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Colloids and Surfaces B: Biointerfaces xxx (2014) xxx–xxx

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Protein corona change the drug release profile of nanocarriers: The “overlooked” factor at the nanobio interface Shahed Behzadi a , Vahid Serpooshan b , Ramin Sakhtianchi c , Beate Müller a , Katharina Landfester a,∗ , Daniel Crespy a , Morteza Mahmoudi b,c,d,∗∗ a

Max Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany Department of Pediatrics, Division of Cardiology, School of Medicine, Stanford University, Stanford, CA, United States c Department of Nanotechnology and Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran d Division of Cardiovascular Medicine, School of Medicine, Stanford University, Stanford, CA, United States b

a r t i c l e

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Article history: Received 17 May 2014 Accepted 3 September 2014 Available online xxx Keywords: Drug release profile Protein corona Nanocarriers Polymeric shell

a b s t r a c t The emergence of nanocarrier systems in drug delivery applications has ushered in rapid development of new classes of therapeutic agents which can provide an essential breakthrough in the fight against refractory diseases. However, successful clinical application of nano-drug delivery devices has been limited mainly due to the lack of control on sustained release of therapeutics from the carriers. A wide range of sophisticated approaches employs the formation of crosslinkable, non-crosslinkable, stimuli-responsive polymer nanocarriers in order to enhance their delivery efficiency. Despite the extensive research conducted on the development of various nanocarriers, the effect of the biological milieu on the drug release profile of these constructs is not yet fully investigated. In particular, the formation of a protein corona on the surface of nanocarriers, when they interact with living organisms in vivo is largely decisive for their biological function. Using a number of synthetized (i.e., superparamagnetic iron oxide nanoparticles and polymeric nanocapsules) and commercialized nanocarriers (i.e., Abraxane® , albumin-bound paclitaxel drug), this study demonstrates that the protein corona can shield the nanocarriers and, consequently, alters the release profile of the drugs from the nanocarriers. More specifically, the protein corona could significantly reduce the burst effect of either protein conjugated nanocarriers or carriers with surface loaded drug (i.e., SPIONs). However, the corona shell only slightly changed the release profile of polymeric nanocapsules. Therefore, the intermediary, buffer effect of the protein shells on the surface of nanoscale carriers plays a crucial role in their successful high-yield applications in vivo. © 2014 Elsevier B.V. All rights reserved.

1. Introduction Nano-science and -technology provide an unprecedented understanding and control of matter at its most fundamental levels (on the atomic and the molecular scale) [1,2]. More specifically, nanoparticles (NPs) have attracted much attention due to their unusual electronic, optical, mechanical, and magnetic properties [1,3]. The unique characteristics of NPs facilitate their use in biomedical applications such as tissue engineering, gene delivery, anti-bacterial/anti-infection, contrast agents for magnetic

∗ Corresponding author. ∗∗ Corresponding author at: Division of Cardiovascular Medicine, School of Medicine, Stanford University, Stanford, CA, United States. Tel.: +14157418577. E-mail addresses: [email protected] (K. Landfester), [email protected], [email protected] (M. Mahmoudi).

resonance imaging, and targeted drug delivery [4–6]. Whereas the outcomes of the studies utilizing various NP systems in biomedical applications have been modest but promising, specific shortcomings still remain; for instance, from the nanomedicine point of view, one important challenge is to design efficient nanoscale drug-delivery systems. For this purpose, nanocarriers must have crucial capabilities in inhibiting instant release (i.e., burst effect) and controlled release of the drugs [7–11]. Upon their entrance in the biological medium, the surface of NPs is covered by various biomolecules (proteins) through a process called “protein corona effect” [12–14]. Therefore, the primary interaction of biological species (e.g., cell and organs) with NPs is strongly influenced by the “hard corona” (i.e., a long-lived protein layer that strongly adsorbed to the surface of the NP and remains stable for several hours) [15–17]. This new biological identity of the NPs can entirely change the direction of the research currently being conducted in the field of nanobiomedicine. Therefore, one can

http://dx.doi.org/10.1016/j.colsurfb.2014.09.009 0927-7765/© 2014 Elsevier B.V. All rights reserved.

