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Magnetic and heating aptitudes of PEG coated La0.73Sr0.27MnO3 and La0.67Sr0.33MnO3 mediators towards hyperthermia methodology
Physica B: Condensed Matter 564 (2019) 125–132
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Magnetic and heating aptitudes of PEG coated La 0.73Sr0.27 MnO3 and La 0.67Sr0.33 MnO3 mediators towards hyperthermia methodology
T
Afsheen Sultana Khana, Nasir Mehbooba, Muhammad Farooq Nasira,∗, Asif Hamayunb a b
Department of Physics, RIPHAH International University, Islamabad 44000, Pakistan Magnetism Laboratory, Department of Physics, COMSATS University, Islamabad 44000, Pakistan
A R T I C LE I N FO
A B S T R A C T
Keywords: Functionalized Lanthanum strontium manganite Citrate-gel route Super-paramagnetic nature Saturation magnetization External radio frequency field Hyperthermia methodology
In the present study functionalized mediator of Lanthanum strontium manganite (LSMO) has been investigated for magnetic fluid hyperthermia (MFH) applications. Perovskite structured (La1 −x Srx MnO3 ) employing two Sr concentrations (x = 0.27 & 0.33) were attempted to coat with long chain structured polymer named Polyethylene glycol (PEG- 6000 g/mol) by adopting novel concentrations (5% & 14% w/v) in order to assess a detailed comparison of the effect of concentration of same coating material on two different LSMO's series. The Citrate-gel route was adopted to synthesize LSMOs nanoparticles (NPs). XRD revealed the super-paramagnetic (SPM) nature of synthesized NPs showing an approximate crystallite size of ∼17 nm. The LSMOs tailored with PEG showed an effective bonding of polymer with NPs exhibited by FTIR spectra. The magnetic parameters of coated NPs subjected to VSM at room temperature displayed an appreciable saturation magnetization and very slight coercivity owing to their SPM behaviour. During each synthesis, the relative proportions of polymer attached to LSMOs were evaluated through TGA analysis accompanied by DTA studies showing successive decomposition processes. The induction heating behaviours of NPs under an external radio frequency field displayed quite an appreciable approach for required Hyperthermia efficacy in the required range of 40–60 °C. Besides this, the coated NPs were dispersed in normal saline as an innovative try forming a ferro-fluid (∼19 mg/ ml) and showed considerable approach towards induction heating for the destruction of cancerous cells employing hyperthermia methodology.
1. Introduction Magnetic nanoparticles (MNPs) have been pursuing extreme significance in numerous fields for the last few decades. Their amazing multidimensional roles have now become unavoidable building blocks in most popular scientific fields of the present era like bioengineering, biomedicine, clinical therapy applications [1], bio-separation [2], magnetic resonance imaging (MRI), magnetically targeted drug delivery mechanism and magnetic hyperthermia cancer therapy [3–5]. Among them, magnetic fluid Hyperthermia (MFH) has been aggravating as the most challenging methodology regarding the possible destruction of tumorous cells in a specific temperature range, using NPs since 1957 [6]. MFH is based on the heat released by MNPs under the action of the external field [7–14]. The method involves the introduction of magnetic particles (mediators) stabilized by biocompatible surfactants into the selected site of the body and heating them by applying an external electromagnetic field of suitable radio-frequency range [15]. The high efficiency of MNP's suspension to absorb energy
∗
from the applied field and convert it into heat has been proved by various experiments. Moreover, tumor cells are more sensitive to heat as compared to healthier ones, so they can be easily destroyed through localized heating, having less effect on healthy tissues surrounding them during the treatment [3] which is the most attractive feature of MFH. It is an alternative treatment to destroy cancerous cells through thermal deterioration at a specific temperature range ∼(42 °C–46 °C) which harmonizes the adverse effects of chemotherapy and radiotherapy [13]. Up to now quite a lot of MNPs have been examined in this perspective like magnetite, maghemite, Spinel Ferrite, Sr-hexaferrite phases, Cobalt-Zinc Ferrites etc. Among them, certain reservations have been observed regarding the use of magnetite, ferrites, and maghemite [1,7,16] due to their high Curie temperature ∼(85–227 °C), large retentivity, over-heating, etc. which makes them dangerous for healthier tissues of the body. La1 −x Srx MnO3 (LSMO) NPs known as manganites have been emerging as surprising mediators towards hyperthermia treatment owing to their exclusive characteristics such as high SAR value, super-paramagnetism with minimal hysteresis loss and larger
Corresponding author. E-mail address: [email protected] (M.F. Nasir).
https://doi.org/10.1016/j.physb.2019.03.039 Received 26 November 2018; Received in revised form 4 March 2019; Accepted 29 March 2019 Available online 03 April 2019 0921-4526/ © 2019 Elsevier B.V. All rights reserved.
Physica B: Condensed Matter 564 (2019) 125–132
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saturation magnetization under the external magnetic field. Moreover, through controlled doping Sr concentration in LSMOs, adjustable Curie temperature is approachable in required therapeutic hyperthermia range (42–46 °C) [17–20]. All of these mentioned features demonstrate LSMOs' worth as excellent mediators for self-regulated hyperthermia. The most mandatory step, which is to be followed for satisfactory invitro and in-vivo applications of LSMO NPs is their appropriate coating by most suitable biocompatible polymers. Studies have shown that in order to attain higher SAR values employing MNPs, it is inevitable to prevent their agglomeration in aqueous suspension. This leads towards the improved colloidal stability of mediators for effective intravenous hyperthermia applications avoiding their immediate uptake by the body's reticuloendothelial system (RES). One of the most appropriate coating agents considered for improved colloidal stability, biocompatibility and SAR value of MNPs, is PEG ((C2 H 4 O)n+1. H2 O) due to its highly hydrophilic nature, nontoxicity, non-immunogenicity and flexibility. PEG is appreciably known as a protein-resistant polymer and reduces the macrophages uptake in biomedical applications thus prolonging blood circulation times [14,21–24]. It has hydrophilic molecules chains, which leads to a good dispersion in aqueous medium i.e. water. It is widely applied as a pharmacological product because it is highly soluble in polar and some non-polar solvents. Moreover, the selection of adequate molecular weight (preferably not greater than 10,000 g/mol) of PEG helps to avoid agglomeration of NPs. The main focus of the study under consideration was to coat two series of LSMO by opting unique weight to volume (w/v%) concentration amounts of PEG in order to evaluate a detailed insight of their response towards add-on polymers for hyperthermia mechanism.
solution was chosen to be 14% as a try. 16.8 mg of solid PEG-6000 crystals were added in 120 ml of DDW and dissolved at 115 °C on a hot plate. 167 mg of LSMO powder was sonicated in 150 ml of DDW to get proper dispersion and then slowly poured PEG solution into it to get a combined 250 ml solution followed by sonication for a few moments. This solution was put to continuous heat at 63 °C for 1 1 h and then at 2 105 °C for almost 2 h. It was kept overnight to cool down and then put 1 to slow stirring for almost 2 hours, using a magnetic stirrer. Resulting 2 particles were washed thrice with DDW, once with acetone (4000 rpm) and were dispersed in acetone keeping for few days till complete drying. Final NPs were named PEG2 (14% w/v @ LSMO) onwards. 2.3. Sample's specifications The four coated samples of LSMO NPs can now be presented below precisely with particular labels for future correspondence.
• LSMO coated with 5% PEG concentration. • LSMO coated with 14% PEG concentration.
(PEG 1) (PEG 2)
2. Experimental section 2.1. Synthesis of LSMO The Citrate-gel process [25] was adopted for the preparation of both series of LSMO NPs. Nitrates of strontium and Lanthanum (Sr(NO3)2 , La(NO3)3. 6H2 O) beside manganese acetate (C4 H6 MnO4 . 4H2 O ) were mixed in double distilled water (DDW) for preparation of a 0.2 M solution and synthesized by following the method reported earlier in our recent study [8]. 2.2. Functionalization routes of LSMO NPs with PEG 2.2.1. Procedure of route 1 This method was first applied to coat La 0.7Sr0.3MnO3 with PEG taking w/v % of polymer solution as 2%, 3.5% and 5% [21]. In the present study, 5% PEG concentration was chosen to coat La 0.73Sr0.27MnO3 and La 0.67Sr0.33MnO3 , adopting the same method as reported earlier but here with slight modifications in coating amounts and also with different values of Sr concentrations in LSMOs series, to investigate new behaviours of mediators. 5 mg of PEG flakes (molecular weight 6000 g/mol, Fluka) were taken and dissolved in 100 ml of DDW at 100 °C till complete dissolution. Meanwhile, 143.7 mg of LSMO fine particles were dispersed in 150 ml of DDW through sonication and prepared PEG solution was then slowly poured into it. Total solution of 250 ml was put on a hot plate with a constant heat of 100 °C for 2 h. This solution was cooled down overnight and then subjected to constant stirring at 1 800 rpm for almost 7 2 hours. These particles were washed twice with deionized water and once with acetone (4000 rpm) and again dispersed in acetone. After few days, final dried particles were obtained and named as PEG1 (5% w/v @ LSMO) afterwards.
