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Accepted Manuscript Title: Design of iron oxide nanoparticles decorated oleic acid and bovine serum albumin for drug delivery Author: Thao Truong-Dinh Tran Toi Van Vo Phuong Ha-Lien Tran PII: DOI: Reference: S0263-8762(15)00011-8 http://dx.doi.org/doi:10.1016/j.cherd.2014.12.016 CHERD 1765 To appear in: Received date: Revised date: Accepted date: 7-7-2014 23-10-2014 19-12-2014 Please cite this article as: Tran, T.T.-D., Van Vo, T., Tran, P.H.-L.,Design of iron oxide nanoparticles decorated oleic acid and bovine serum albumin for drug delivery, Chemical Engineering Research and Design (2015), http://dx.doi.org/10.1016/j.cherd.2014.12.016 This is a PDF file of an unedited manuscript that has been accepted for publication As a service to our customers we are providing this early version of the manuscript The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain Design of iron oxide nanoparticles decorated oleic acid and bovine serum albumin for drug delivery Thao Truong-Dinh Tran*, Toi Van Vo and Phuong Ha-Lien Tran* Pharmaceutical Engineering Laboratory, Biomedical Engineering Department, International University, Vietnam National University – Ho Chi Minh City, Vietnam ip t cr us an M 10 d 11 Ac ce p 13 te 12 14 *Correspondence to: 15 Phone: (84-8) - 37244270 Ext 3337 16 Fax: (84-8) - 37244271 17 E-mail address: ttdthao@hcmiu.edu.vn (Thao Truong-Dinh Tran) 18 thlphuong@hcmiu.edu.vn (Phuong Ha-Lien Tran) Page of 23 19 Abstract This study aimed to originally develop a new nanoparticulate drug delivery system of 21 iron oxide nanoparticles (Fe3O4) for biomedical applications Oleic acid and bovine serum 22 albumin were decorated on the surface of iron oxide nanoparticles in new pattern by 23 conjugation The decoration was kicked off by the functionalization of arginine on the surface 24 of the iron oxide nanoparticles It was then followed by the conjugation of oleic acid and 25 bovine serum albumin through the amide bond Scanning electron microscopy, transmission 26 electron microscopy, powder X-ray diffraction and Fourier transform infrared spectroscopy 27 were used to characterize and determine mechanism of the decorated nanoparticles 28 Paclitaxel was chosen as the model drug in the study The nanoparticles demonstrated a 29 potential utility in delivery of anticancer drugs 30 Keywords: iron oxide nanoparticles, drug delivery, anticancer drug, oleic acid, bovine serum 31 albumin Ac ce p te d M an us cr ip t 20 Page of 23 32 Introduction One of the most important applications of nanotechnology is nanomedicine, which 34 applies the technique to the prevention, diagnosis and treatment of diseases [1-3] Fabrication 35 of nanoparticles has drawn much interest in developing a new generation of more effective 36 cancer therapies since nanoparticles show highly promising in the improvement of drug 37 efficacy, especially drugs with a narrow therapeutic window or low bioavailability such as 38 anticancer drugs [4] Moreover, nanoparticles are under particular researches since they can 39 selectively access to tumor due to their small size and versatile modified physicochemical 40 properties [5] Solid tumors facilitate preferential accumulation of nanosized drug delivery 41 systems due to their specific structure where the vasculature is different in both functional 42 and morphological aspects, from the one in normal tissues [6, 7] Generally, tumor blood 43 vessels are larger in size, more heterogeneous in distribution and more permeable [8] The 44 increased vascular permeability and the impaired lymphatic drainage in rapidly growing 45 tumors allow an accumulation of nanoparticles in the tumor [9] When the absorption occurs, 46 the drug is released The technique overcomes disadvantages of the conventional solution 47 including rapid clearance from the blood circulation due to low molecular weight, and low 48 accumulation at the tumor site for treatment In addition, anticancer drugs