Please cite this article in press as: S. Behzadi, et al., Protein corona change the drug release profile of nanocarriers: The “overlooked” factor at the nanobio interface, Colloids Surf. B: Biointerfaces (2014), http://dx.doi.org/10.1016/j.colsurfb.2014.09.009

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expect to have deep understanding on the comprehensive occurred interactions at the nano-bio interfaces to design safe, reliable, and high-yield NPs, for desired biomedical purpose. In this case, extensive studies were dedicated to probe every individual crucial factor, which should be considered at the nano-bio interfaces [18]. However, the arisen disappointing results (which mainly achieved based on the conflicts in the reported papers for cytotoxicity and/or biological fate evaluation of the exact same NPs) revealed that there are still too many “hidden” factors at nanoparticle-biological complex medium [19]. For instance, it has been discovered that the protein corona can cover the targeting molecules on the surface of NPs and causes loss of specificity in targeting [20,21]. In another study, it was shown that the corona formation slows down the fibrillation process of the amyloidic proteins (e.g., amyloid beta), regardless to the physicochemical properties of the NPs [22]. Here, in this paper, another important ignored factor is introduced for drug delivery systems. In this case, we are going to probe the effect of protein corona, which can shield the nanocarriers, on the release profile of the drugs from the various nanocarriers (i.e., superparamagnetic iron oxide nanoparticles, polymeric nanocapsules, and Abraxane® ). 2. Materials and methods 2.1. Superparamagnetic iron oxide nanoparticles 2.1.1. Materials PEG diol (MW 1 kDa), fumaryl chloride, calcium hydride, and propylene oxide were all purchased from Aldrich (Milwaukee, MN, USA). Ammonium persulfate, methylene chloride (DCM) and dimethylaminoethyl methacrylate (DMAEMA) were purchased from Merck (Germany). Fumaryl chloride was purified by distillation at 161 ◦ C under ambient pressure. Tamoxifen was obtained from Pharma Chemie Company (Tehran, Iran). Anhydrous DCM was obtained by distillation under reflux condition for 1 h in the presence of calcium hydride. All other materials were purchased from Aldrich (Milwaukee, MN, USA). The solvents were reagent grades and used without any further purification. 2.1.2. Preparation of PEGF For the preparation of the polyethyleneglycol-co-fumarate (PEGF) macromers, the Temenoff method [23] was employed (see Fig. S1 of supporting information (SI) for details). Briefly, PEG diol (0.03 mol) was dissolved in anhydrous DCM (100 ml) in a 250 ml reaction flask equipped with a reflux condenser and a magnetic stirrer. During the polymerization process, the HCl was produced as side product. In order to remove the produced HCl, we used propylene oxide which can extensively bind to it. Then, DCM (50 ml with purified fumaryl chloride) was added dropwise into the reaction flask (for a period of 1 h at −2 ◦ C under nitrogen atmosphere; it is notable that the solution in the flask was vigorously stirred by a magnetic stirrer). The reaction temperature was then raised into 25 ◦ C and conserved overnight followed by an extensive washing (with 0.1 N NaOH) for removal of the byproducts such as chlorinated propanols. Finally, the PEGF macromer was obtained by evaporation under vacuum, and then dried at 25 ◦ C in vacuum for 24 h. The final product was stored at −15 ◦ C for further use. 2.1.3. Preparation of PEGF-coated superparamagnetic iron oxide nanoparticles Mono-dispersed superparamagnetic iron oxide nanoparticles (SPIONs) were synthesized by the thermal decomposition of ironoleate [24]. Typically, 18 g (20 mmol) of iron-oleate complex and 5.7 g of oleic acid (20 mmol) were dissolved in 100 g of 1-octadecene at room temperature. The reaction mixture was then degassed at 80 ◦ C for a period of 2 h. The obtained solution was heated to a