2.4. Instrumentation specifications The XRD signatures of as-synthesized pure NPs were attained using Cu-Kα radiation of wavelength λ = 1.54 A° employing (X-Pert Philips X-ray diffractometer) having 2°/minute angular scan from 20° to 80°. The presence of PEG on the surface of LSMOs was determined by FTIR impressions using (Shimadzu IR–Tracer 100) spectrometer in the midInfrared region 400–4000 cm−1. The magnetic measurements at room temperature were evaluated by MH- curves in a range (0–10 kOe) with 7400 Lakeshore magnetometer. The induction heating studies of samples both in solid and suspension forms, at 513 kHz external field (15.9 kA/m), were evaluated in detail (Magnetherm Nanotherics). Thermogravimetric studies were done using (PerkinElmer TGA) and
2.2.2. Procedure of route 2 This experimental try was done to study the effect of increasing PEG concentration with reduced time duration on the surface coating of LSMOs. According to a study, 10–20% PEG concentration can be taken for surface modification of NPs. So in this method, (w/v) % ratio of PEG 126
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Fig. 1. XRD signatures of pure LSMO with Sr content (a) (0.27) (b) (0.33) annealed at 700 °C.
(Mettler Toledo TGA) in order to find out the relatively attached amount of polymer on NP's surface followed by their decomposition mechanisms, at heat increment of 10 °C/min (up to 800 °C) under a nitrogen atmosphere. 3. Results and discussion 3.1. Structural analysis The polycrystalline patterns of LSMOs (0.27 & 0.33) 700 °C annealed, corresponding to different crystallite planes are presented by their XRD analysis in Fig. 1. The indexing of prominent peaks was figured out to be in quite good agreement with their Joint Committee on Powder Diffraction Standards (JCPDS) reference card numbers (00056-0616) and (89–4466) for LSMO (0.27) and LSMO (0.33) respectively [26]. The comparison reveals no impurity peaks and perovskite phase of samples. The nature of the crystalline structure of both LSMOs was found to be rhombohedral having group number 167 (space group La 0.73Sr0.27 MnO3 R-3c). The lattice dimensions of are a = b = 0.5500 nm, c = 1.33491 nm and those for La 0.67Sr0.33 MnO3 are found to be a = b = 0.5495 nm and c = 1.3372 nm. Furthermore, the broadened peaks presented in XRD patterns provide an indication of the nano-crystalline phase of annealed samples. The crystallite sizes are evaluated employing Debye-Scherrer formula,
dXRD
K λ = β cosθ
Fig. 2. FTIR signatures of PEG coated samples (a) LSMO (0.27) (b) LSMO (0.33).
(1)
cm−1 of LSMO is due to its OeCeO bond. This peak shifts slightly at 2316 cm−1 and 2341 cm−1 for samples PEG1 and PEG2 respectively. For pure PEG polymer, the peak at 962 cm−1 belongs to the stretching of the CeO bond and shifts at 960 cm−1 in FTIR curve of coated sample PEG1@LSMO [21]. The bands existing at about 1278 cm−1 and 1462 cm−1 correspond to eCH2 twisting and the eCH2 vibration of pure PEG6000 respectively [22,29] and it is exactly at 1278 cm−1 in coated PEG1 sample showing the presence of PEG on NPs. The absorption band at 1147 cm−1 is ascribed by the CeO and CeC stretching bonds of PEG polymer and are present at ∼1140 cm−1 and 1159 cm−1 for coated samples PEG1 and PEG2 respectively [21,22,29]. Moreover, the band observed at ∼2897 cm−1 is attributed to the specific CeH stretched vibrations in PEG [21] and shifts to about 2812 cm−1 in the modified PEG2 sample. All these peaks show the satisfactory attachment of PEG molecules to LSMO (0.27) surface. FTIR marks of coated La0.67 Sr0.33 MnO3 are displayed in Fig. 2(b).
The most intense peaks are located at 2θ = 32.77° and 2θ = 32.80° for LSMO (0.27) and (0.33) respectively with average crystallite sizes of ∼18 nm and 17 nm respectively showing excellent agreement with those reported by Daengsakul [27]. Moreover, the average particle size of ∼17 nm confirmed the required super-paramagnetic nature of annealed NPs so the heat dissipated by them could be focused more to be due to Neel's relaxation [15,28] as compared to hysteresis losses. 3.2. FTIR discussion The attachment of PEG on the surface of NPs for two LSMOs’ series is presented by Fig. 2(a) and (b). Fig. 2(a) illustrates the surface modification of LSMO (0.27), along with signature peaks of pure PEG-6000, displayed here for comparison. The impression of uncoated LSMO at 1464 cm−1 refers to the presence of carbonates while that at 1647 cm−1 shows the adsorption of water [19,21,26]. The strong peak at ∼2360 127
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coating route polymer's connection to the surface of MNPs has been established successfully. 3.3. VSM studies The powdered samples (both uncoated and coated) were subjected to the external magnetic field (0–10,000 Oe) at room temperature employing Lakeshore VSM to study their magnetic properties. The attained M-H curves are presented in Fig. 3(a) and (b) for the two series of samples respectively, exhibiting their saturation magnetization (Ms) with respect to the applied field, where saturation magnetization accounts for the highest achieved value of magnetic moment per unit mass of the sample. All samples were taken to be in equal mass ∼8 mg. The curves describe the SPM behaviour of all samples showing an evident saturation magnetization up to 15 emu/g. This value is quite substantial at room temperature as it is known that the value of (Ms) decreases by increasing temperature and it tends to increase with particles’ size. In the present study, the size restriction of NPs is the utmost requirement for bio-medical applications hence, observed values of magnetization are quite appreciable. In addition, all samples are displaying SPM curves with very narrow hysteresis loops for slight coercivity (Hc) of ∼50 Oe and minor retentivity (Mr), essentially desired for hyperthermia applications. The sample named as PEG1 is found to have a slight reduction in (Ms) as compared to bare LSMO (0.27) in Fig. 3(a). This effect might be attributed to the polymer's existence on the NPs exterior which is responsible for the decrease in their magnetic coupling, proportional to the amount of polymer adsorbed there [11,12,21]. But the same PEG1 shows a slight overlapping M-H curve with the bare LSMO (0.33) in Fig. 3(b), showing approximately same saturation magnetization aptitude. Surprisingly, the sample named as PEG2 has shown a quite different behaviour of slight enhancement in saturation magnetization than bare LSMOs in both Fig. 3(a) and (b). Such kind of results has also been reported earlier for La 0.67Sr0.33MnO3 modified by polypyrrole and also for oleic acid coating on magnetite respectively [30,31]. This behaviour can be attributed to the charge transfer process that occurs between the conducting polymer and the layers of LSMO NPs. The π electron pairs of carbon chains of polymer (PEG) travels below to the surface of NPs and substitute the missing oxygen p-orbitals there, resulting in enhancement of double exchange mechanism between Mn+3 and Mn+4 states of LSMO [30]. This finally appears as an increased saturation magnetization in 14% PEG-coated samples as shown below (see Table 1). The important magnetic descriptions of both LSMOs’ series from respective M-H curves are summarized in Table 2. It is quite noticeable that uncoated LSMO (0.27) achieves slightly higher saturation magnetization as compared to LSMO (0.33). The stronger magnetic dipole moment interactions among NPs could be attributed to being responsible for this enhanced (Ms) in LSMO (0.27) as compared to that for LSMO (0.33). In the structural composition of LSMO, Strontium being a divalent ion (Sr +2 ) is responsible for the creation of increased vacancies at Mn+4 sites in the sample leading to enhanced double exchange interaction [8,32]. Interestingly the double
Fig. 3. M-H curves of samples (a) LSMO (0.27), (b) LSMO (0.33) at room temperature.