tend to present 49 with a large volume of distribution leading to toxicity towards healthy tissues due to their 50 small size and/or their high hydrophobicity in the conventional treatment Ac ce p te d M an us cr ip t 33 51 A tool for observation of tumor response during cancer therapy is very important and 52 indispensable in treatment of this disease Magnetic resonance imaging (MRI) is a common 53 approach widely used for diagnosis in biomedical application Development of contrast 54 agents for further improving tissue resolution on the image hence, have drawn much interest Page of 23 Novel nanomedicine based drug delivery systems as directions to deliver anticancer drugs to 56 tumor for effective therapy and diagnostics have been incessantly investigated [10] Those 57 systems not only reduce side effects of anticancer drugs but also utilize the nano structure as 58 an MRI contrast agent Iron oxide nanoparticles (IONPs) have emerged as feasible materials 59 for tumor imaging and targeted anticancer drug delivery [11-15] Various IONPs have been 60 clinically used as contrast agents due to their high contrast effects and biocompatibility 61 However, the use of these products as a drug carrier system has been still under investigation 62 It has been reported that under physiological pH conditions the IONPs are not charge and 63 precipitated because the isoelectric point of IONPs is [16] Consequently, agglomerated 64 particles are rapidly cleared by macrophages in the reticuloendothelial system (RES) before 65 they can reach to target cells [17-20] One of the feasible approaches is coating the 66 nanoparticles by a biocompatible material [21] which can act to shield the IONPs from 67 surrounding environment and can also be functionalized then Type of surface coating, its 68 concentration and a wide variety of experimental factors such as stirring rate, stirring time, 69 pH, etc determine the overall size of the colloids which may also play a significant role in 70 biodistribution [22-24] Besides, the drug loading capacity of the hydrophobic part depends 71 on compatibility between hydrophobic functional groups and poorly water-soluble drugs 72 encapsulated [25] A design of surface-modified IONPs hence, would determine drug loading 73 capacity and probably encapsulation efficiency also [25] Oleic acid (OA) is a biocompatible 74 fatty acid and also an agent that induces the stability of many nanoparticle systems It can 75 play a role of a capping agent for the particles to form a protective monolayer through a 76 strong bond Nanoparticles with a hydrophobic coating through the attachment of the polar 77 end groups to the surface hence are obtained with monodisperse and highly uniform [26, 27] Ac ce p te d M an us cr ip t 55 Page of 23 The system with oleic acid coating only is not suitable for biomedical applications because 79 they possess hydrophobic surfaces with a large surface area to volume ratio which cause 80 agglomeration and formation of large clusters, resulting in the increased particle size [28] 81 However, OA is the essential part of the IONPs coating for anticancer hydrophobic drug to be 82 loaded [29] Therefore, for biomedical applications in aqueous environments, in addition to 83 OA part, the presence of a hydrophilic coating is favorable Albumin nanoparticles have 84 recently withdrawn attraction due to the preparation under mild conditions and the capability 85 of various kinds of molecules incorporation [30] Bovine serum albumin (BSA) is a 86 preferable carrier in drug delivery systems to facilitate sophisticated biological nanostructures 87 easily adaptable to human body [31] The surface of the IONPs hence, was further conjugated 88 with BSA Paclitaxel, a hydrophobic anticancer agent, was chosen in the study as the model 89 drug The decorated multifunctional nanoparticles in this research is expected to offer 90 advantages over conventional formulations in further studies including combination of 91 effective