus enabling the strong electrostatic interaction-based capture of the material. Though, the real challenge for the usual methods is the hardness in isolating heparin at high concentrations from the digestion mixture. To address this issue, we offer a novel idea for the preparation of dendrimer-functionalized nanotubes with a high surface area for efficient recovery of heparin. Recently, dendrimers (i.e., highly and regularly branched molecules) have attracted increasing attention because of their unique structure and features, such as well-defined globular structure, narrow size distribution, relatively large molecular size, and ease of derivatization via various functional groups.13,14 As a result, researchers have explored potential applications for these materials, such as antimicrobial activities, imaging, gene transfection, drug delivery, and more.15,16 Multi-amine terminated poly(amidoamine) (PAMAM) is an extensively studied family of dendrimers that features a highly branched structure and high density of nitrogen atoms.17 We propose that PAMAM may be a good candidate for the efficient recovery of negatively charged molecules, including

heparin.

PAMAM-functionalized

supports,

such

as

magnetic

chitosan 3

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microparticles,18 mesoporous alumina nanofibers,19 polyacrylonitrile composite nanofibers,20 multiwalled carbon nanotubes,21 cotton fabrics,22 and titania nanoarchitectures23 have been successfully employed for selective adsorption of anionic compounds via electrostatic interactions between negatively charged groups of the anionic compounds and the protonated −NH2 groups of the dendrimer. In our strategy, we used halloysite nanotubes (HNTs) as the support for PAMAM functionalization. HNTs, sub-micron sized one-dimensional tubular clay structures,24 are composed of two-layered aluminosilicate (Al2Si2O5(OH)4.nH2O), featuring Al−OH groups on the internal surface and Si−O−Si groups on the outside of the nanotube.25 The material demonstrates versatile features, including high porosity and surface area, chemically tunable internal and external surfaces, as well as being biocompatible and environmentally friendly.26 These features have enabled HNTs to be used as suitable supports for applications such as adsorbents, membranes, and for enzyme immobilization.27 Finally, HNTs are more costeffective compared to other nanomaterials, like carbon nanotubes.28 In addition to functionalizing the HNTs with PAMAM, we also decorated the materials with Fe3O4 nanoparticles to allow magnetic separation from the solution mixture.29 The preparation procedure is shown in Scheme 1. The prepared samples were characterized by different techniques, such as X-ray photoelectron spectroscopy (XPS), transmission electron microscopy (TEM), scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), and zeta potential. We measured the adsorption efficiency of the PAMAM-functionalized HNTs decorated with Fe3O4 nanoparticles and compared the results to the adsorption efficiency of Amberlite FPA98 Cl resin, an adsorbent used in commercial heparin extraction processes. The effects of operational parameters on the adsorption efficiency of heparin were also investigated using three-dimensional (3D) response surface plots and two-dimensional (2D) contour plots. Additionally, we analyzed the equilibrium results of heparin adsorption by various kinetic and isotherm models, as well as the adsorption efficiency for heparin isolated from the complex biological tissue of porcine intestinal mucosa.


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Scheme 1. Schematic diagram showing the fabrication of PAMAM-functionalized Fe3O4decorated HNTs.

RESULTS AND DISCUSSION Characterization. We hypothesized that heparin adsorption could be improved by increasing the number of amine functional groups in the adsorbent. To this end, one PAMAM- molecule contains 4 amine end groups. Thus, functionalizing the HNTs with PAMAM- dendrimers (in addition to Fe3O4), we anticipated that significant heparin adsorption could be achieved. Figure 1(a-d) display SEM micrographs of HNTs and PAMAM-Fe3O4-HNTs at different magnifications. The HNTs were tubular shaped, featuring a length of 1–2 µm and an inner diameter of 40–50 nm, the structure of which remained stable even after the surface modification chemistry. From the SEM micrographs (Figure 1(c,d)) and TEM image (Figure 5 ACS Paragon Plus Environment


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1(e)), it is obvious that Fe3O4 nanoparticles were fine decorated on the PAMAM-Fe3O4HNTs surface. The average diameter of the Fe3O4 particles was ~30–50 nm.

Figure 1. SEM micrographs of (a,b) HNTs and (c,d) PAMAM-Fe3O4/HNTs at different magnifications. The yellow dashed circles indicate the Fe3O4 nanoparticles. (e) TEM image of PAMAM-Fe3O4/HNTs. (d) FTIR spectra of heparin, HNTs, and PAMAM-Fe3O4/HNTs before and after heparin adsorption.