The rightmost peak of uncoated LSMO at 428 cm−1 is related to the bending of the MneOeMn bond angle whereas its most characteristic peak at 580 cm−1 belongs to the stretching mode of metal-oxygen bond owing to the internal change in the MneOeMn bond length of MnO6 octahedra [11,19,26,27]. Also the band at 868 cm−1 is attributed towards the CeO bond due to atmospheric CO2, reported by Ref. [19]. The most prominent peak of pure PEG-6000 at 842.9 cm−1 in Fig. 2(b) belongs to its eCH2 swinging bond [21,29] which is shifted to 858 cm−1 in both PEG-coated samples as shown. Furthermore, the various bands' vibrations at 418, 457, 472, 528, 569 cm−1 etc. exhibit the adequate existence of PEG on LSMO NPs. All these curves illustrate that in each
Table 1 Review of important FTIR impressions. Absorption Peaks (cm−1)
Specifications of concerned functional groups
References
428 580 842 962 1147 1278, 1462 2360 2897
(MneOeMn) bond angle variation of pure LSMO (MneOeMn) bond length variation of pure LSMO (eCH2) swinging bond of pure PEG (CeO) stretching of pure PEG (CeO) and (CeC) stretching of pure PEG (eCH2) twisting & (eCH2) vibration of pure PEG (OeCeO) stretched vibrations of pure LSMO (CeH) stretched vibrations of pure PEG
[19,26] [11,19,21,27] [21,29] [21] [21,22,29] [22,29] [36] [21]
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Table 2 Summarized magnetization statistics of NPs. Sample
Uncoated PEG1 PEG2
La 0.67Sr0.33 MnO3
La 0.73Sr0.27 MnO3 Ms (emu/ g)
Mr (emu/ g)
Hc (Oe)
Ms (emu/ g)
Mr (emu/ g)
Hc (Oe)
13.39 9.64 14.45
0.761 0.524 0.786
58.83 57 57
10.527 10.55 14.96
0.461 0.478 0.594
50.21 52.07 39.6
exchange interaction gradually decreases with increasing Sr doping fraction, due to the insufficiency of hopping electrons which is believed to be responsible for the slight reduction of magnetization in LSMO (0.33) [33,34]. On the other hand, it is quite obvious to see that particles have better aptitudes towards reduced Mr and Hc for LSMO (0.33) samples than LSMO (0.27) but astonishingly PEG2 coated samples have exhibited high magnetization for both series. 3.4. Induction heating analysis at radio frequency To analyze the mandatory hyperthermia heating aptitude of both bare and coated samples in response to an external magnetic field, the same amount of fine powder for all samples were subjected to an RF induction unit. Each sample was put in ∼1.5 ml plastic vial surrounded by a polystyrene jacket thick enough for the essential adiabatic magnetic heating measurements. The temperature rise of NPs was recorded by a fibre optic temperature sensor which was well inserted inside the sample's column. The whole set-up was introduced at about central axis of an induction coil having 9 turns. Trying to maintain the temperature of the coil, the induction unit was coupled to a chiller for continuous water circulation so that the heat produced by MNPs could have been analyzed properly. The adiabatic thermal curves of magnetic NPs were attained under an alternating field (513 kHz, 15.9 kA/m). The selection of a frequency for hyperthermia treatment is made on the fact that it should be preferably greater than 50 kHz to avoid skeletal muscles' simulations and lower than 2 MHz for adequate penetration depth inside tissues [3,9]. Furthermore, the single domain NPs are supposed to possess comparatively reduced Neel's relaxation times than large-sized particles hence generating better SAR values at a higher frequency as reported earlier [3,8]. Therefore the two series of samples in the current study were decided to be examined at 513 kHz to explore their hyperthermia efficacy and exhibited through Fig. 4 (a) and 4(b).
Fig. 4. Thermal curves of PEG coated samples (a) LSMO (0.27) (b) LSMO (0.33).
3.4.2. Estimation of SAR value In hyperthermia study one of the most vital features of LSMO NPs is their Specific Absorption Rate (SAR) which approximates their spontaneous response towards applied frequency. SAR is defined to be the capability of NPs to generate heat, resulting by the rapid flipping of their magnetic moments under an external alternating field [8,21]. It is also defined as the amount of heat dissipated per unit mass of the magnetic sample in an applied RF field [17]. In hyperthermia treatment, NPs having large SAR values are the utmost desire for destroying tumorous cells [17,35]. The following formula is applied to calculate SAR value,
3.4.1. Analysis of hyperthermia aptitude The obtained results came out to be quite satisfactory in achieving the required hyperthermia therapeutic range (42–45 °C) showing the active response of examined samples at the selected frequency. Maintaining the same insulating conditions, the responses of sample LSMO (0.33) are revealed to be more swift than that of LSMO (0.27). This illustrates that La 0.67Sr0.33MnO3 possess the better potential to approach the hyperthermia range in just ∼12 s than La 0.73Sr0.27MnO3 . This result might be attributed towards the fact of reduced particle size of MNPs in LSMO (0.33) [27], generating more heat due to the rapid flipping of magnetic dipole moments than that found in LSMO (0.27) [21]. The heat generated by all samples appears to be reduced for coated magnetic NPs than uncoated ones owing to the presence of polymer on them [8]. But astonishingly in only one case, the initial temperature by PEG2 @ LSMO (0.33) has been found to be stable at ∼27 °C for more than 7 s and then attained considerable increase, resulting in improved heating onwards. It might be noted that after a few moments, all samples have attained their maximum temperatures with no further pronounced increase thereafter even in the presence of a.c. field showing that they are acting like “heat switches”, most essential for self-regulated hyperthermia.
mass of sample ΔT ⎞ SAR = c ⎛ ⎝ Δt ⎠ mass of Manganese
(2)
“c” is defined to be the specific heat for LSMO (0.66 J/g.K) [15,17]. All powdered samples were weighed up to be 20 mg. The mass of Manganese (Mn) was calculated by the approach used in Ref. [8] and it was found to be ∼4.819 mg and 4.88 mg for LSMO (0.27) and LSMO (0.33) respectively. ΔT The term Δ t gives the initial slope of the kinetic RF-curve exhibited by a sample. The steep slope observed at few early seconds actually measures the better heating efficacy of NPs due to relative orientations of magnetic moments inside it with the external field. Hence it is desirable in hyperthermia treatment to attain the essential temperature as swiftly as possible in turn leading to less exposure time to the external field. The slopes of induction heating curves were
( )
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At the same frequency, SAR values for samples of LSMO (0.33) are found to be improved than those found for LSMO (0.27) except PEG2 due to its initial heat delay. Hence La 0.67Sr0.33MnO3 can be considered to be comparatively suitable mediators for hyperthermia application with comparatively less exposure time towards the external field. It might also be noted that PEG 2 (14% w/v) has shown better aptitude of SAR value with LSMO (0.27) whereas that with LSMO (0.33) has been displayed by PEG1 (5% w/v).
3.4.3. Induced heating in magnetic ferro-fluids The utmost unavoidable step for in-vivo applications is to form a well-dispersed solution of coated NPs in most suitable carrier medium e.g. water, Dextran, PBS [12,14] etc. In this perspective, the choice of normal Saline (0.9% NaCl) was made as an inventive effort to make the desired suspension of functionalized NPs for safer intravenous applications. Since it has been in practice for drug deliveries in chemotherapy and bio-medicine for the past many years, saline is suggested to be the most biocompatible, economical and safer aqueous medium for humans. At present, a suspension was formed by dispersing ∼19 mg of powdered NPs in 1 ml volume of saline i.e. a ferro-fluid of “19 mg/ml”, for each sample. The plastic vials containing these suspensions were exposed to induction heating at a frequency (∼513 kHz) applied for solid samples before, in order to get the detailed comparison. The results are illustrated through Fig. 6 (a) and (b). The responses of pure LSMOs’ suspensions have also been presented for relative
Fig. 5. Initial slopes of RF curves (a) LSMO (0.27) (b) LSMO (0.33) for first ten seconds.
figured out for the initial ten seconds for the given samples under applied field and are displayed in Fig. 5(a) and (b). It is obvious to see that the required temperature is achieved more speedily in LSMO (0.33) than in (0.27) sample. The most probable reason being the rapid flipping of magnetic dipole moments of NPs with very short relaxation time at applied frequency. The sample PEG2 has however exhibited different behaviour as it has given a spontaneous response with LSMO (0.27) but very little impulse with LSMO (0.33) initially, although it reaches to a quite better saturation temperature later on (Fig. 4b). The reason behind this has already pointed out in section 3.4.1. For a comprehensive analysis, the related parameters of all samples are summarized in Table 3.
Table 3 Summarized RF Induction heating parameters.