reflux temperature at a heating rate of 3 ◦ C/min and then kept for 30 min under inert atmosphere. Immediately after the reaction, the container was cooled down to room temperature followed by addition of acetone (500 ml) to precipitate the prepared SPIONs. The obtained SPIONs were pelleted (using centrifugation) and redispersed in hexane. The prepared SPIONs are hydrophobic. Therefore, in order to hydrophilize them, the ligand exchange method was employed to coat them with PEGF [25]. Briefly, 4 ml of the SPION solution (1 mg/ml iron) was mixed with the PEGF solution in 90 ml DMSO at room temperature for 72 h in a shaking incubator. The SPIONs were then separated from DMSO solution by magnetic-activated cell sorting (MACS® ) system and re-dispersed into 1 ml of DI water. In order to ensure the removal of the unbounded PEGF into the surface of SPIONs, the washing process was extensively (7 times) repeated. The obtained water-soluble SPIONs were stable at room temperature without detectable precipitation for several months. 2.1.4. Preparation of crosslinked-PEGF-coated SPIONs The redox crosslinking reaction (in the presence of ammonium persulfate [(NH4 )2 S2 O8 ], as initiator system, and DMAEMA, as accelerator) was performed for cross-linking the unsaturated bonds (in the PEGF structure) at the surface of PEGF coated SPIONs. The prepared coated SPIONs were characterized (see Table S1 for details) and kept at 4 ◦ C for future use. 2.1.5. Drug loading in the surface of coated nanoparticles The anti-estrogen drug for breast cancer treatment, Tamoxifen citrate (TMX), was employed as a model drug. In order to have efficient drug loading at the surface of the coated SPIONs, the lyophilized coated SPIONs (either non-cross-linked or crosslinked PEGF) were added into a phosphate buffered saline (PBS) solution containing 1 mg/ml drug. In this situation, the PBS solution (contained drug) was penetrated into the PEGF coating (due to its hydrogel property). The drug loaded SPIONs were then collected by MACS and re-dispersed in fresh PBS. In order to have a fair comparison with the NPs coated with proteins, drug loaded particles remained in PBS for 15 min, followed by 2× centrifugation (13,000 × g; 15 min) at 15 ◦ C. The collected particles were re-dispersed in PBS and the drug release data were collected for a duration of 30 h at 15 ◦ C. Two milliliters of each sample were centrifuged at the selected release times; the solutions were then introduced in an ultraviolet (UV) spectrometer (Milton Roy Spectronic 601) for the evaluation of drug content (TMX has absorbance at 277 nm). The entire drug release and adsorption measurements were performed in triplicates and the standard deviations were calculated. 2.1.6. Preparation of hard corona-coated nanoparticles The drug loaded particles (with iron concentration of 100 ␮g/ml) were incubated with 10% and 100% concentrations of FBS for 1 h at 37 ◦ C. To obtain a hard corona complex, NPs were centrifuged (13,000 × g, 15 min, at 15 ◦ C) to pellet the particle-protein complexes. The pellet was then re-suspended in 500 ␮l of PBS and centrifuged to remove unbonded or loosely attached proteins. The collected particles were re-dispersed in PBS and the drug releases data were collected for the duration of 200 h. 2.1.7. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS PAGE) Upon completion of the last centrifugation step, the various SPION-protein corona pellets were re-suspended in protein loading buffer and boiled for 5 min at 100 ◦ C. Subsequently, an equal sample volume of the obtained protein solution was loaded in 15% polyacrylamide gels and gel electrophoresis was performed at 120 V and

Please cite this article in press as: S. Behzadi, et al., Protein corona change the drug release profile of nanocarriers: The “overlooked” factor at the nanobio interface, Colloids Surf. B: Biointerfaces (2014), http://dx.doi.org/10.1016/j.colsurfb.2014.09.009