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We also studied the HNTs before and after modification using FTIR. Figure 1(f) demonstrates the FTIR spectra of heparin, the HNTs, and PAMAM-Fe3O4/HNTs before and after heparin adsorption. The FTIR spectrum of HNTs exhibits two intense bands at 3688 and 3623 cm-1, which we allocated to the O–H group vibrations. The peaks at 1124 and 1005 cm-1 were associated with Si–O stretching, and we assigned the peak at 910 cm-1 to Al–O. Most absorption band situations did not change after HNTs modification by the Fe3O4 nanoparticles and PAMAM, suggesting that the basic structure of the nanotubes remains constant. However, in the FTIR spectrum of the PAMAM-Fe3O4/HNTs, a band at 669 cm-1 was observed, which we ascribed to the Fe-O bending vibration from the magnetite phase. In addition, in the FTIR spectra of the PAMAM-Fe3O4/HNTs, a new band at 2930 cm-1 was seen that can be assigned to C–H asymmetric stretching. In addition, the small peaks at 1473 and 1559 cm−1 belong to the C–N stretch vibration of amines and –NH2 groups, respectively, which were newly observed for PAMAM-Fe3O4/HNTs. These results indicate that the dendrimer coupling agent, the only source for C–H and N–H bonds, was successfully functionalized onto the HNTs. The FTIR spectra of PAMAM-Fe3O4/HNTs before and after heparin adsorption showed that the intensity of most of the absorption bands decreased after heparin exposure, which proposes the successful adsorption of heparin molecules onto the PAMAM-Fe3O4/HNTs. The nitrogen content was estimated based on the (CHN) elemental analysis. The nitrogen contents for 3-APTRS and PAMAM were found to be 6.1% and 10.2%, respectively.

Heparin Adsorption. We next studied the heparin adsorption capability of the different adsorbents utilizing the methylene-blue-assisted spectrophotometric technique.30,31 Figure 2(a) demonstrates the equilibrium adsorption rate (%) and adsorption capacity (qe, mg/g) of the HNT and PAMAM-Fe3O4/HNT samples in comparison with Amberlite FPA98 Cl resin. The unmodified HNTs failed to adsorb heparin, which was expected because of the negatively charged outer surface of the nanotubes. In contrast, the PAMAM-Fe3O4/HNTs demonstrated strong adsorption of heparin (77.63% was adsorbed after 60 min, adsorption capacity = 5.82 mg/g), which we hypothesized was a result of the opposing electrostatic charges of the materials. Meanwhile, the Amberlite FPA98 Cl resin absorbed just 65.21% of the heparin after 60 min, for an adsorption capacity of 4.88 mg/g. The surface charges of adsorbent were estimated at a pH range of 2 to 12 in terms of the zeta potential, to evaluate the electrostatic interactions between the heparin molecules and 7 ACS Paragon Plus Environment


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HNT adsorbents (Figure 2(b)). Heparin had a negative zeta potential at all pH values studied, likely because of the negatively charged sulfate groups found in the heparin structure, which remain permanently ionized under these conditions.32 It is also apparent from the plot that the surface charge of the unmodified HNTs remained negative for this same pH range because of the negative surface potential of SiO2, although there is a small positive contribution from the Al2O3 of the nanotube’s inner-surface.33 However, the zeta potential of the PAMAMFe3O4/HNTs was positive at a wide pH range (2–10.2) because of the protonation of −NH2 groups (isoelectric point at pH 10.2).

Figure 2. (a) Adsorption capacity (qe, mg/g) and adsorption rate (%) of heparin for diverse adsorbents, including HNTs, PAMAM-Fe3O4/HNTs, and Amberlite FPA98 Cl resin (adsorbent dosage 100 mg, initial heparin concentration 30 mg/L, temperature 45 °C, pH 7, and time 60 min). (b) Zeta potential of heparin, HNTs, and PAMAM-Fe3O4/HNTs as a function of pH.

Effect of Operational Variables. As the adsorption efficiency of heparin by PAMAMFe3O4/HNTs was found to be higher than the other adsorbents, we chose to study the effect of various operational variables on the material’s adsorption efficiency, including initial heparin concentration, adsorbent dosage, time, temperature, and pH (Figure 3). 3D surface plots are a useful method for understanding the effect of these different factors and 2D contour plots help us to identify the interactions between variables. The plots were obtained by keeping three variables constant and varying the other two variables within the experimental ranges.