tumor treatment and tumor observation during the therapy, and reducing the side 92 effects of chemotherapy cr us an M d te Ac ce p 93 ip t 78 94 Materials and Methods 95 2.1 Materials 96 L-arginine, iron oxide (NHS), nanoparticles (Fe3O4 - LOT#MKBG0737V), dicyclohexylcarbodiimide (DCC), N- 97 hydroxysuccinimide 2-(N- 98 morpholino)ethanesulfonic acid (MES) were purchased from Sigma-Aldrich (St Louis, MO, 99 USA) N,N-Dimethylformamide, oleic acid, triethylamine, sodium hydroxide, potassium Page of 23 dihydrogen phosphate were purchased from Xilong Group (China) Bovine serum albumin 101 (BSA – LOT#0000079719) powder was purchased from Himedia Laboratories Pvt Ltd 102 (India) Sodium phosphate was purchase from Guangdong Guanhua Sci-Tech Co., Ltd 103 (China) 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (EDC) was 104 purchased from Merck Schuchardt (Germany) The solvents used were high-performance 105 liquid chromatography (HPLC) grade All other chemicals were of analytical grade and were 106 used without further purification us cr ip t 100 an 107 2.2 Methods 109 2.2.1 Preparation of IONPs decorated by OA and BSA 110 2.2.1.1 Amine functionalization of IONPs M 108 500 mg IONPs was firstly dispersed in 50 ml pH (KH2PO4 0.1M, adjusted by NaOH 112 1M) by the tip sonicator in with 25 W of power supply (Qsonica, Model No Q700) at 113 room temperature L-arginine was dissolved in pH buffer (prepared as mentioned above) to 114 yield a solution of 1.25 mg/ml Then, 50 ml L-arginine solution was added to dispersed- 115 IONPs This mixture was continuously sonicated in 30 with 10 W of power supply at 116 room temperature The amine-functionalized IONPs (A-IONPs) were separated by an 117 external magnet (5 cm in length) and the solution was discarded 100 ml of distilled water 118 was then added to the nanoparticles for washing The washing process was repeated thrice 119 The sample was then dried in oven at 40 ˚C Ac ce p te d 111 120 121 2.2.1.2 Conjugation of OA to A-IONPs Page of 23 OA was conjugated to the free amine on IONPs through an amide bond linkages 123 between carboxylates and amines [32] Firstly, 100 mg OA was activated by DCC and NHS 124 (1:1:1) in 20 ml dimethylformamide containing 1% triethylamine (DMF-TEA) for 30 A 125 dispersion of 500 mg A-IONPs in 50 ml DMF-TEA was then added to the above mixture so 126 that the activated OA could react with the free amine on IONPs This mixture was 127 magnetically stirred in 120 for the reaction (stirring rate 700 rpm with 5cm in length of 128 magnetic bar) The final product (OA-IONPs) was separated by an external magnet and 129 washed with dimethylformamide (similar to washing process in 2.2.1.1) The sample was 130 then dried in oven at 40 ˚C an us cr ip t 122 132 M 131 2.2.1.3 Conjugation of BSA to OA-IONPs BSA was also conjugated to the residual free amine on OA-IONPs through an amide 134 bond linkages between carboxylates and amines [32] First, 150 mg of BSA was activated by 135 408 mg of EDC and 302 mg of NHS in 250 ml MES buffer (pH 6) This mixture was kept 136 magnetically stirring for 30 at room temperature (stirring rate 700 rpm with 5cm in 137 length of magnetic bar) The activated BSA was then reacted with the residual amine group 138 by adding 250 ml of pH 7.5 (16% of NaH2PO4 0.1M and 84% of Na2HPO4 0.1M, adjusted by 139 NaOH 1M) containing 300 mg of OA-IONPs to the above mixture The BSA-conjugated 140 OA-IONPs (BOA-IONPs) were obtained after 120 and introduced to the separation by 141 an external magnet and then, washed with distilled water (similar to washing process in 142 2.2.1.1) The sample was finally dried in oven at 40 ˚C Ac ce p te d 133 143 144 2.2.2 Paclitaxel loading in BOA-IONPs Page of 23 Firstly, BOA-IONPs were dispersed in distilled water at the concentration of 2.5 146 mg/ml Then, solution of 100 µl of paclitaxel in ethanol (50 mg/ml) was added to 20 ml of 147 BOA-IONPs suspension The nanoparticle suspension was left for 5h under stirring 148 Paclitaxel-loaded