La 0.73Sr0.27 MnO3
La 0.67Sr0.33 MnO3
Sample Description
Final attained Temp. Tf (°C)
Slopes Δ T/Δ t (°C/s) (1–10 s)
SAR (W/g)
Uncoated PEG1 PEG2 Uncoated PEG1 PEG2
56.5 53.1 55.8 64.5 63 64
1.16163 1.01414 1.21583 2.45758 2.49697 0.94545
3.18 2.77 3.33 6.64 6.75 2.55
Fig. 6. RF induction curves of Saline-based suspensions PEG-coated (a) LSMO (0.27). (b) LSMO (0.33) at 513 kHz. 130
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Fig. 8. Thermogravimetric patterns of LSMO (0.33).
weight loss thereafter till 300 °C corresponds to the decomposition of chelating agent along with organic CeH components present in pure LSMO following smooth curve onwards [36]. PEG1 decomposes greatly up to 16% between (200–450 °C) showing its relatively stronger bonding with LSMO whereas PEG2 disintegrates earlier till 350 °C. It is quite obvious to see that after 600 °C no appreciable weight loss occurs even up to 800 °C so LSMO NPs possess a stable structure and the coating polymer seems to evaporate till ∼300 °C. The maximum heat absorption and emission regions of LSMO (0.27) samples are highlighted by the peaks of the DTA curve in Fig. 7 (b) showing the corresponding weight loss transitions of relevant TGA curves. The crystallization of samples is represented by uprising mounts showing heat evolution in the exothermic reactions from 200 to 400 °C in Fig. 7 (a). Moreover, the descending curves after 500 °C correspond to the absorption of heat by the examined sample in this range. The prominent weight loss transitions of LSMO (0.33) samples are furnished by TGA curves of Fig. 8. It could be seen that the presence of polymers is obvious on the surface of NPs by their subsequent decomposition and prominent transitions occur within 200–300 °C and then stable onwards. The present behaviour is somewhat different from that observed in TGA paths of LSMO (0.27) showing that % weight of all LSMO (0.33) increases first in the range 51–200 °C and then reduces. This kind of response of LSMO (0.33) has also been reported earlier for Sodium Oleate coated La 0.67Sr0.33MnO3 in our recent study [8] and also for La 0.7Sr0.3MnO3 in Ref. [14]. The comparison of Figs. 7(a) and 8 shows that among the two mediators, PEG's attachment was found to be stronger with LSMO (0.27) whereas among the two concentrations PEG 1 (5%) has shown more presence on LSMO (0.27). Moreover, the TGA studies reveal the interaction of the attached polymer with MNPs obvious to be chemical adsorption also termed as chemisorption.
Fig. 7. Thermogravimetric measurements (a) TGA (b) DTA curves of LSMO (0.27).
analysis. Although the heating response is less in comparison of powdered samples, this was done just to have an insight into their behaviour in aqueous form. It is noticeable that in Saline the better approach towards heating response is exhibited by PEG1 samples. It might also be noted that saturation temperatures are less and slowly approached in dispersions as compared to that in powdered forms. Hence it could be considered as an inventive approach suggesting the possible use of Saline as an “NPs carrying agent” for safer in-vivo hyperthermia applications in the future. However, employing further modifications in certain parameters like applied frequency, particle concentration, applied field etc. in a most suitable tolerable range, can help to achieve the optimized therapeutic range (42–45 °C) in PEG-coated LSMOs ferrofluids.
4. Conclusion Perovskite LSMO synthesized via citrate–gel method with Sr concentrations 0.27 and 0.33 was successfully coated with a biocompatible and long chain structured polymer PEG opting new concentrations and modifications. The prepared NPs were examined through different analytical procedures revealing their single domain crystallite size (∼17 nm) and were successfully functionalized by the PEG attachment on their surface. The as-synthesized and coated NPs were found to exhibit super-paramagnetic nature revealed by magnetic curves giving quite effective saturation magnetization at room temperature and negligible retentivity, being essential for hyperthermia aptitude. Moreover, efficient heating response and appreciable SAR values were given by the PEG-coated NPs’ powders at 513 kHz frequency of the
3.5. Thermogravimetric studies In order to figure out the relative amounts of polymers adsorbed on the surface of NPs following their decompositional behaviours, TGA curves for samples of series LSMO (0.27) are presented in Fig. 7 (a). These curves reveal the relative percentage weight reductions of all powdered samples up to 800 °C except uncoated sample showing its stability. The weight loss % for PEG1 is found to be (12–16%) while that for PEG2 is (2–4%) clearly depicting the considerable amount of PEG stuck to NPs surface in both coating routes. The water vaporization is responsible for initial weight loss up till 100 °C [14]. Whereas the 131
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applied a.c. field. Thermogravimetric analysis revealed that the decomposition of attached amounts of polymer was found to be up to ∼300 °C and NPs seemed to be stable even at ∼800 °C. This detailed investigation shows that PEG has more reasonable bonding with LSMO (0.27) whereas PEG functionalized LSMO (0.33) has given larger SAR values. Moreover, among the two concentrations of PEG (5% & 14%), 5% has exhibited approach towards better SAR values whereas 14% has given the best response with LSMO (0.33) in achieving highest final temperature. The saline-based ferrofluids (∼19 mg/ml) of coated NPs exhibited noticeable heating at the applied frequency and can be considered for safer intravenous applications in future. It will be more challenging to analyze the saline dispersions of coated NPs at further higher but tolerable frequencies to optimize their therapeutic range up to 45 °C for the destruction of cancerous cells and their approach towards self-regulated in-vitro hyperthermia applications.
[12] S.V. Jadhav, D.S. Nikam, Studies on colloidal stability of PVP-coated LSMO nanoparticles for magnetic fluid hyperthermia, New J. Chem. 37 (2013) 3121–3130. [13] K. McBride, J. Cook, Evaluation of La1 −x Srx MnO3 (0≤x < 0.4) synthesized via a modified sol-gel method as mediators for magnetic fluid hyperthermia, CrystEngComm 18 (2016) 407–416. [14] N.D. Thorat, Raghvendra, Syed A.M. Tofail, Multimodal superparamagnetic nanoparticles with unusually enhanced specific absorption rate for synergetic cancer therapeutics and magnetic resonance imaging, ACS Appl. Mater. Interfaces 8 (23) (2016) 14656–14664. [15] P.T. Phong, D.H. Manh, Structural and magnetic study of La 0.7Sr0.3 MnO3 nanoparticles and A.C magnetic heating characteristics for hyperthermia applications, Physica B 444 (2014) 94–102. [16] D.S. Nikam, S.V. Jadhav, Colloidal stability of polyethylene glycol functionalized Co0.5 Zn 0.5Fe2 O4 nanoparticles: effect of pH, sample and salt concentration for hyperthermia application, RSC Adv. 4 (2014) 12662–12671. [17] S. Manzoor, Ashfaq Ahmed, Amin ur Rashid, S.N. Ahmad, S.A. Shaheen, Study of magnetothermal properties of Strontium doped Lanthanum manganite nanoparticles for Hyperthermia applications, IEEE Trans. Magn. vol. 49, (7) (2013) 3504–3507. [18] Z. Jirák, J. Kuličková, Titania-coated manganite nanoparticles: synthesis of the shell, characterization and MRI properties, J. Magn. Magn. 427 (2017) 245–250. [19] S. Biswas, S. Keshri, Antibiotic loading and release studies of LSMO nanoparticles embedded in an acrylic polymer, Phase Trans. 89 (12) (2016) 1203–1212. [20] K.S. Martirosyan, Thermosensitive magnetic nanoparticles for self-controlled hyperthermia cancer treatment, J. Nanomed. Nanotechol. 3 (6) (2012) 1000e112. [21] S.V. Jadhav, D.S. Nikam, PVA and PEG functionalised LSMO nanoparticles for magnetic fluid hyperthermia application, Mater. Char. 102 (2015) 209–220. [22] A. Masoudi, H. Reza Madaah Hosseini, Mohammad Ali Shokrgozar, Reza Ahmadi, Mohammad Ali Oghabian, The effect of poly(ethylene glycol) coating on colloidal stability of superparamagnetic iron oxide nanoparticles as potential MRI contrast agent, Int. J. Pharm. (Amst.) 433 (2012) 129–141. [23] A.P. Khandhar, R.M. Ferguson, Tailored magnetic nanoparticles for optimizing magnetic fluid hyperthermia, J. Biomed. Mater. Res. A 100A (2012) 728–737. [24] S. García-Jimenoa, J. Estelrich, Ferrofluid based on polyethylene glycol-coated iron oxide nanoparticles: characterization and properties, Colloid. Surf. Physicochem. Eng. Asp. 420 (2013) 74–81. [25] K.R. Bhayani, S.N. Kale, Protein and polymer immobilized La 0.7Sr0.3 MnO3 nanoparticles for possible biomedical applications, Nanotechnology 18 (2007) 345101 (7 pp). [26] S. Keshri, V. Kumar, Synthesis and characterization of LSMO manganite-based biocomposite, Phase Trans. A Multinatl. J. 87 (5) (2014) 468–476. [27] S. Daengsakul, C. Thomas, Magnetic and cytotoxicity properties of La1 −x Srx MnO3 (0 < x < 0.5) nanoparticles prepared by a simple thermal hydro-decomposition, Nanoscale Res. Lett. 4 (2009) 839–845. [28] A. Urtizberea, E. Natividad, Specific absorption rates and magnetic properties of Ferrofluids with interaction effects at low concentrations, J. Phys. Chem. C 114 (2010) 4916–4922. [29] Sara Mondini, C. Drago, Colloidal stability of iron oxide nanocrystals coated with a PEG- based tetra-catechol surfactant, Nanotechnology 24 (2013) 105702 (14 pp). [30] O. Pana, C. Leostean, Magnetization enhancement of magnetic nanoparticles coated with polypyrrole, AIP Conf. Proc. 1425 (2012) 135–138. [31] P. Guardia, B. Batlle – Brugal, Surfactant effects in magnetite nanoparticles of controlled size, J. Magn. Magn. Mater. 316 (2007) 756–759. [32] A. Asamitsu, Y. Morimoto, Magnetostructural phase transition in La1 −x Srx MnO3 with controlled Carrier density, Phys. Rev. B 54 (1996) 1716–1723. [33] N. Zhang, W. Yang, W. Ding, D. Xing, Y. Du, Grain size-dependent magnetism in fine particle perovskite La1 −x Srx MnOz , Solid State Commun. 109 (1999) 537–542. [34] A. Urushibara, Y. Moritomo, T. Arima, A. Asamitsu, G. Kido, Y. Tokura, Insulatormetal transition and giant magnetoresistance in La1 −x Srx MnO3 , Phys. Rev. B 51 (20) (1995) 14103–14109. [35] E. Natividad, M. Castro, Accurate measurement of the specific absorption rate using a suitable adiabatic magnetothermal setup, Appl. Phys. Lett. 92 (2008) 093116 (3pp). [36] S. Ravi, A. Karthikeyan, Effect of calcination temperature on La 0.7Sr0.3MnO3 nanoparticles synthesized with modified sol-gel route, Phys. Procedia 54 (2014) 45–54.