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Figure 3. The 3D response surface and 2D contour plots of the adsorption rate (%) of heparin by PAMAM-Fe3O4/HNTs as a function of different operational parameters. (a-b) The interaction between initial heparin concentration and time (adsorbent dosage 100 mg, temperature 45 °C, and pH 7). (c-d) The interaction between adsorbent dosage and time (initial heparin concentration 30 mg/L, temperature 45 °C, and pH 7). (e-f) The interaction between temperature and time (adsorbent dosage 100 mg, initial heparin concentration 30 mg/L, and pH 7). (g-h) The interaction between pH and time (adsorbent dosage 100 mg, initial heparin concentration 30 mg/L, and temperature 45 °C).

Interaction between initial heparin concentration and time. Figure 3(a,b) show the influence of the initial heparin concentration and time on the adsorption efficiency of heparin by PAMAM-Fe3O4/HNTs, when the adsorbent dosage, temperature, and pH were kept constant at 100 mg, 45 °C, and 7, respectively. The results show that the adsorption rate decreased from 91.2% to 57.10% over 60 min by increasing the initial concentration of heparin from 20 to 50 mg/L. There is a limited quantity of surface-active sites on the PAMAM-Fe3O4/HNTs, which can become saturated when the concentration of heparin is high.34 However, as revealed in Figure 4(a), the adsorption capacity of PAMAMFe3O4/HNTs increased by increasing the initial concentration of heparin. The amount of heparin adsorbed at equilibrium increased from 2.50 to 7.19 mg/g as we increased the initial heparin concentration from 10 to 60 mg/L. Increasing the initial heparin concentration can create a driving force to overwhelmed mass transfer resistance of the solution to the PAMAM-Fe3O4/HNT surfaces.35


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Figure 4. Adsorption capacity (qe, mg/g) of heparin by PAMAM-Fe3O4/HNTs as a function of operational parameters, including: (a) initial heparin concentration (adsorbent dosage 100 mg, temperature 45 °C, pH 7, and time 60 min); (b) adsorbent dosage (initial heparin concentration 30 mg/L, temperature 45 °C, pH 7, and time 60 min); (c) temperature (adsorbent dosage 100 mg, initial heparin concentration 30 mg/L, pH 7, and time 60 min); and (d) pH (adsorbent dosage 100 mg, initial heparin concentration 30 mg/L, temperature 45 °C, and time 60 min).

Interaction between adsorbent dosage and time. Figure 3(c,d) show the effect of the PAMAM-Fe3O4/HNTs dosage and time on the adsorption efficiency of heparin when the initial heparin concentration, temperature, and pH were kept constant at 30 mg/L, 45 °C, and 7, respectively. Increasing the adsorbent dosage enhanced the amount of adsorbed heparin onto PAMAM-Fe3O4/HNTs. The adsorption rate increased from 51.76% to 85.87% by increasing the PAMAM-Fe3O4/HNT dosage from 50 to 150 mg, which is likely because of the accessibility of a greater number of possible binding sites of PAMAM-Fe3O4/HNTs relative to the constant number of heparin molecules.36 However, as revealed in Figure 4(b), 11 ACS Paragon Plus Environment