BOA-IONPs were separated by a magnet and washed several times with 149 distilled water The total amount of paclitaxel in the supernatant and washing solution was 150 measured to determine the percentage of drug loading and loading efficiency All 151 measurements were performed in triplicate The Paclitaxel loading efficiency and % drug 152 loading of the process were calculated as follows: an M 153 157 158 159 , te − =- Where: Ac ce p 156 % d 154 155 us cr ip t 145  x: initial amount of paclitaxel for loading  y: amount of free paclitaxel in supernatant and washing solution  z: total amount of blank nanoparticles and loaded paclitaxel 2.2.3 Paclitaxel release studies 160 Paclitaxel-loaded BOA-IONPs (5 mg) were placed in a test tube containing 10 ml of 161 phosphate buffer (pH 7.4) and then, incubated in a shaking water bath at 37 °C (The shaking 162 frequency is 120 rpm) At pre-determined time intervals, paclitaxel-loaded BOA-IONPs were Page of 23 separated using an external magnet While these nanoparticles were re-suspended in 10 ml of 164 pH 7.4 fresh buffer for the continuous release study, the amount of paclitaxel released was 165 determined from the aliquot using HPLC All experiments were performed in triplicate 166 Percent cumulative release rate of paclitaxel were calculated as follows: cr 167 ip t 163 xn: % drug release at n hour 169 xbefore n: % drug release at the time point just before n hour 170 171 172 Ac ce p te d M an us 168 2.2.4 HPLC analysis Paclitaxel concentration was determined by HPLC system (Dionex UltiMate 3000, 173 Thermoscientific Inc., USA) with Luna 5µ C18 analytical column (150x4.6 mm) 174 Acetonitrile and distilled water at the ratio 67:33 was used as mobile phase with the flow rate 175 at ml/min The UV detector was set to a wavelength of 227 nm The running time was 176 The standard solutions were constructed in the range of 0.5–20 ppm for Page of 23 177 calibration with good linearity (R2= 0.9997) Acetonitrile was used as diluted solution and 178 blank solution Twenty microliters of samples were injected into HPLC system for analysis 179 2.2.5 Scanning electron microscopy (SEM) and Transmission electron microscopy (TEM) ip t 180 SEM (JSM-6480LV, Jeol, USA) was used to characterize surface morphology of 182 nanoparticles Fried sample was deposited on a carbon tape and coated with a thin layer of 183 Platin All samples were examined under accelerating voltage of 10 kV us cr 181 Also, TEM (JEM-1400 plus, Jeol, USA) was used to examine nanoparticle 185 morphology A drop of nanoparticles dispersion was placed on a copper grid Acceleration 186 voltage was kept constant at 100kV 2.2.6 Powder X-ray diffraction (PXRD) d 188 M 187 an 184 A D8 Advance diffractometer (Bruker, Germany) using Ni-filtered, CuKα (λ = 190 1.54060 Å) radiation, was used to investigate the crystallinity of the samples Samples were 191 held on quartz frame Diffraction pattern was obtained at a voltage of 40kV and at a current 192 of 40 mA The samples were scanned in increments of 0.02o from 5o to 80o (diffraction angle 193 2θ) at sec/step, using a zero background sample holder 195 Ac ce p 194 te 189 2.2.7 Fourier transform infrared spectroscopy (FTIR) 196 A FTIR spectrophotometer (Bruker Vertex 70, Germany) was used to investigate the 197 spectra of functionalized iron oxide nanoparticles The wavelength was scanned from 500 to 198 4000 cm-1 with a resolution of cm-1 KBr pellets were prepared by gently mixing mg of 199 the sample with 200 mg KBr 10 Page 10 of 23 200 Results and discussion 201 3.1 Characterization of BOA-IONPs In this study, surface of IONPs was decorated with OA and BSA for biomedical 203 applications of theranostics (Figure 1) Arginine was firstly coated on the surface of IONPs 204 The presence of the free amine group provided an opportunity for the conjugation of OA and 205 BSA through the formation of amide bond BSA offered the biocompatibility enhancement of 206 nanoparticles; whereas, OA molecule was