Acknowledgement We are obliged to acknowledge The Higher Education Commission of Pakistan for funding the work through the grant under project SRGP # 691. We are also thankful to Magnetism Laboratory COMSATS University Islamabad Pakistan for the kind facilitation regarding the experimental work. References [1] Emil Pollert, Karel Zaveta, Nano-crystalline oxides in magnetic fluid hyperthermia, in: Nguyen T.K. Thanh (Ed.), Magnetic Nanoparticles from Fabrication to Clinical Applications, CRC Press, 2012, pp. 449–470. [2] P.A. Liberti, C.G. Rao, L.W.M.M. Terstappen, Optimisation of ferrofluids and protocols for the enrichment of breast tumor cells in blood, J. Magn. Magn. Mater. Rao 33 (2001) 301307. [3] N.D. Thorat, R. Bohara, Multifunctional magnetic nanostructures for cancer hyperthermia therapy, in: Alina Maria Holban, Alexandru Grumezescu (Eds.), Nanoarchitectonics for Smart Delivery and Drug Targeting, William Andrew, App. Sci. Publishers, 2016, pp. 589–612. [4] N. Abdul Jaffar, K.B. Lias, N. Buniyamin, An overview of metamaterials used in applicators in hyperthermia cancer treatment procedure, IEEE International Conference on Electrical, Electronics and System Engineering (ICEESE), 2017, pp. 32–36. [5] N. Nizam-Uddin, Ibrahim Elshafiey, SAR optimization for wideband hyperthermia treatment system, IEEE 8th International Conference on Information Technology (ICIT), 2017, pp. 956–959. [6] Ihab M. Obaidat, Bashar Issa, Yousef Haik, Magnetic properties of magnetic nanoparticles for efficient hyperthermia, Nanomaterials 5 (2015) 63–89. [7] E. Pollert, P. Veverka, Search of new core materials for magnetic fluid hyperthermia: preliminary chemical and physical issue, Prog. Solid State Chem. 37 (2009) 1–14. [8] A.S. Khan, Muhammad Farooq Nasir, A. Humayun, Magnetic and heating properties of La1 −x Sr1 −x MnO3 (x = 0.27 & 0.33) mediators coated by Sodium Oleate for magnetic fluid Hyperthermia applications, Phys. B Condens. Matter 550 (2018) 1–8. [9] E. Pollert, O. Kaman, Core-shell La1 −x Srx MnO3 nanoparticles as colloidal mediators for magnetic fluid hyperthermia, Phil. Trans. R. Soc. A. 368 (2010) 4389–4405. [10] A.A. Kuznetsov, O.A. Shlyakhtin, Smart” mediators for self - controlled inductive heating, 2002 heating, Eur. Cells Mater. 3 (2) (2002) 75–77. [11] S.V. Jadhav, D.S. Nikam, The influence of coating on structural, magnetic and colloidal properties of manganite on heating mechanism for magnetic fluid hyperthermia application, New J. Chem. 38 (2014) 3678–3687.
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Magnetic and heating aptitudes of PEG coated La 0.73Sr0.27 MnO3 and La 0.67Sr0.33 MnO3 mediators towards hyperthermia methodology
T
Afsheen Sultana Khana, Nasir Mehbooba, Muhammad Farooq Nasira,∗, Asif Hamayunb a b
Department of Physics, RIPHAH International University, Islamabad 44000, Pakistan Magnetism Laboratory, Department of Physics, COMSATS University, Islamabad 44000, Pakistan
A R T I C LE I N FO
A B S T R A C T
Keywords: Functionalized Lanthanum strontium manganite Citrate-gel route Super-paramagnetic nature Saturation magnetization External radio frequency field Hyperthermia methodology
In the present study functionalized mediator of Lanthanum strontium manganite (LSMO) has been investigated for magnetic fluid hyperthermia (MFH) applications. Perovskite structured (La1 −x Srx MnO3 ) employing two Sr concentrations (x = 0.27 & 0.33) were attempted to coat with long chain structured polymer named Polyethylene glycol (PEG- 6000 g/mol) by adopting novel concentrations (5% & 14% w/v) in order to assess a detailed comparison of the effect of concentration of same coating material on two different LSMO's series. The Citrate-gel route was adopted to synthesize LSMOs nanoparticles (NPs). XRD revealed the super-paramagnetic (SPM) nature of synthesized NPs showing an approximate crystallite size of ∼17 nm. The LSMOs tailored with PEG showed an effective bonding of polymer with NPs exhibited by FTIR spectra. The magnetic parameters of coated NPs subjected to VSM at room temperature displayed an appreciable saturation magnetization and very slight coercivity owing to their SPM behaviour. During each synthesis, the relative proportions of polymer attached to LSMOs were evaluated through TGA analysis accompanied by DTA studies showing successive decomposition processes. The induction heating behaviours of NPs under an external radio frequency field displayed quite an appreciable approach for required Hyperthermia efficacy in the required range of 40–60 °C. Besides this, the coated NPs were dispersed in normal saline as an innovative try forming a ferro-fluid (∼19 mg/ ml) and showed considerable approach towards induction heating for the destruction of cancerous cells employing hyperthermia methodology.
1. Introduction Magnetic nanoparticles (MNPs) have been pursuing extreme significance in numerous fields for the last few decades. Their amazing multidimensional roles have now become unavoidable building blocks in most popular scientific fields of the present era like bioengineering, biomedicine, clinical therapy applications [1], bio-separation [2], magnetic resonance imaging (MRI), magnetically targeted drug delivery mechanism and magnetic hyperthermia cancer therapy [3–5]. Among them, magnetic fluid Hyperthermia (MFH) has been aggravating as the most challenging methodology regarding the possible destruction of tumorous cells in a specific temperature range, using NPs since 1957 [6]. MFH is based on the heat released by MNPs under the action of the external field [7–14]. The method involves the introduction of magnetic particles (mediators) stabilized by biocompatible surfactants into the selected site of the body and heating them by applying an external electromagnetic field of suitable radio-frequency range [15]. The high efficiency of MNP's suspension to absorb energy
∗
from the applied field and convert it into heat has been proved by various experiments. Moreover, tumor cells are more sensitive to heat as compared to healthier ones, so they can be easily destroyed through localized heating, having less effect on healthy tissues surrounding them during the treatment [3] which is the most attractive feature of MFH. It is an alternative treatment to destroy cancerous cells through thermal deterioration at a specific temperature range ∼(42 °C–46 °C) which harmonizes the adverse effects of chemotherapy and radiotherapy [13]. Up to now quite a lot of MNPs have been examined in this perspective like magnetite, maghemite, Spinel Ferrite, Sr-hexaferrite phases, Cobalt-Zinc Ferrites etc. Among them, certain reservations have been observed regarding the use of magnetite, ferrites, and maghemite [1,7,16] due to their high Curie temperature ∼(85–227 °C), large retentivity, over-heating, etc. which makes them dangerous for healthier tissues of the body. La1 −x Srx MnO3 (LSMO) NPs known as manganites have been emerging as surprising mediators towards hyperthermia treatment owing to their exclusive characteristics such as high SAR value, super-paramagnetism with minimal hysteresis loss and larger
Corresponding author. E-mail address: [email protected] (M.F. Nasir).
https://doi.org/10.1016/j.physb.2019.03.039 Received 26 November 2018; Received in revised form 4 March 2019; Accepted 29 March 2019 Available online 03 April 2019 0921-4526/ © 2019 Elsevier B.V. All rights reserved.