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the adsorption capacity of PAMAM-Fe3O4/HNTs decreases with increasing adsorbent dosage. The amount of heparin adsorbed at equilibrium decreased from 8.24 to 3.00 mg/g by increasing the PAMAM-Fe3O4/HNT dosage from 25 to 250 mg. This reduction can be because of the aggregation/agglomeration of PAMAM-Fe3O4/HNT particles at higher amounts, which can result in a reduction in the total surface area of the PAMAM-Fe3O4/HNT and an increase in the diffusion path length of the heparin molecules.37 Interaction between temperature and time. Figure 3(e,f) demonstrates the influence of temperature and time on the adsorption efficiency of heparin. The rate of adsorption increased from 69.1% to 95.42% by increasing the temperature from 30 to 60 °C. This may be due to the increasing rate of diffusion of the heparin molecules across the exterior boundary layer and into the interior pores of the PAMAM-Fe3O4/HNTs because of the decreased viscosity of the solution with increasing temperature.38,39 The equilibrium adsorption capacity of PAMAM-Fe3O4/HNTs was also affected by temperature (Figure 4(c)). The heparin amount adsorbed at equilibrium increased from 5.11 to 7.50 mg/g by increasing the temperature from 25 to 65 °C. The increasing adsorption efficiency of heparin by PAMAM-Fe3O4/HNTs with increasing temperature suggests the possibility of an endothermic process during adsorption. Interaction between solution pH and time. Figure 3(g,h) demonstrates the influence of solution pH and time on the efficiency of heparin adsorption. The results show that the best heparin adsorption by PAMAM-Fe3O4/HNTs occurs at pH 7. The adsorption rate of heparin increased from 47.50% to 77.63% by increasing the pH from 4 to 7. This increasing adsorption efficiency of heparin onto PAMAM-Fe3O4/HNTs by increasing pH may be because of the deprotonation of the −COOH groups on the heparin structure, increasing the electrostatic interaction between the positively charged NH2 groups of the dendrimers and the negatively charged sulfate carboxylate groups of heparin molecules. However, the adsorption rate decreased to 40.20% by increasing the pH value to 10. The adsorption capacity for the PAMAM-Fe3O4/HNTs at pH 4, 7, and 10 was 3.56, 5.82, and 3.02 mg/g, respectively (Figure 4(d)). Heparin adsorption by PAMAM-Fe3O4/HNTs occurs via electrostatic interactions between the negatively charged sulfate and carboxylate groups found in the heparin structure and the protonated −NH2 groups of the dendrimers. This decreasing adsorption efficiency of heparin with increasing pH may be because of the deprotonation of the NH3+ (or NH2+) groups. The available active sites on the surface HNTs for binding of negatively charged heparin molecules can be decreased by deprotonation of the NH3+ (or NH2+) groups. The 12 ACS Paragon Plus Environment

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possible interactions between PAMAM-Fe3O4/HNTs and heparin molecules as a function of pH is demonstrated in Scheme 2.

Scheme 2. Schematic illustration of probable interactions between PAMAM-functionalized Fe3O4/HNTS and heparin as a function of pH.

Mechanism Study. XPS is a useful technique that enables us to study the chemical surfaces and interactions of heparin with the active sites of the PAMAM-Fe3O4/HNTs. XPS wide-scan spectra of PAMAM-Fe3O4/HNTs and PAMAM-Fe3O4/HNTs@heparin are shown in Figure S1 of the Supporting Information. The C1s core level of PAMAM-Fe3O4/HNTs indicated five deconvoluted peaks at 282.3, 284.8, 286.5, 288.4, and 290.6 eV, which could be related to the Si-C, C-C or C-H, C-N, C=O, and π–π* transition, respectively (Figure 5(a)). The highresolution O1s spectra of PAMAM-Fe3O4/HNTs indicated three peak components that appeared at binding energies of 529.6, 532.0, and 532.8 eV, which we attribute to the Al–O– H or Fe-O, Si–O–Si, and C=O species, respectively (Figure 5(b)).40,41 The N1s core levels of PAMAM-Fe3O4/HNTs exhibited a sharp spectrum that divided into two deconvoluted peaks at 400.0 and 401.3 eV, corresponding to the N-C(sp3) and N-C(sp2) bonds, respectively (Figure 5(c)). These results acknowledged again that the PAMAM-Fe3O4/HNTs surface was successfully modified with the amine groups that are found at the end of the branches of the functional PAMAM-dendrimer. We further studied the interaction of adsorbed heparin molecules on the PAMAMFe3O4/HNTs in order to study the mechanism of the heparin adsorption process. The highresolution C1s spectra of PAMAM-Fe3O4/HNTs@heparin showed some changes related to 13 ACS Paragon Plus Environment