used to carry the poorly water-soluble drug us cr ip t 202 207 an 208 209 NH2 211 NH 212 te C NH NH O Ac ce p O C O NH NH C R1 O NH N H 222 R1 C 221 O O C C C O R2 NH 220 C H N 219 R2 O 218 NH R1 R2 217 NH2 NH2 216 HN NH 215 NH d 213 214 M 210 R2 R2 223 Figure Illustration of synthesis iron oxide nanoparticles decorated oleic acid and bovine 224 serum albumin (R1 - conjugated oleic acid, R2 – conjugated bovine serum albumin) 12 Page 11 of 23 The morphology of BOA-IONPs was observed by SEM (Figure 2A) and TEM 226 (Figure 2C, 2D) Generally, these nanoparticles had an average diameter of 28.33 ± 5.77 nm 227 They are a fairly uniform size distribution, spherical shape with a smooth surface as showed 228 in the SEM image Figure 2C and 2D show that BOA-IONPs were covered by the outer layer 229 as compared to IONPs (Figure 2B) and had the diameter below 50 nm These results 230 indicated that OA and BSA were potentially functionalized on the surface of IONPs cr ip t 225 (B) te 231 d M an us (A) (C) Ac ce p (D) 232 233 234 Figure SEM of BOA-IONPs (A) and TEM images of IONPs (B), BOA-IONPs (C, D) 13 Page 12 of 23 To investigate whether the crystalline structure of IONPs in BOA-IONPs was 236 changed or not, PXRD was used to analyze the samples of IONPs and BOA-IONPs The 237 PXRD diffractogram of IONPs indicated a highly crystalline structure with characteristic 238 peaks at 30.2º, 35.7º, 43.3º, 57.2º and 62.9º (Figure 3) The functionalization of amine groups 239 and conjugation of OA and BSA on the surface on IONPs did not affect those peaks In other 240 words, the characteristic peaks of IONPs still maintained under the conditions Therefore, the 241 PXRD results confirmed the the nanocrystalline structure of Fe3O4 [33] in BOA-IONPs us cr ip t 235 Ac ce p te d M an 242 14 Page 13 of 23 The formation mechanism of nanoparticles was elucidated through FTIR analysis 248 Figure shows FTIR spectra of OA, A-IONPs and OA-IONPs Regarding the FTIR 249 spectrum of A-IONPs, the peak at 580 cm-1 can be attributed to the vibration of Fe-O [34] 250 The peaks of arginine at 1610 and 1419 cm−1 are those of COO− asymmetric and symmetric 251 stretch, respectively [35] which were shifted to 1648 and 1400 cm−1 in the coated particles 252 These results suggested the binding of the carboxylic group of arginine to the IONPs The 253 presence of amine groups from arginine provides a means to conjugate OA and BSA 254 Regarding the FTIR spectrum of OA, the carbonyl group of OA was showed at 1710 cm-1 It 255 has been reported that the strong C=O absorption will be shifted to lower wavenumbers if the 256 molecule is conjugated [36, 37] In this case, the C=O peak was shifted to right at 1640 cm-1 257 which was attributed to the peak of amide bond formation [38-40] This result confirmed that 258 OA was successfully conjugated to the amine groups Moreover, BSA was also conjugated to 259 the surface of nanoparticles to provide hydrophilicity and increase the motility in biological 260 fluids As showed in Figure 5, the peak of amide bond in OA-IONPs was at 1640 cm-1 as 261 explained above However, this peak was stronger in the spectrum of BOA-IONPS which 262 was attributed to the formation of another amide bond because of the conjugation of BSA and 263 amine group [39] Besides, the peak at 580 cm-1 which can be attributed to the vibration of 264 Fe-O also appeared in BOA-IONPs Therefore, these results confirmed the conjugation of 265 BSA and OA-IONPs Ac ce p te d M an us cr ip t 247 266 267 268 269 15 Page 14 of 23 1400 an us 1648 cr 1710 A - IONPs ip t OA OA - IONPs 2000 1500 1000 500 -1 Wavelength (cm ) d 270 2500 M 3000 1640 Figure FT-IR spectra of oleic acid (OA), arginine-functionalization iron oxide 272 nannoparticles (A-IONPs) and iron oxide nanoparticles decorated oleic acid (OA-IONPs) Ac ce p 273 te 271 16 Page 15 of 23 cr ip t 273 us 1540 BOA - IONPs 1560 1580 an 1640 1540 1580 d 1560 M BSA te OA - IONPs Ac ce p 1640 2000 274 1800 1600 1400 1200 1000 800 600 