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400 mA for about 60 min (for each sample). The gels were stained by the silver staining method. 2.1.8. Methods The morphologies of various SPIONs were analyzed by transmission electron microscopy (TEM) using JEOL-2010 and FEI Tecnai F20 electron microscopes operating at 200 kV. To prepare the samples for TEM, a drop of the SPION suspension was placed on a copper grid and dried. Dynamic light scattering (DLS) measurements were performed with a Malvern PCS-4700 instrument equipped with a 256-channel correlator. The 488.0 nm line of a Coherent Innova-70 Ar ion laser (250 mW) was used as incident beam. The scattering angles  ranged between 40◦ and 140◦ . The temperature was maintained at 25 ◦ C with an external circulator. Each measurement was an average of six repetitions (one min each) and repeated five times. Data analysis was performed according to standard procedures and interpreted through a cumulant expansion of the field autocorrelation function to the second order. In order to obtain the distribution of decay rates, a constrained regularization method, CONTIN, was used to invert the experimental data. Fourier transform infrared (FTIR) spectra (4000–400 cm−1 ) were obtained using a Bruker, Equinox 55 spectrophotometer at 4 cm−1 resolution and 32 scans. All samples were prepared as KBr discs. 1 H NMR spectra were recorded in CDCl3 at 25 ◦ C (Bruker Ultrashield® 400 MHz, Germany). Phase characterization was accomplished using the XRD (Siemens, D5000, Germany) technique with Cu K␣ radiation. XRD samples were prepared by drying the obtained particles in a vacuum oven at 40 ◦ C for 12 h after centrifugation. UV/Vis spectroscopy of the drug release was measured with a Lambda 950 spectrophotometer (PerkinElmer, USA). 2.2. Nanocapsules 2.2.1. Materials Poly(methyl methacrylate) (PMMA) (Mw ∼ 35000 g/mol) and chloroform (99+%) were purchased from Acros Organic. 4Nitroanisole (97%) was purchased from Sigma–Aldrich. Hexadecane (99%) and sodium dodecyl sulfate (SDS) were purchased from Merck. 10% Bis-Tris Protein Gel-Novex® and SeeBlue® Plus2 Prestained Protein were purchased from Life technologies. 2.2.2. Preparation of nanocapsules PMMA (250 mg), hexadecane with 1.5 wt% of 4-nitroanisole (250 mg), and 5 ml chloroform were mixed and stirred at 800 rpm for 30 min. 10 ml of a SDS aqueous solution (0.33 mg/ml) was then added, followed by stirring at 1350 rpm for 1 h. The mixture was sonicated with a sonifier (Branson W450D Digital, quarter inch tip) for 2 min (30 s pulse and 10 s pause) in the presence of an ice-bath. Miniemulsion was kept stirring in an oil bath at 40 ◦ C for 16 h to evaporate the chloroform. 2.2.3. Release studies The active ingredient used in this study is 4-nitroanisole. The active ingredient must be soluble in the oil phase (i.e., hexadecane) and also soluble in the aqueous release medium. The concentration gradient of the active ingredient between the oil phase and the aqueous release medium is the driving force for the release. 4-Nitroanisole has a solubility in the oil around 1.7 wt% and of 589 mg L−1 in the aqueous release medium at room temperature. Release studies were performed by pouring a sample of the nanocapsules dispersion (5 ml) diluted in 15 ml of deionized water, 10% FBS, or 100% FBS into a dialysis tube, which was placed in distilled water (500 ml). The amount of released 4nitroanisole was determined by measuring the concentration of the active ingredient in the aqueous release medium with high performance liquid chromatography (HPLC) (setup: Agilent Series 1200;