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the PAMAM-Fe3O4/HNT spectrum. The peak at 284.8 eV was broadened and the intensity of the peaks at 288.8 and 289.9 eV decreased and increased, respectively, which could be related to the adsorption of heparin molecules (Figure 5(d)). For the O1s core level of PAMAM-Fe3O4/HNTs@heparin, a new peak at 531.7 eV appeared, which we assigned to the S-O group of heparin (Figure 5(e)).42,43 The high-resolution XPS N1s spectrum of PAMAMFe3O4/HNTs@heparin shown in Figure 5(f) displays a new sharp peak at 403.1 eV in comparison to the N1s core level of PAMAM-Fe3O4/HNTs. The new component could result from the protonated -NH2 groups (-NH3+) generating salts with -SO-4 functional groups of the heparin molecules.43-45 The S2p region of PAMAM-Fe3O4/HNTs@heparin presented one broad peak (Figure 5(g)), where the signal was deconvoluted into two peak components at 164.4 eV and 167.0 eV, which could be attributed to the sulfate groups of adsorbed heparin, further confirming the adsorption of heparin and the strong interaction of sulfate groups with the amine groups of the PAMAM-Fe3O4/HNTs. We assessed the influence of ionic strength on the adsorption capacity of PAMAMFe3O4/HNTs towards heparin with the addition of 0.5-4 mol/L NaCl (Figure 5 (h)). With an enhance in the NaCl concentration the adsorption capacity was expectantly diminished and fell to zero in the presence of saturated NaCl. Furthermore, the zeta potential of PAMAM-Fe3O4/HNTs during the adsorption of heparin was evaluated as a function of time (Figure 5(i)).46 The surface positive charge of the PAMAM-Fe3O4/HNTs after exposure to heparin decreased and became negative after 100 min reaction time, which further confirmed the interaction of the -NH2 groups of the PAMAM- dendrimers with the reactive functional groups (-SO4-, -NHSO3-, COO-) of heparin. These findings demonstrated that the functionalized amine groups on the surface of the HNTs were capable to highly interact with the sulfate groups of heparin due to the strong electrostatic interaction and the unique advantages afforded by the structure of the HNTs, such as high porosity, high surface area, and chemically active external and internal surfaces.


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Figure 5. High resolution (a,d) C1s, (b,e) O1s, and (c,f) N1s XPS spectra of PAMAMFe3O4/HNTs and PAMAM-Fe3O4/HNTs@heparin, respectively and (g) S2p spectrum of the PAMAM-Fe3O4/HNTs@heparin. (h) The effect of NaCl on adsorption capacity (qe, mg/g) of PAMAM-Fe3O4/HNTs towards heparin. (i) The zeta potential of PAMAMFe3O4/HNTs@heparin as a function of time.

Adsorption kinetic studies. We studied the kinetics of heparin adsorption by PAMAMFe3O4/HNTs for various initial concentrations of the targeted molecule using two kinetic models (the pseudo-first-order and pseudo-second-order) and one diffusion model (WeberMorris; Table S1 of the Supporting Information) in order to elaborate the mechanism of heparin adsorption as a function of reaction time. The calculated kinetic variables for the adsorption of heparin by PAMAM-Fe3O4/HNTs are shown in Table 1. We compared the fitting of the obtained reaction time data for all models by comparing the correlation coefficients (R2) of their linear plots. As can be observed in Table 1, heparin adsorption by PAMAM-Fe3O4/HNTs at various concentrations followed a pseudo-second-order sorption rate most closely (R2> 0.959), with good agreement between the theoretically estimated adsorption capacities, with the experimentally determined ones, qexp (Figure 6(a)). This result confirms that the heparin adsorption mechanism by PAMAM-Fe3O4/HNTs is related to the adsorbate and adsorbent and that chemisorption is the rate-limiting rate-controlling step involving valence forces via the exchange and or sharing of electrons.47 Moreover, the initial adsorption rate and equilibrium rate constant increased as we elevated the initial heparin concentration, which supports our hypothesis that a high heparin concentration increases the driving force of heparin adsorption and that the recovery of heparin from aqueous solution by PAMAM-Fe3O4/HNTs occurs via a chemisorption mechanism.