Wavelength (cm-1) 275 Figure FT-IR spectra of OA-IONPs, bovine serum albumin (BSA) and iron oxide 276 nanoparticles decorated oleic acid and bovine serum albumin (BOA-IONPs) 277 17 Page 16 of 23 278 3.3 Paclitaxel loading and encapsulation efficiency In this study, paclitaxel was chosen as anticancer drug Paclitaxel was loaded in BOA- 280 IONPs by adsorption on oleic moiety under stirring Percentage of drug loading and 281 encapsulation efficiency were measured by indirect method The amount of paclitaxel loading 282 was calculated from unencapsulated drug in the supernatant by HPLC analysis Paclitaxel 283 was successfully loaded in BOA-IONPs with high encapsulation efficiency Specifically, 284 percentage of encapsulation efficiency was measured to be 93% ± 2.8% Percentage of 285 paclitaxel loading was 8.5% ± 0.23% an us cr ip t 279 287 M 286 3.4 In vitro release study Figure shows that the percent cumulative release rate of paclitaxel from BOA-IONPs 289 at pH 7.4 in 30 days The release profile demonstrates a burst release observed at the initial 290 stage, followed by a slower and continuous release Particularly, paclitaxel was released 14%, 291 24% and 34 % after 1, 2, days, respectively A gradual decrease in release rate was 292 observed after days The initial burst release offers an opportunity to obtain high 293 concentrations of paclitaxel in the target tissue while the potential of prolonged release offers 294 the ability to prevent persistent excessive vascular smooth muscle cell proliferation [41] The 295 rapid release at the initial time may be due to the adsorption of drug on the exterior surface 296 [42] and hydrophilic regions The prolonged release may be attributed to the drug attached to 297 OA [43] Ac ce p te d 288 298 18 Page 17 of 23 299 Ac ce p te d M an us cr ip t 300 19 Page 18 of 23 demonstrated the successful conjugation of OA and BSA on the surface of iron oxide 308 nanoparticles More importantly, it was found that paclitaxel was loaded in BOA-IONPs with 309 a high encapsulated efficiency The in vitro release paclitaxel suggested that BOA-IONPs 310 could be a promising dug carrier for cancer therapy Moreover, the current nanoparticles with 311 magnetic core are potential for theranostics Further studies are required to evaluate the 312 application of these nanoparticles in diagnostic cr ip t 307 an 314 us 313 Acknowledgments: This research is funded by Vietnam National University – Ho Chi Minh City under 316 grant number C2014-28-09 We would like to thank to International University for their 317 continued, generous and invaluable support to our studies as well as greatly boost the 318 efficiency of our research activities We also thank to Mr Khanh Nghia Tran for his research 319 assistance in the preparation of nanoparticles d te Ac ce p 320 M 315 20 Page 19 of 23 References 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 [1] P.H.-L Tran, T.T.-D Tran, T.V Vo, Polymer Conjugate-Based Nanomaterials for Drug Delivery, J Nanosci Nanotechnol., 14 (2014) 815-827 [2] S Bamrungsap, Z Zhao, T Chen, L Wang, C Li, T Fu, W Tan, Nanotechnology in therapeutics: a focus on nanoparticles as a drug delivery system, Nanomed., (2012) 1253-1271 [3] X.-X Song, Z.-J Liu, Q Tang, Folate Grafted Prussian Blue Entrapped with Gadolinium(III) as a New Contrast Agent for Tumor-Targeted Magnetic Resonant Imaging, J Nanosci Nanotechnol., 13 (2013) 5233-5239 [4] N.P Praetorius, T.K Mandal, Engineered Nanoparticles in Cancer Therapy, Recent Pat Drug Delivery Formulation, (2007) 37-51 [5] P Gill, Nanocarriers, nanovaccines, and nanobacteria as nanobiotechnological concerns in modern vaccines, Sharif University of Technology, 20 (2013) 1003-1013 [6] J.K Vasir, M.K Reddy, V.D Labhasetwar, Nanosystems in Drug Targeting: Opportunities and Challenges, Current Nanoscience, (2005) 47-64 [7] C Jiang, J Niu, M Li, Y Teng, H Wang, Y Zhang, Tumor Vasculature-Targeted Recombinant Mutated Human TNF-α Enhanced the Antitumor Activity of Doxorubicin by Increasing Tumor Vessel Permeability in Mouse Xenograft Models, PLoS One, (2014) e87036 [8] S.H Jang, M.G Wientjes, D Lu, J.L.