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Column: Macherey-Nagel HRX; Eluent: CH3 CN/Water + 0.1%TFA 65/35) at 320 nm. By measuring the concentration of 4-nitroanisole in the release medium as a function of time, the release profile of the active ingredient could be determined. The release data were obtained from three times independent measurements. 2.2.4. Preparation of nanocapsules coated with a hard corona The preparation of the hard-corona was obtained by centrifugation. The spin velocity and time was optimized according to the NCs shell strength, size, and density. To separate the NC-protein complexes from the media containing the excess proteins (supernatant), 1.5 ml of the NCs dispersion was centrifuged (8000 × g, 1 h, 20 ◦ C) after the release experiments and the NC-protein complexes was then resuspended in 1.5 ml of DI water. To remove completely unbound and loosely attached proteins from the NC-hard corona, the centrifugation step was repeated 3 times. 2.2.5. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS PAGE) After preparation of the hard corona coated nanocapsules, the capsules were re-suspended in protein loading buffer and boiled for 5 min at 100 ◦ C. Subsequently, an equal sample volume was loaded in 10% polyacrylamide gels and gel electrophoresis was performed at 60 V and 300 mA for about 120 min. The gels were stained with the Coomassie Blue Staining Method. 2.3. Abraxane 2.3.1. In situ drug release from Abraxane 1.25 mg of Abraxane, which contains 10% of paclitaxel, was placed into tubes containing 1 ml Phosphate Buffered Saline (PBS, pH ∼ 7.4). To investigate the in situ effect of protein corona (i.e., in the presence of excess plasma) on the release profile of Abraxane, different release media were prepared by adding 9 ml of PBS, HP (human plasma) 100%, FBS 100%, HP 10% (90% PBS + 10% HP), or FBS 10% (90% PBS + 10% FBS). The final release media (10 ml) were incubated under agitation (Heidolph, Unimax 1010, Germany, 100 rpm) at 37 ◦ C. For preparation of human plasma blood was withdrawn from 10 volunteers from the National Cell Bank staff (Pasteur Institute of Iran, Tehran, Iran), and collected into 10 ml K2EDTA coated tubes (BDBioscience (UK)). Plasma was prepared following the HUPO BBB SOP guidelines. At desirable time intervals, tubes were centrifuged (Sigma, 3-30K, Germany) at 20,000 rpm for 30 min (at 4 ◦ C). The amount of released paclitaxel was determined by measuring drug concentration in the supernatant. To extract paclitaxel and determine the drug content, 2 ml dichloromethane (DCM) was added and the organic phase was collected and left at room temperature to evaporate the DCM. This was followed by adding 1.5 ml of mixture of acetonitrile and water (65/35, v/v) to dissolve the drug. High-performance liquid chromatography (HPLC) (Young Lin Instrument, Acme 9000, Korea) was performed to analyze the drug content. 2.3.2. Drug release in the absence of excess proteins To investigate the hard corona effect (in the absence of excess proteins) on the drug release profile, 1.25 mg of Abraxane was placed in micro-tubes containing 100 ␮l PBS (pH ∼ 7.4). 900 ␮l of PBS, HP 100%, FBS 100%, HP 10% or FBS 10% was added to the tubes, followed by 30 min incubation under agitation (100 rpm) at 37 ◦ C. Subsequently, tubes were centrifuged at 15,000 rpm for 30 min (4 ◦ C). The resulted sediments were re-dispersed in 10 ml PBS and the final release media (10 ml) were incubated under agitation (100 rpm) at 37 ◦ C. At desirable time intervals, tubes were centrifuged at 20,000 rpm for 30 min (4 ◦ C) and the amount of drug

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Fig. 2. (a) TEM and (b) SEM images of the nanocapsules.

compared to the 10% FBS (as the number and intensity of protein bands for 100% FBS were higher that 10% FBS; see Figs. S3 and S4 of SI). The release behavior of PEGF-coated SPIONs (before and after crosslinking), without corona or with 10 or 100% hard corona, was assessed by incubation of carriers in PBS in a 30 h time, at 15 ◦ C, course (Fig. 3a). Non-crosslinked and crosslinked NPs

Fig. 1. (a) TEM images of the prepared SPIONs (at different magnifications); (b) selected area diffraction pattern of the TEM image shown in (a) and its corresponding energy dispersive X-ray pattern; (c) TEM images of the crosslinked PEGF-coated SPIONs at different magnifications.

release was determined by measuring drug concentration in the supernatant by HPLC. 3. Results 3.1. Synthetic nanocarriers The synthetic nanocarriers under investigation include poly(ethylene glycol) fumarate (PEGF)-coated superparamagnetic iron oxide NPs (SPIONs), which were prepared as a model of ultra-small nanosystem according to previous reports [23–24] (see Fig. 1 and Figs. S1–S3 of the SI for details) and polymer nanocapsules (see Fig. 2). The PEGF-coated SPIONs with narrow size distribution (Fig. 1), with or without crosslinking, were loaded with tamoxifen citrate drug. In order to coat the NPs with a protein corona, the crosslinked coated SPIONs, the nanocapsules, and the abraxane were interacted with both 10 and 100% of fetal bovine serum (FBS). Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS PAGE) was employed to probe the corona pattern on the surface of all types of nanoparticles. The obtained corona patterns of the crosslinked NP samples illustrated the high affinity of proteins to the surface of NPs. According to the SDS-PAGE gel results, the 100% FBS showed higher amounts of associated proteins on the surface of SPIONs and nanocapsules

Fig. 3. (a) Release profile of tamoxifen from various SPIONs over 30 h; (b) release profile of tamoxifen from various SPIONs over 30 h; heating of the solution were performed at 50 ◦ C for 5 min.