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Table 1. Kinetic variables for the heparin adsorption by PAMAM-Fe3O4/HNTs at various initial concentrations of heparin. Pseudo-second-order Intra-particle Pseudo-first-order constants diffusion constants constants Co (m qe,exp Kint h g (mg k1 q1 k2 q2 (mg (mg L- g-1) (min− (mg (g R2 (g (mg (mg (g R2 I R2 1 1 -1 -1 -1 1/ ) min g ) min) ) g ) min) ) 1 2 -1 ) ) ) 0.16 0.74 52.7× 1 2.71 0.38 0.96 0.15 0.97 10 2.5 27.03 0.330 −3 53 91 8 95 55 68 72 0 0.28 0.76 26.6× 1 4.93 0.64 0.95 0.595 0.24 0.98 20 4.56 27.93 −3 86 04 5 94 91 8 31 36 0 0.49 0.61 37.8× 1 6.06 1.39 0.98 0.737 0.69 0.93 5.82 30 19.57 −3 25 21 61 4 3 68 5 46 08 0 0.69 0.50 47.6× 1 6.99 2.32 0.99 1.08 0.84 40 6.87 15.75 0.845 15 99 3 9 32 9 5 0−3 0.78 0.48 65.2× 1 7.38 3.55 0.99 0.897 1.32 0.84 7.19 60 14.95 75 48 45 5 9 7 6 5 37 0−3 However, the first-order and pseudo-second-order kinetic models cannot interpret the diffusion mechanism of heparin on the adsorbent, therefore we applied the Weber and Morris intra-particle diffusion model to explain the kinetics of heparin adsorption.48 If intra-particle diffusion was the only rate limiting step, the regression of qt vs. t1/2 should be linear and pass through the origin. However, if there is multi-linearity in the intra-particle diffusion plot, other processes, such as equilibrium adsorption and surface diffusion, can also be rate controlling steps. The full process of heparin adsorption can be described by four main steps: (1) heparin molecules migrate from the bulk solution to the PAMAM-Fe3O4/HNTs surface through bulk diffusion;49 (2) diffusion of heparin through the framework of the dendrimer; (3) intra-particle or pore diffusion of the heparin; and (4) chemical interaction or complex generation.50 The slowest of these steps will affect the overall rate of the adsorption process.49 The intra-particle diffusion plots we obtained by the Weber and Morris model are illustrated in Figure 6(b). The intra-particle diffusion parameters and piecewise linear nature plots were found by plotting qt vs. t1/2, implying that two distinct diffusion steps control the adsorption process. Therefore, intra-particle diffusion of heparin molecules on the surface of PAMAMFe3O4/HNTs could be partially performed through the intra-particle diffusion mechanism.51,52 It can be observed from Table 1 that the rate constants for intra-particle diffusion increased with increasing initial heparin concentrations, which could be related to the external surface 17 ACS Paragon Plus Environment


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adsorption or boundary layer effect, which itself could be explained from the significant effect of the driving force at higher initial concentrations of heparin.53 Additionally, the value of I in the second portion of the Weber and Morris equation is associated to the thickness of the boundary layer (Table S1),54 where a higher value of I (Table 1) implies that there is a superior influence of the boundary layer on heparin diffusion across the active sites of the PAMAM-Fe3O4/HNT surface.55 Thus, higher values for the intercept of the Weber and Morris equation at higher concentrations of heparin indicate the controlling effect of surface diffusion as the rate controlling step of heparin adsorption, where for lower thicknesses of the boundary layer of the dendrimer the adsorption mechanism proceeds through external mass transfer, eventually followed by intra-particle diffusion mass transfer.

Figure 6. (a) Pseudo-second-order, (b) intra-particle diffusion kinetic models, (c) adsorption isotherms, and (d) plots of ln(K) vs. 1/T for the heparin adsorption by PAMAMFe3O4/HNTs. Equilibrium isotherm studies. The adsorbent functional group design strongly depends on our knowledge and understanding of the specific interaction of the sorbate/adsorbent at equilibrium and also the adsorption degree of the sorbate onto the solid phase at a constant 18 ACS Paragon Plus Environment

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temperature. One of the best ways to clarify adsorption mechanisms is using equilibrium isotherms. We evaluated the equilibrium results using the Freundlich, Langmuir, and Sips isotherms, in which the plots and isotherm constants are revealed in Figure 6(c) and Table 2, respectively. The Freundlich model describes physical adsorption on heterogeneous surfaces featuring a heterogeneous energy distribution, whereas the Langmuir model represents monolayer adsorption on homogenous sites.56,57 Our experimental equilibrium results of heparin adsorption by PAMAM-Fe3O4/HNTs were best fit with the Langmuir isotherm (Table 2 and Figure 6(c)), which implies that the chemisorption of heparin occurs in a monolayer onto identical active sites of PAMAM-Fe3O4/HNTs with similar affinities, and that the adsorption of heparin could be a heterogeneous catalytic reaction, in which the surface reaction is the rate controlling step.58

Table 2. Equation parameters of the Langmuir, Freundlich, and Sips fittings to the initial heparin concentration results. KL KF n R2 Isotherm models qm Langmuir 10.42 0.9910 4.98× 10−1 Freundlich 1.255 2.172 0.9707 −2 −1 0.9977 8.184 Sips 6.43× 10 1.86× 10 Adsorption thermodynamic studies. Based on the equilibrium data determined from the effect of different temperatures, we calculated the entropy change (∆S, J/(mol K)) enthalpy change (∆H, J/mol), Gibbs free energy change (∆G, J/mol), and of the adsorption process of the PAMAM-Fe3O4/HNTs toward heparin using the Gibbs (1) and van’t Hoff (2) equations:59,60 ∆G = −RT lnK