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saturation magnetization under the external magnetic field. Moreover, through controlled doping Sr concentration in LSMOs, adjustable Curie temperature is approachable in required therapeutic hyperthermia range (42–46 °C) [17–20]. All of these mentioned features demonstrate LSMOs' worth as excellent mediators for self-regulated hyperthermia. The most mandatory step, which is to be followed for satisfactory invitro and in-vivo applications of LSMO NPs is their appropriate coating by most suitable biocompatible polymers. Studies have shown that in order to attain higher SAR values employing MNPs, it is inevitable to prevent their agglomeration in aqueous suspension. This leads towards the improved colloidal stability of mediators for effective intravenous hyperthermia applications avoiding their immediate uptake by the body's reticuloendothelial system (RES). One of the most appropriate coating agents considered for improved colloidal stability, biocompatibility and SAR value of MNPs, is PEG ((C2 H 4 O)n+1. H2 O) due to its highly hydrophilic nature, nontoxicity, non-immunogenicity and flexibility. PEG is appreciably known as a protein-resistant polymer and reduces the macrophages uptake in biomedical applications thus prolonging blood circulation times [14,21–24]. It has hydrophilic molecules chains, which leads to a good dispersion in aqueous medium i.e. water. It is widely applied as a pharmacological product because it is highly soluble in polar and some non-polar solvents. Moreover, the selection of adequate molecular weight (preferably not greater than 10,000 g/mol) of PEG helps to avoid agglomeration of NPs. The main focus of the study under consideration was to coat two series of LSMO by opting unique weight to volume (w/v%) concentration amounts of PEG in order to evaluate a detailed insight of their response towards add-on polymers for hyperthermia mechanism.
solution was chosen to be 14% as a try. 16.8 mg of solid PEG-6000 crystals were added in 120 ml of DDW and dissolved at 115 °C on a hot plate. 167 mg of LSMO powder was sonicated in 150 ml of DDW to get proper dispersion and then slowly poured PEG solution into it to get a combined 250 ml solution followed by sonication for a few moments. This solution was put to continuous heat at 63 °C for 1 1 h and then at 2 105 °C for almost 2 h. It was kept overnight to cool down and then put 1 to slow stirring for almost 2 hours, using a magnetic stirrer. Resulting 2 particles were washed thrice with DDW, once with acetone (4000 rpm) and were dispersed in acetone keeping for few days till complete drying. Final NPs were named PEG2 (14% w/v @ LSMO) onwards. 2.3. Sample's specifications The four coated samples of LSMO NPs can now be presented below precisely with particular labels for future correspondence.
• LSMO coated with 5% PEG concentration. • LSMO coated with 14% PEG concentration.
(PEG 1) (PEG 2)
2. Experimental section 2.1. Synthesis of LSMO The Citrate-gel process [25] was adopted for the preparation of both series of LSMO NPs. Nitrates of strontium and Lanthanum (Sr(NO3)2 , La(NO3)3. 6H2 O) beside manganese acetate (C4 H6 MnO4 . 4H2 O ) were mixed in double distilled water (DDW) for preparation of a 0.2 M solution and synthesized by following the method reported earlier in our recent study [8]. 2.2. Functionalization routes of LSMO NPs with PEG 2.2.1. Procedure of route 1 This method was first applied to coat La 0.7Sr0.3MnO3 with PEG taking w/v % of polymer solution as 2%, 3.5% and 5% [21]. In the present study, 5% PEG concentration was chosen to coat La 0.73Sr0.27MnO3 and La 0.67Sr0.33MnO3 , adopting the same method as reported earlier but here with slight modifications in coating amounts and also with different values of Sr concentrations in LSMOs series, to investigate new behaviours of mediators. 5 mg of PEG flakes (molecular weight 6000 g/mol, Fluka) were taken and dissolved in 100 ml of DDW at 100 °C till complete dissolution. Meanwhile, 143.7 mg of LSMO fine particles were dispersed in 150 ml of DDW through sonication and prepared PEG solution was then slowly poured into it. Total solution of 250 ml was put on a hot plate with a constant heat of 100 °C for 2 h. This solution was cooled down overnight and then subjected to constant stirring at 1 800 rpm for almost 7 2 hours. These particles were washed twice with deionized water and once with acetone (4000 rpm) and again dispersed in acetone. After few days, final dried particles were obtained and named as PEG1 (5% w/v @ LSMO) afterwards.
2.4. Instrumentation specifications The XRD signatures of as-synthesized pure NPs were attained using Cu-Kα radiation of wavelength λ = 1.54 A° employing (X-Pert Philips X-ray diffractometer) having 2°/minute angular scan from 20° to 80°. The presence of PEG on the surface of LSMOs was determined by FTIR impressions using (Shimadzu IR–Tracer 100) spectrometer in the midInfrared region 400–4000 cm−1. The magnetic measurements at room temperature were evaluated by MH- curves in a range (0–10 kOe) with 7400 Lakeshore magnetometer. The induction heating studies of samples both in solid and suspension forms, at 513 kHz external field (15.9 kA/m), were evaluated in detail (Magnetherm Nanotherics). Thermogravimetric studies were done using (PerkinElmer TGA) and
2.2.2. Procedure of route 2 This experimental try was done to study the effect of increasing PEG concentration with reduced time duration on the surface coating of LSMOs. According to a study, 10–20% PEG concentration can be taken for surface modification of NPs. So in this method, (w/v) % ratio of PEG 126
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Fig. 1. XRD signatures of pure LSMO with Sr content (a) (0.27) (b) (0.33) annealed at 700 °C.
(Mettler Toledo TGA) in order to find out the relatively attached amount of polymer on NP's surface followed by their decomposition mechanisms, at heat increment of 10 °C/min (up to 800 °C) under a nitrogen atmosphere. 3. Results and discussion 3.1. Structural analysis The polycrystalline patterns of LSMOs (0.27 & 0.33) 700 °C annealed, corresponding to different crystallite planes are presented by their XRD analysis in Fig. 1. The indexing of prominent peaks was figured out to be in quite good agreement with their Joint Committee on Powder Diffraction Standards (JCPDS) reference card numbers (00056-0616) and (89–4466) for LSMO (0.27) and LSMO (0.33) respectively [26]. The comparison reveals no impurity peaks and perovskite phase of samples. The nature of the crystalline structure of both LSMOs was found to be rhombohedral having group number 167 (space group La 0.73Sr0.27 MnO3 R-3c). The lattice dimensions of are a = b = 0.5500 nm, c = 1.33491 nm and those for La 0.67Sr0.33 MnO3 are found to be a = b = 0.5495 nm and c = 1.3372 nm. Furthermore, the broadened peaks presented in XRD patterns provide an indication of the nano-crystalline phase of annealed samples. The crystallite sizes are evaluated employing Debye-Scherrer formula,
dXRD
K λ = β cosθ
Fig. 2. FTIR signatures of PEG coated samples (a) LSMO (0.27) (b) LSMO (0.33).
(1)
cm−1 of LSMO is due to its OeCeO bond. This peak shifts slightly at 2316 cm−1 and 2341 cm−1 for samples PEG1 and PEG2 respectively. For pure PEG polymer, the peak at 962 cm−1 belongs to the stretching of the CeO bond and shifts at 960 cm−1 in FTIR curve of coated sample PEG1@LSMO [21]. The bands existing at about 1278 cm−1 and 1462 cm−1 correspond to eCH2 twisting and the eCH2 vibration of pure PEG6000 respectively [22,29] and it is exactly at 1278 cm−1 in coated PEG1 sample showing the presence of PEG on NPs. The absorption band at 1147 cm−1 is ascribed by the CeO and CeC stretching bonds of PEG polymer and are present at ∼1140 cm−1 and 1159 cm−1 for coated samples PEG1 and PEG2 respectively [21,22,29]. Moreover, the band observed at ∼2897 cm−1 is attributed to the specific CeH stretched vibrations in PEG [21] and shifts to about 2812 cm−1 in the modified PEG2 sample. All these peaks show the satisfactory attachment of PEG molecules to LSMO (0.27) surface. FTIR marks of coated La0.67 Sr0.33 MnO3 are displayed in Fig. 2(b).