-S Au, Drug delivery and transport to solid tumors, Pharm Res., 20 (2003) 1337-1350 [9] A Tiwari, A Tiwari, Bioengineered Nanomaterials, Taylor & Francis, 2013 [10] P.H Tran, T.T Tran, T.V Vo, B.J Lee, Promising iron oxide-based magnetic nanoparticles in biomedical engineering, Arch Pharm Res., 35 (2012) 2045-2061 [11] A Kumar, P.K Jena, S Behera, R.F Lockey, S Mohapatra, S Mohapatra, Multifunctional magnetic nanoparticles for targeted delivery, Nanomedicine : nanotechnology, biology, and medicine, (2010) 64-69 [12] E Munnier, S Cohen-Jonathan, C Linassier, L Douziech-Eyrolles, H Marchais, M Soucé, K Hervé, P Dubois, I Chourpa, Novel method of doxorubicin–SPION reversible association for magnetic drug targeting, Int J Pharm., 363 (2008) 170-176 [13] S Liu, B Jia, R Qiao, Z Yang, Z Yu, Z Liu, K Liu, J Shi, H Ouyang, F Wang, M Gao, A Novel Type of Dual-Modality Molecular Probe for MR and Nuclear Imaging of Tumor: Preparation, Characterization and in Vivo Application, Mol Pharm., (2009) 1074-1082 [14] U.O Häfeli, J.S Riffle, L Harris-Shekhawat, A Carmichael-Baranauskas, F Mark, J.P Dailey, D Bardenstein, Cell Uptake and in Vitro Toxicity of Magnetic Nanoparticles Suitable for Drug Delivery, Mol Pharm., (2009) 1417-1428 [15] M Talelli, C.J.F Rijcken, T Lammers, P.R Seevinck, G Storm, C.F van Nostrum, W.E Hennink, Superparamagnetic Iron Oxide Nanoparticles Encapsulated in Biodegradable Thermosensitive Polymeric Micelles: Toward a Targeted Nanomedicine Suitable for Image-Guided Drug Delivery, Langmuir, 25 (2009) 2060-2067 [16] Q.A Acton, Epoxy Compounds—Advances in Research and Application: 2013 Edition, ScholarlyEditions, 2013 [17] S.M Moghimi, A.C Hunter, J.C Murray, Long-Circulating and Target-Specific Nanoparticles: Theory to Practice, Pharmacol Rev., 53 (2001) 283-318 [18] B Romberg, W.E Hennink, G Storm, Sheddable coatings for long-circulating nanoparticles, Pharm Res., 25 (2008) 55-71 [19] V.P Torchilin, V.S Trubetskoy, Which polymers can make nanoparticulate drug carriers longcirculating?, Adv Drug Delivery Rev., 16 (1995) 141-155 [20] M Vittaz, D Bazile, G Spenlehauer, T Verrecchia, M Veillard, F Puisieux, D Labarre, Effect of PEO surface density on long-circulating PLA-PEO nanoparticles which are very low complement activators, Biomaterials, 17 (1996) 1575-1581 Ac ce p te d M an us cr ip t 320 21 Page 20 of 23 te d M an us cr ip t [21] T Neuberger, B Schöpf, H Hofmann, M Hofmann, B von Rechenberg, Superparamagnetic nanoparticles for biomedical applications: Possibilities and limitations of a new drug delivery system, J Magn Magn Mater., 293 (2005) 483-496 [22] F Roohi, J Lohrke, A Ide, G Schütz, K Dassler, Studying the effect of particle size and coating type on the blood kinetics of superparamagnetic iron oxide nanoparticles, Int J Nanomedicine, (2012) 4447 [23] E.D Smolensky, H.Y.E Park, T.S Berquó, V.C Pierre, Surface functionalization of magnetic iron oxide nanoparticles for MRI applications–effect of anchoring group and ligand exchange protocol, Contrast Media Mol Imaging, (2011) 189-199 [24] H Mohammad-Beigi, S Yaghmaei, R Roostaazad, H Bardania, A Arpanaei, Effect of pH, citrate treatment and silane-coupling agent concentration on the magnetic, structural and surface properties of functionalized silica-coated iron oxide nanocomposite particles, Physica E: Lowdimensional Systems and Nanostructures, 44 (2011) 618-627 [25] D Smejkalova, K Nešporová, G Huerta-Angeles, J Syrovatka, D Jirak, A Gálisová, V Velebny, Selective in vitro anticancer effect of superparamagnetic iron oxide nanoparticles loaded in hyaluronan polymeric micelles, Biomacromolecules, (2014) [26] L.M Bronstein, X Huang, J Retrum, A Schmucker, M Pink, B.D Stein, B Dragnea, Influence of Iron Oleate Complex Structure on Iron Oxide Nanoparticle Formation, Chem Mater., 19 (2007) 36243632 [27] L Zhang, R He, H.