(1)

lnK = ∆So/R-∆Ho/RT

(2)

in which R (8.314 J (mol·K)-1) is the ideal gas constant, T (K) is the temperature, and k (L g1

) is the distribution coefficient of the adsorbate (qe Ce-1). We obtained the ∆H and ∆S values

from the slope and intercept of the linear plot of lnK vs. 1/T (Figure 6(d)). The linear R2obtained from the van’t Hoff plot shown in Figure 6(d) at different times were over 0.96, making the assessment of the obtained values of ∆H and ∆S based on Eq. (2) reasonable and feasible. With increasing reaction temperature, the value of ∆G was negative, which confirms that adsorption of heparin by PAMAM-Fe3O4/HNTs is spontaneous and thermodynamically feasible (Table 3). The ∆H for the uptake of heparin was negative, demonstrating that the adsorption of heparin onto the active sites of the PAMAM-Fe3O4/HNTs is exothermic in 19 ACS Paragon Plus Environment


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nature, likely because of the electrostatic interaction between the materials.61 The positive ∆S value suggests the spontaneous adsorption of heparin onto the PAMAM-Fe3O4/HNTs, which implies the entropy of the system increases after adsorption, possibly due to the disorganization and release of several water molecules. The positive ∆S value also indicates the strong tendency of heparin adsorption toward the PAMAM-Fe3O4/HNTs, which results in increased randomness at the solution-solid interface.62

Table 3. Thermodynamic variables for the heparin adsorption by PAMAM-Fe3O4/HNTs as a function of temperature. -∆Ho ∆So -∆Go (kJ·mol-1) Time (J (mol K)298 308 318 328 338 (min) (J mol-1) 1 ) 10 0.5279 2.068 616.9 637.6 658.3 679.0 699.6 20

0.5412

2.204

657.3

679.3

701.4

723.4

745.5

30

0.4963

2.115

631.0

652.1

673.3

694.5

715.6

40

0.5196

2.229

665.0

687.3

709.6

731.8

754.1

50

0.5237

2.263

674.9

697.5

720.1

742.8

765.4

60

0.5146

2.250

671.1

693.6

716.2

738.7

761.2

Reusability. We also studied the reusability of the PAMAM-Fe3O4/HNTs and compared to the Amberlite FPA98 Cl resin, as it is an important factor for decreasing the cost of practical applications (Figure 7(a)). Between each heparin exposure cycle, we treated the nanotubes with saturated NaCl (see Section 2.5). After regeneration, the PAMAM-Fe3O4/HNTs were exposed to a fresh heparin solution (50 mg L-1). The results disclosed that the adsorption efficiency of the PAMAM-Fe3O4/HNTs towards heparin gradually decreased after several of these cycles. However, even after several uses, the adsorption efficiency of the PAMAMFe3O4/HNTs was still higher than the Amberlite FPA98 Cl resin. The adsorption capacity of fresh PAMAM-Fe3O4/HNTs was 5.82 mg/g. Under the similar operational conditions, the heparin adsorption capacities of PAMAM-Fe3O4/HNTs in the 2nd and 7th adsorption cycles were 5.04 and 4.52 mg/g, respectively. After seven cycles of consecutive adsorptiondesorption processes, the adsorption capacity remained at 77.66% of the initial adsorption capacity value. These results confirm the reusability of the PAMAM-Fe3O4/HNTs adsorbent prepared in the work and demonstrate that the PAMAM-Fe3O4/HNTs can be regenerated 20 ACS Paragon Plus Environment

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using saturated NaCl. In addition, the PAMAM-Fe3O4/HNTs can be completely collected from solution within 10 s by utilizing an external magnetic field (Figure 7(b)). Therefore, the PAMAM-Fe3O4/HNTs feature high stability and reusability along with excellent magnetic separation, all of which are significant advantages for economic recovery of heparin.