The most intense peaks are located at 2θ = 32.77° and 2θ = 32.80° for LSMO (0.27) and (0.33) respectively with average crystallite sizes of ∼18 nm and 17 nm respectively showing excellent agreement with those reported by Daengsakul [27]. Moreover, the average particle size of ∼17 nm confirmed the required super-paramagnetic nature of annealed NPs so the heat dissipated by them could be focused more to be due to Neel's relaxation [15,28] as compared to hysteresis losses. 3.2. FTIR discussion The attachment of PEG on the surface of NPs for two LSMOs’ series is presented by Fig. 2(a) and (b). Fig. 2(a) illustrates the surface modification of LSMO (0.27), along with signature peaks of pure PEG-6000, displayed here for comparison. The impression of uncoated LSMO at 1464 cm−1 refers to the presence of carbonates while that at 1647 cm−1 shows the adsorption of water [19,21,26]. The strong peak at ∼2360 127
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coating route polymer's connection to the surface of MNPs has been established successfully. 3.3. VSM studies The powdered samples (both uncoated and coated) were subjected to the external magnetic field (0–10,000 Oe) at room temperature employing Lakeshore VSM to study their magnetic properties. The attained M-H curves are presented in Fig. 3(a) and (b) for the two series of samples respectively, exhibiting their saturation magnetization (Ms) with respect to the applied field, where saturation magnetization accounts for the highest achieved value of magnetic moment per unit mass of the sample. All samples were taken to be in equal mass ∼8 mg. The curves describe the SPM behaviour of all samples showing an evident saturation magnetization up to 15 emu/g. This value is quite substantial at room temperature as it is known that the value of (Ms) decreases by increasing temperature and it tends to increase with particles’ size. In the present study, the size restriction of NPs is the utmost requirement for bio-medical applications hence, observed values of magnetization are quite appreciable. In addition, all samples are displaying SPM curves with very narrow hysteresis loops for slight coercivity (Hc) of ∼50 Oe and minor retentivity (Mr), essentially desired for hyperthermia applications. The sample named as PEG1 is found to have a slight reduction in (Ms) as compared to bare LSMO (0.27) in Fig. 3(a). This effect might be attributed to the polymer's existence on the NPs exterior which is responsible for the decrease in their magnetic coupling, proportional to the amount of polymer adsorbed there [11,12,21]. But the same PEG1 shows a slight overlapping M-H curve with the bare LSMO (0.33) in Fig. 3(b), showing approximately same saturation magnetization aptitude. Surprisingly, the sample named as PEG2 has shown a quite different behaviour of slight enhancement in saturation magnetization than bare LSMOs in both Fig. 3(a) and (b). Such kind of results has also been reported earlier for La 0.67Sr0.33MnO3 modified by polypyrrole and also for oleic acid coating on magnetite respectively [30,31]. This behaviour can be attributed to the charge transfer process that occurs between the conducting polymer and the layers of LSMO NPs. The π electron pairs of carbon chains of polymer (PEG) travels below to the surface of NPs and substitute the missing oxygen p-orbitals there, resulting in enhancement of double exchange mechanism between Mn+3 and Mn+4 states of LSMO [30]. This finally appears as an increased saturation magnetization in 14% PEG-coated samples as shown below (see Table 1). The important magnetic descriptions of both LSMOs’ series from respective M-H curves are summarized in Table 2. It is quite noticeable that uncoated LSMO (0.27) achieves slightly higher saturation magnetization as compared to LSMO (0.33). The stronger magnetic dipole moment interactions among NPs could be attributed to being responsible for this enhanced (Ms) in LSMO (0.27) as compared to that for LSMO (0.33). In the structural composition of LSMO, Strontium being a divalent ion (Sr +2 ) is responsible for the creation of increased vacancies at Mn+4 sites in the sample leading to enhanced double exchange interaction [8,32]. Interestingly the double
Fig. 3. M-H curves of samples (a) LSMO (0.27), (b) LSMO (0.33) at room temperature.
The rightmost peak of uncoated LSMO at 428 cm−1 is related to the bending of the MneOeMn bond angle whereas its most characteristic peak at 580 cm−1 belongs to the stretching mode of metal-oxygen bond owing to the internal change in the MneOeMn bond length of MnO6 octahedra [11,19,26,27]. Also the band at 868 cm−1 is attributed towards the CeO bond due to atmospheric CO2, reported by Ref. [19]. The most prominent peak of pure PEG-6000 at 842.9 cm−1 in Fig. 2(b) belongs to its eCH2 swinging bond [21,29] which is shifted to 858 cm−1 in both PEG-coated samples as shown. Furthermore, the various bands' vibrations at 418, 457, 472, 528, 569 cm−1 etc. exhibit the adequate existence of PEG on LSMO NPs. All these curves illustrate that in each
Table 1 Review of important FTIR impressions. Absorption Peaks (cm−1)
Specifications of concerned functional groups
References
428 580 842 962 1147 1278, 1462 2360 2897
(MneOeMn) bond angle variation of pure LSMO (MneOeMn) bond length variation of pure LSMO (eCH2) swinging bond of pure PEG (CeO) stretching of pure PEG (CeO) and (CeC) stretching of pure PEG (eCH2) twisting & (eCH2) vibration of pure PEG (OeCeO) stretched vibrations of pure LSMO (CeH) stretched vibrations of pure PEG
[19,26] [11,19,21,27] [21,29] [21] [21,22,29] [22,29] [36] [21]
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Table 2 Summarized magnetization statistics of NPs. Sample
Uncoated PEG1 PEG2
La 0.67Sr0.33 MnO3
La 0.73Sr0.27 MnO3 Ms (emu/ g)
Mr (emu/ g)
Hc (Oe)
Ms (emu/ g)
Mr (emu/ g)
Hc (Oe)
13.39 9.64 14.45
0.761 0.524 0.786
58.83 57 57
10.527 10.55 14.96
0.461 0.478 0.594
50.21 52.07 39.6
exchange interaction gradually decreases with increasing Sr doping fraction, due to the insufficiency of hopping electrons which is believed to be responsible for the slight reduction of magnetization in LSMO (0.33) [33,34]. On the other hand, it is quite obvious to see that particles have better aptitudes towards reduced Mr and Hc for LSMO (0.33) samples than LSMO (0.27) but astonishingly PEG2 coated samples have exhibited high magnetization for both series. 3.4. Induction heating analysis at radio frequency To analyze the mandatory hyperthermia heating aptitude of both bare and coated samples in response to an external magnetic field, the same amount of fine powder for all samples were subjected to an RF induction unit. Each sample was put in ∼1.5 ml plastic vial surrounded by a polystyrene jacket thick enough for the essential adiabatic magnetic heating measurements. The temperature rise of NPs was recorded by a fibre optic temperature sensor which was well inserted inside the sample's column. The whole set-up was introduced at about central axis of an induction coil having 9 turns. Trying to maintain the temperature of the coil, the induction unit was coupled to a chiller for continuous water circulation so that the heat produced by MNPs could have been analyzed properly. The adiabatic thermal curves of magnetic NPs were attained under an alternating field (513 kHz, 15.9 kA/m). The selection of a frequency for hyperthermia treatment is made on the fact that it should be preferably greater than 50 kHz to avoid skeletal muscles' simulations and lower than 2 MHz for adequate penetration depth inside tissues [3,9]. Furthermore, the single domain NPs are supposed to possess comparatively reduced Neel's relaxation times than large-sized particles hence generating better SAR values at a higher frequency as reported earlier [3,8]. Therefore the two series of samples in the current study were decided to be examined at 513 kHz to explore their hyperthermia efficacy and exhibited through Fig. 4 (a) and 4(b).
Fig. 4. Thermal curves of PEG coated samples (a) LSMO (0.27) (b) LSMO (0.33).
3.4.2. Estimation of SAR value In hyperthermia study one of the most vital features of LSMO NPs is their Specific Absorption Rate (SAR) which approximates their spontaneous response towards applied frequency. SAR is defined to be the capability of NPs to generate heat, resulting by the rapid flipping of their magnetic moments under an external alternating field [8,21]. It is also defined as the amount of heat dissipated per unit mass of the magnetic sample in an applied RF field [17]. In hyperthermia treatment, NPs having large SAR values are the utmost desire for destroying tumorous cells [17,35]. The following formula is applied to calculate SAR value,
3.4.1. Analysis of hyperthermia aptitude The obtained results came out to be quite satisfactory in achieving the required hyperthermia therapeutic range (42–45 °C) showing the active response of examined samples at the selected frequency. Maintaining the same insulating conditions, the responses of sample LSMO (0.33) are revealed to be more swift than that of LSMO (0.27). This illustrates that La 0.67Sr0.33MnO3 possess the better potential to approach the hyperthermia range in just ∼12 s than La 0.73Sr0.27MnO3 . This result might be attributed towards the fact of reduced particle size of MNPs in LSMO (0.33) [27], generating more heat due to the rapid flipping of magnetic dipole moments than that found in LSMO (0.27) [21]. The heat generated by all samples appears to be reduced for coated magnetic NPs than uncoated ones owing to the presence of polymer on them [8]. But astonishingly in only one case, the initial temperature by PEG2 @ LSMO (0.33) has been found to be stable at ∼27 °C for more than 7 s and then attained considerable increase, resulting in improved heating onwards. It might be noted that after a few moments, all samples have attained their maximum temperatures with no further pronounced increase thereafter even in the presence of a.c. field showing that they are acting like “heat switches”, most essential for self-regulated hyperthermia.