-C Gu, Oleic acid coating on the monodisperse magnetite nanoparticles, Appl Surf Sci., 253 (2006) 2611-2617 [28] J Huang, L Wang, R Lin, A.Y Wang, L Yang, M Kuang, W Qian, H Mao, Casein-Coated Iron Oxide Nanoparticles for High MRI Contrast Enhancement and Efficient Cell Targeting, ACS Appl Mater Interfaces, (2013) 4632-4639 [29] T.K Jain, M.A Morales, S.K Sahoo, D.L Leslie-Pelecky, V Labhasetwar, Iron Oxide Nanoparticles for Sustained Delivery of Anticancer Agents, Mol Pharm., (2005) 194-205 [30] M Karimi, P Avci, R Mobasseri, M.R Hamblin, H Naderi-Manesh, The novel albumin-chitosan core-shell nanoparticles for gene delivery: preparation, optimization and cell uptake investigation, J Nanopart Res, 15 (2013) 1651 [31] R M., M Jahanshahi, G.D Najafpour, Production of biological nanoparticles from bovine serum albumin for drug delivery, Afr J Biotechnol., (2006) 1918-1923 [32] G.T Hermanson, Chapter - Zero-Length Crosslinkers, in: G.T Hermanson (Ed.) Bioconjugate Techniques (Second Edition), Academic Press, New York, 2008, pp 213-233 [33] H Yang, C Zhang, X Shi, H Hu, X Du, Y Fang, Y Ma, H Wu, S Yang, Water-soluble superparamagnetic manganese ferrite nanoparticles for magnetic resonance imaging, Biomaterials, 31 (2010) 3667-3673 [34] I.J Bruce, T Sen, Surface Modification of Magnetic Nanoparticles with Alkoxysilanes and Their Application in Magnetic Bioseparations, Langmuir, 21 (2005) 7029-7035 [35] N Ahmad, M Ahmad, M Aslam, S.N Singh, S.S Talwar, Synthesis of Arginine Functionalized Iron Oxide Nanorods, Advanced Science, Engineering and Medicine, (2012) 132-136 [36] A Kolbe, C Griehl, S Biehler, Molecular interactions in conjugates of dicarboxylic acids and amino acids, J Mol Struct., 661-662 (2003) 239-246 [37] N Nakamura, F Kiuchi, Y Tsuda, Infrared Spectra of Conjugated Amides : Reassignment of the C=O and C=C Absorptions, Chem Pharm Bull., 36 (1988) 2647-2651 [38] D.H Lee, R.A Condrate, FTIR spectral characterization of thin film coatings of oleic acid on glasses: I Coatings on glasses from ethyl alcohol, J Mater Sci., 34 (1999) 139-146-146 [39] B Ou, D Li, Preparation of polystyrene/silica nanocomposites by radical copolymerization of styrene with silica macromonomer, Science in China Series B: Chemistry, 50 (2007) 385-391 [40] X Yuan, H Li, Y Yuan, Preparation of cholesterol-modified chitosan self-aggregated nanoparticles for delivery of drugs to ocular surface, Carbohydr Polym., 65 (2006) 337-345 Ac ce p 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 22 Page 21 of 23 [41] U Westedt, M Kalinowski, M Wittmar, T Merdan, F Unger, J Fuchs, S Schaller, U Bakowsky, T Kissel, Poly(vinyl alcohol)-graft-poly(lactide-co-glycolide) nanoparticles for local delivery of paclitaxel for restenosis treatment, J Control Release, 119 (2007) 41-51 [42] M Alonso, S Cohen, T Park, R Gupta, G Siber, R Langer, Determinants of Release Rate of Tetanus Vaccine from Polyester Microspheres, Pharm Res., 10 (1993) 945-953 [43] J.S Chawla, M.M Amiji, Biodegradable poly([var epsilon]-caprolactone) nanoparticles for tumor-targeted delivery of tamoxifen, Int J Pharm., 249 (2002) 127-138 ip t 419 420 421 422 423 424 425 Ac ce p te d M an us cr 426 23 Page 22 of 23 426 427  Oleic acid and bovine serum albumin were decorated on the surface of iron oxide nanoparticles in new pattern 428  Potential utility in delivery of anticancer drugs 429 Ac ce p te d M an us cr ip t 430 24 Page 23 of 23 ... Figure Illustration of synthesis iron oxide nanoparticles decorated oleic acid and bovine 224 serum albumin (R1 - conjugated oleic acid, R2 – conjugated bovine serum albumin) 12 Page 11 of 23 The... spectra of OA-IONPs, bovine serum albumin (BSA) and iron oxide 276 nanoparticles decorated oleic acid and bovine serum albumin (BOA-IONPs) 277 17 Page 16 of 23 278 3.3 Paclitaxel loading and encapsulation.. .Design of iron oxide nanoparticles decorated oleic acid and bovine serum albumin for drug delivery Thao Truong-Dinh Tran*, Toi Van Vo and Phuong Ha-Lien Tran* Pharmaceutical