Please cite this article in press as: S. Behzadi, et al., Protein corona change the drug release profile of nanocarriers: The “overlooked” factor at the nanobio interface, Colloids Surf. B: Biointerfaces (2014), http://dx.doi.org/10.1016/j.colsurfb.2014.09.009

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Fig. 4. Release profile of 4-nitroanisole from either bare- or corona-coatednanocapsules over 80 h.

without protein corona showed burst effects of 55.4% ± 1.3 and 33.1% ± 1.9, respectively. In agreement with previous report [23], the crosslinked PEGF-coated SPIONs were able to attenuate the burst effect to around 70% of non-crosslinked NPs. On the other hand, the protein corona-coated NPs demonstrated significantly greater control over burst effect; more specifically, 10% and 100% corona coated SPIONs only showed 10.2% ± 1.7 and 4.1% ± 1.2 drug release at first 1 h of drug release, respectively (compare to the crosslinked particles: 33.1% ± 1.9). In order to further evaluate the influence of the protein shell structure on shielding the drug, the hard corona coated samples were heated to 50 ◦ C for a period of 5 min (Fig. 3b). This resulted in partial disruption of the protein coronas structure which in turn led to the rapid drug release from corona-coated NPs (arrows in Fig. 3b). It is notable that one can also expect the fact that an increasing in temperature may enhance the diffusion coefficient of drug molecules, leading to the higher drug release. However, as there were no considerable changes in the drug release profile of NPs without protein corona during the heating procedure, it can be concluded that the protein corona disruption was the dominant effect on the drug release profile. Interestingly, whereas the protein corona showed significant effects on the drug loaded SPIONs where the drug was loaded at the surface of NPs, it did not significantly impart the release profile of the payload from the nanocapsules (see Fig. 4). 3.2. Commercial nanocarriers For the FDA approved nano-carrier (Abraxane) exposed to various FBS concentrations (10% and 100%), the protein corona was formed on the surface of NPs (Fig. 5a). The drug release profiles were probed on the bare and corona coated Abraxane (on the complexes both in situ (in the presence of excess proteins; soft corona) and free from excess proteins (hard corona)) using high-performance liquid chromatography (HPLC) method (Fig. 5b). In addition to FBS, the drug release profiles in presence of the human plasma were probed (see Fig. 6a and b). 4. Discussion In this study, we examined the potential effect of protein corona formation on shielding the drugs and disturbing their controlled release. Using various types of synthetic (tamoxifenloaded crosslinked superparamagnetic iron oxide NPs (SPIONs)

Fig. 5. (a) 15% and 20% SDS-PAGE gel of paclitaxel drug and proteins obtained from abraxane and abraxane-protein complexes free from excess proteins, following incubation with FBS at various concentrations (10% and 100%); the molecular weights (kDa) of the proteins in the standard ladder are reported on the left for reference; panels show the SEM images of bare and corona coated Abraxane (scale bars are 50 nm). (b) Paclitaxel release profile from pristine Abraxane and Abraxanecorona complexes either in situ or after removal of excess proteins (hard corona) after incubation with FBS at various concentrations (i.e., 10% and 100%).

and 4-nitroanisole-loaded nanocapsules), and the U.S. Food and Drug Administration (FDA) approved, commercialized, drug loaded nanocarriers (Abraxane® , albumin-bound paclitaxel injection), we demonstrated that the drug release of nanocarriers is significantly attenuated in biological environments. More specifically, the protein corona showed significant effects on the release profile of the drug loaded SPIONs; however, there was no considerable effect of protein corona on the release profile of the payload from the nanocapsules (see Fig. 4). This observation can be explained by the fact that the hard corona is thinner (

Protein corona change the drug release profile of nanocarriers: the "overlooked" factor at the nanobio interface.

The emergence of nanocarrier systems in drug delivery applications has ushered in rapid development of new classes of therapeutic agents which can pro...
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