mass of sample ΔT ⎞ SAR = c ⎛ ⎝ Δt ⎠ mass of Manganese
(2)
“c” is defined to be the specific heat for LSMO (0.66 J/g.K) [15,17]. All powdered samples were weighed up to be 20 mg. The mass of Manganese (Mn) was calculated by the approach used in Ref. [8] and it was found to be ∼4.819 mg and 4.88 mg for LSMO (0.27) and LSMO (0.33) respectively. ΔT The term Δ t gives the initial slope of the kinetic RF-curve exhibited by a sample. The steep slope observed at few early seconds actually measures the better heating efficacy of NPs due to relative orientations of magnetic moments inside it with the external field. Hence it is desirable in hyperthermia treatment to attain the essential temperature as swiftly as possible in turn leading to less exposure time to the external field. The slopes of induction heating curves were
( )
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At the same frequency, SAR values for samples of LSMO (0.33) are found to be improved than those found for LSMO (0.27) except PEG2 due to its initial heat delay. Hence La 0.67Sr0.33MnO3 can be considered to be comparatively suitable mediators for hyperthermia application with comparatively less exposure time towards the external field. It might also be noted that PEG 2 (14% w/v) has shown better aptitude of SAR value with LSMO (0.27) whereas that with LSMO (0.33) has been displayed by PEG1 (5% w/v).
3.4.3. Induced heating in magnetic ferro-fluids The utmost unavoidable step for in-vivo applications is to form a well-dispersed solution of coated NPs in most suitable carrier medium e.g. water, Dextran, PBS [12,14] etc. In this perspective, the choice of normal Saline (0.9% NaCl) was made as an inventive effort to make the desired suspension of functionalized NPs for safer intravenous applications. Since it has been in practice for drug deliveries in chemotherapy and bio-medicine for the past many years, saline is suggested to be the most biocompatible, economical and safer aqueous medium for humans. At present, a suspension was formed by dispersing ∼19 mg of powdered NPs in 1 ml volume of saline i.e. a ferro-fluid of “19 mg/ml”, for each sample. The plastic vials containing these suspensions were exposed to induction heating at a frequency (∼513 kHz) applied for solid samples before, in order to get the detailed comparison. The results are illustrated through Fig. 6 (a) and (b). The responses of pure LSMOs’ suspensions have also been presented for relative
Fig. 5. Initial slopes of RF curves (a) LSMO (0.27) (b) LSMO (0.33) for first ten seconds.
figured out for the initial ten seconds for the given samples under applied field and are displayed in Fig. 5(a) and (b). It is obvious to see that the required temperature is achieved more speedily in LSMO (0.33) than in (0.27) sample. The most probable reason being the rapid flipping of magnetic dipole moments of NPs with very short relaxation time at applied frequency. The sample PEG2 has however exhibited different behaviour as it has given a spontaneous response with LSMO (0.27) but very little impulse with LSMO (0.33) initially, although it reaches to a quite better saturation temperature later on (Fig. 4b). The reason behind this has already pointed out in section 3.4.1. For a comprehensive analysis, the related parameters of all samples are summarized in Table 3.
Table 3 Summarized RF Induction heating parameters.
La 0.73Sr0.27 MnO3
La 0.67Sr0.33 MnO3
Sample Description
Final attained Temp. Tf (°C)
Slopes Δ T/Δ t (°C/s) (1–10 s)
SAR (W/g)
Uncoated PEG1 PEG2 Uncoated PEG1 PEG2
56.5 53.1 55.8 64.5 63 64
1.16163 1.01414 1.21583 2.45758 2.49697 0.94545
3.18 2.77 3.33 6.64 6.75 2.55
Fig. 6. RF induction curves of Saline-based suspensions PEG-coated (a) LSMO (0.27). (b) LSMO (0.33) at 513 kHz. 130
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Fig. 8. Thermogravimetric patterns of LSMO (0.33).
weight loss thereafter till 300 °C corresponds to the decomposition of chelating agent along with organic CeH components present in pure LSMO following smooth curve onwards [36]. PEG1 decomposes greatly up to 16% between (200–450 °C) showing its relatively stronger bonding with LSMO whereas PEG2 disintegrates earlier till 350 °C. It is quite obvious to see that after 600 °C no appreciable weight loss occurs even up to 800 °C so LSMO NPs possess a stable structure and the coating polymer seems to evaporate till ∼300 °C. The maximum heat absorption and emission regions of LSMO (0.27) samples are highlighted by the peaks of the DTA curve in Fig. 7 (b) showing the corresponding weight loss transitions of relevant TGA curves. The crystallization of samples is represented by uprising mounts showing heat evolution in the exothermic reactions from 200 to 400 °C in Fig. 7 (a). Moreover, the descending curves after 500 °C correspond to the absorption of heat by the examined sample in this range. The prominent weight loss transitions of LSMO (0.33) samples are furnished by TGA curves of Fig. 8. It could be seen that the presence of polymers is obvious on the surface of NPs by their subsequent decomposition and prominent transitions occur within 200–300 °C and then stable onwards. The present behaviour is somewhat different from that observed in TGA paths of LSMO (0.27) showing that % weight of all LSMO (0.33) increases first in the range 51–200 °C and then reduces. This kind of response of LSMO (0.33) has also been reported earlier for Sodium Oleate coated La 0.67Sr0.33MnO3 in our recent study [8] and also for La 0.7Sr0.3MnO3 in Ref. [14]. The comparison of Figs. 7(a) and 8 shows that among the two mediators, PEG's attachment was found to be stronger with LSMO (0.27) whereas among the two concentrations PEG 1 (5%) has shown more presence on LSMO (0.27). Moreover, the TGA studies reveal the interaction of the attached polymer with MNPs obvious to be chemical adsorption also termed as chemisorption.
Fig. 7. Thermogravimetric measurements (a) TGA (b) DTA curves of LSMO (0.27).
analysis. Although the heating response is less in comparison of powdered samples, this was done just to have an insight into their behaviour in aqueous form. It is noticeable that in Saline the better approach towards heating response is exhibited by PEG1 samples. It might also be noted that saturation temperatures are less and slowly approached in dispersions as compared to that in powdered forms. Hence it could be considered as an inventive approach suggesting the possible use of Saline as an “NPs carrying agent” for safer in-vivo hyperthermia applications in the future. However, employing further modifications in certain parameters like applied frequency, particle concentration, applied field etc. in a most suitable tolerable range, can help to achieve the optimized therapeutic range (42–45 °C) in PEG-coated LSMOs ferrofluids.
4. Conclusion Perovskite LSMO synthesized via citrate–gel method with Sr concentrations 0.27 and 0.33 was successfully coated with a biocompatible and long chain structured polymer PEG opting new concentrations and modifications. The prepared NPs were examined through different analytical procedures revealing their single domain crystallite size (∼17 nm) and were successfully functionalized by the PEG attachment on their surface. The as-synthesized and coated NPs were found to exhibit super-paramagnetic nature revealed by magnetic curves giving quite effective saturation magnetization at room temperature and negligible retentivity, being essential for hyperthermia aptitude. Moreover, efficient heating response and appreciable SAR values were given by the PEG-coated NPs’ powders at 513 kHz frequency of the
3.5. Thermogravimetric studies In order to figure out the relative amounts of polymers adsorbed on the surface of NPs following their decompositional behaviours, TGA curves for samples of series LSMO (0.27) are presented in Fig. 7 (a). These curves reveal the relative percentage weight reductions of all powdered samples up to 800 °C except uncoated sample showing its stability. The weight loss % for PEG1 is found to be (12–16%) while that for PEG2 is (2–4%) clearly depicting the considerable amount of PEG stuck to NPs surface in both coating routes. The water vaporization is responsible for initial weight loss up till 100 °C [14]. Whereas the 131
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applied a.c. field. Thermogravimetric analysis revealed that the decomposition of attached amounts of polymer was found to be up to ∼300 °C and NPs seemed to be stable even at ∼800 °C. This detailed investigation shows that PEG has more reasonable bonding with LSMO (0.27) whereas PEG functionalized LSMO (0.33) has given larger SAR values. Moreover, among the two concentrations of PEG (5% & 14%), 5% has exhibited approach towards better SAR values whereas 14% has given the best response with LSMO (0.33) in achieving highest final temperature. The saline-based ferrofluids (∼19 mg/ml) of coated NPs exhibited noticeable heating at the applied frequency and can be considered for safer intravenous applications in future. It will be more challenging to analyze the saline dispersions of coated NPs at further higher but tolerable frequencies to optimize their therapeutic range up to 45 °C for the destruction of cancerous cells and their approach towards self-regulated in-vitro hyperthermia applications.
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