Real sample test. Figure 7(c) compares the adsorption rate (%) and equilibrium adsorption capacity (qe, mg/g) of heparin PAMAM-Fe3O4/HNTs and Amberlite FPA98 Cl resin for a real sample composed of heparin digested from porcine intestinal mucosa (500 mg L-1). Base on the results obtained for the real sample experiments, the adsorption capacity and adsorption rate of heparin by PAMAM-Fe3O4/HNTs are higher than the Amberlite FPA98 Cl resin, commercially used adsorbent in heparin extraction processes.

Figure 7. (a) Adsorption-desorption cycles of PAMAM-Fe3O4/HNTs and Amberlite FPA98 Cl for heparin recovery. (b) The magnetic separation of heparin-loaded PAMAM21 ACS Paragon Plus Environment


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Fe3O4/HNTs by a magnet. (c) Adsorption capacity (qe, mg/g) and adsorption rate (%) of heparin in a real sample in the presence of PAMAM-Fe3O4/HNTs vs. Amberlite FPA98 Cl resin (NaCl concentration 0.7 mol/L and pH 9).

Economic Evaluation. In addition to efficient activity, economic cost is another key determinant of whether a new system can be used for a commercial process, such as heparin extraction. HNTs are a low-cost mineral (US$ 4/kg), and our initial estimations indicate that the cost of the post-modifications including Fe3O4, 3-APTES, and PAMAM is about US$ 20– 25/kg. The combined price of the modified HNT product is still considerably lower than the Amberlite FPA98 Cl resin (US$ 135/kg), enabling the use of this environmentally friendly material in the selective, efficient recovery of heparin.

CONCLUSIONS Here, we described a novel idea for the preparation of novel multi-amine terminated dendrimer-functionalized HNTs for the selective, scalable recovery of heparin. The HNTs were used as the support and 3-APTES was functionalized onto the nanotube surface to activate the silanol groups, followed by successful functionalization with PAMAM. The HNTs were further decorated and magnetized with Fe3O4 nanoparticles to allow the materials to be magnetically separated from a solution mixture. The spectroscopic and imaging data verified that the strategy used for fabrication was able to successfully prepare PAMAMFe3O4/HNTs. Next, the comparative adsorption efficiency of the PAMAM-Fe3O4/HNTs toward heparin was evaluated in comparison with Amberlite FPA98 Cl resin, commercially used adsorbent in heparin extraction processes. The PAMAM-Fe3O4/HNTs showed higher heparin adsorption efficiency, both in terms of the capacity (5.82 mg/g) and adsorption rate (77.63%) compared to the Amberlite FPA98 Cl resin, which we hypothesized was due to the unique advantages afforded by the nanotube structure and the abundant amine terminated groups of PAMAM. The zeta potential of PAMAM-Fe3O4/HNTs was positive at a wide pH range, with an isoelectric point at pH 10.2. The XPS and zeta potential results confirmed that the –NH3+ functional groups on the surface of the PAMAM-Fe3O4/HNTs were highly activated toward the sulfate group of heparin due to the strong electrostatic interaction. We investigated different isotherm and kinetic models for the equilibrium adsorption of heparin by PAMAM-Fe3O4/HNTs, with the pseudo-second-order kinetic model and the Langmuir 22 ACS Paragon Plus Environment

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isotherm model providing the best fit to the equilibrium data. We also demonstrated that the modified HNTs can be recovered using saturated NaCl solution and employed for recurring heparin adsorption without substantial loss in adsorption capacity. In addition, the heparinloaded PAMAM-Fe3O4/HNTs can be completely collected from solution within 10 s by utilizing an external magnetic field. Because of this reusability and separations efficiency, we posit that the PAMAM-Fe3O4/HNTs can be utilized as an efficient and low-cost adsorbent for the selective recovery of heparin at large scale.

ACKNOWLEDGMENTS This work made use of the Cornell Center for Materials Research's Shared Facilities, which are supported through the NSF MRSEC program (DMR-1719875). This publication was made possible by the research funding provided by Shineway (WH Group, China).

SUPPORTING INFORMATION Experimental section including materials, fabrication of PAMAM-functionalized Fe3O4decorated HNTs, adsorption experiments, and recovery of PAMAM-Fe3O4/HNTs. Adsorption isotherm and kinetics equations. XPS wide-scan spectra of PAMAMFe3O4/HNTs and PAMAM-Fe3O4/HNTs@heparin.

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Graphical Abstract

Magnetic dendritic halloysite nanotubes were prepared and used for highly selective recovery of heparin digested from porcine intestinal mucosa.


Magnetic Dendritic Halloysite Nanotube for Highly Selective Recovery

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