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Chubarov, A. Serum Albumin for Magnetic Nanoparticles Coating. Encyclopedia. Available online: https://encyclopedia.pub/entry/20390 (accessed on 19 March 2025).
Chubarov A. Serum Albumin for Magnetic Nanoparticles Coating. Encyclopedia. Available at: https://encyclopedia.pub/entry/20390. Accessed March 19, 2025.
Chubarov, Alexey. "Serum Albumin for Magnetic Nanoparticles Coating" Encyclopedia, https://encyclopedia.pub/entry/20390 (accessed March 19, 2025).
Chubarov, A. (2022, March 09). Serum Albumin for Magnetic Nanoparticles Coating. In Encyclopedia. https://encyclopedia.pub/entry/20390
Chubarov, Alexey. "Serum Albumin for Magnetic Nanoparticles Coating." Encyclopedia. Web. 09 March, 2022.
Serum Albumin for Magnetic Nanoparticles Coating
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This entry is adapted from the peer-reviewed paper 10.3390/magnetochemistry8020013

Magnetic nanoparticles (MNPs) have great potential in biochemistry and medical science. In particular, iron oxide nanoparticles have demonstrated a promising effect in various biomedical applications due to their high magnetic properties, large surface area, stability, and easy functionalization. However, colloidal stability, biocompatibility, and potential toxicity of MNPs in physiological environments are crucial for their in vivo application. In this context, many research articles focused on the possible procedures for MNPs coating to improve their physic-chemical and biological properties. The fabrication strategy of biocompatible iron oxide nanoparticles using human serum albumin (HSA) is viable. HSA is mainly a transport protein with many functions in various fundamental processes. It is a highly potential candidate for nanoparticles coating and theranostics area and can provide biocompatibility, prolonged blood circulation, and possibly resolve the drug-resistance cancer problem. 

iron oxide nanoparticles functionalization coating serum albumin drug delivery toxicity biostability

1. Introduction

Magnetic nanoparticles (MNPs) open a wide range of applications, including contrast agents area for magnetic resonance imaging (MRI), material science, magnetic delivery, magnetic fluid hyperthermia, structural biology, drug and gene delivery, theranostics [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17]. Iron oxide MNPs are promising tags due to their high stability, cost-effectivity, and optimal MRI and hyperthermia characteristics [18]. Manipulation with an external magnetic field provides easy separation of MNPs from any liquids and desired location. Moreover, combining approaches of induction local heating in the tumor region, anticancer drugs, and effective monitoring by MRI has a great potential in targeted drug delivery and theranostics area (therapy + diagnostics) [7][11][12][15]. One of the most perspectives ferromagnetic MNPs is magnetite, Fe3O4. However, Fe3O4 is not stable upon oxidation and possesses high surface energy, leading to aggregation. Therefore, surface functionalization is required for such MNPs. The wrong coating leads to instability in the bloodstream and acute or delayed toxicity due to the highly reactive oxygen species (ROS) formation in cell lines and animal models [2][11][19][20][21][22][23][24]. Protein coating usually possesses biocompatibility, biodegradability, less immunogenicity, and lower cytotoxicity of MNPs [25][26][27][28]. Recently, biotechnological applications of human serum albumin (HSA), including bioinspired materials and nanoparticles coating, were reported [29][30][31][32]. Instead, the above-mentioned protein coating features, albumin, one of the major human plasma proteins, reduces unwanted adsorption of blood components and increases the efficiency of tissue and cell targeting [29][30][31][33]. Albumin-constructions transcytosis in the cells is provided by gp60, g30, gp18, and FcRn receptors binding. Moreover, accumulation in a tumor is facilitated by binding to the SPARC receptor and the enhanced permeation and retention effect (EPR) [34][35][36][37][38][39][40][41]. The albumin structure contains many drugs or natural ligand binding sites, which can be used for therapeutics loading.

2. Albumin-Coated Magnetic Nanoparticles Properties

Nanocarriers provide new perspectives in the delivery of anticancer drugs and imaging probes. In particular, MNPs have various applications such as MRI, hyperthermia, controlled drug delivery, etc. (Figure 1). However, several disadvantages have to mention. Low biostability, possible toxicity, and low tissue specificity are among them. Recently, novel strategies such as bioinspired surface coating, coating functionalization with address molecules, and reporter groups have emerged [13]. Here presents the mechanism of the below-presented problems and their possible solutions due to albumin protein coating with further surface functionalization. Albumin is a good candidate for the biosensor, bioimaging, and theranostics carrier [42][43][44]. Due to its unique properties, albumin coating has several advantages mentioned in the previous sections. Possible surface modification leads to various smart systems with address groups, imaging probes, drug complexes, and conjugates (Figure 1 and Figure 2). Another advantage is a passive (EPR-effect) and targeted delivery to cancer tissue due to the albumin receptor interactions.
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Figure 1. Applications of albumin-coated MNPs.
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Figure 2. Covalent and noncovalent strategy features and examples of albumin modification. The most common, easy-synthesized, cheap, and commercially available reagents for the covalent procedure are presented.

2.1. Albumin Coating Effect on MNPs Water Solution Stability and Biostability

The main issue of MNPs is long-term inherent instability. MNPs tend to agglomerate due to the high surface energy and the strong magnetic attraction between particles. Moreover, simple physiological-like high salt concentrations strongly affect the colloidal stability of MNPs. For the Fe3O4 MNPs, magnetism loss occurs under oxygen oxidation. These two main routes can be handled by surface functionalization [12][13][19][33]. Coated MNPs have various advantages over bare MNPs. One more thing is once MNPs enter the blood, biological molecules, especially proteins, cover their surface. So-called protein corona is one reason for the rapid clearance of nanoparticles from the bloodstream after intravenous injection [33]. Since preventing such irregular coating is complex, forming stable pre-coating with optimal characteristics before the injection is required. Organic polymers and low-molecular-weight surfactant coating are among the most popular procedures [10][12][19][45].
A modern approach is using biomolecules coating for improved biocompatibility [3][12]. Albumin adsorption prevents nucleation and the aggregation of MNPs, increases colloidal stability, and is optimal for the in vivo use of nanoparticles [26][45][46][47][48][49][50][51][52][53][54]. For example, BSA-coated MNP remained excellent colloidal stability at 0.15 M sodium chloride concentration for more than one week. In comparison, tannic acid-coated MNPs already formed aggregates at 0.05 M and higher sodium chloride concentration [45]. The albumin-coated nanoparticles size did not alter for a long time in various pH and bioreagents temperature storage range and under 37°C [26][47][49]. There were no significant changes in blood serum/plasma [26]. Albumin preformed MNPs corona is good protection of non-specific interactions with blood components, immune response, and extended half-life (see Section 2) [26][33][45][46][53][54]. Some approaches use tannic, carboxylic acid (lauric, myristic, or oleic), hyaluronic acid, etc., for ferrofluid colloidal stabilization and optimal nucleus size formation with further albumin coating for biostability [52][55][56][57][58][59].

2.2. Preventing Toxicity and Targeted Delivery In Vivo of Albumin-Coated MNPs

The toxicological research of MNPs is a significant step for in vivo application. The main mechanisms of the cytotoxic effects of MNPs are reactive oxygen species (ROS) formation, ferrous ions release, change in the activity of ion channels, cytoskeleton disruption, and dysregulation of gene expression [13][24]. The possible concepts of toxicity are summarized in Figure 3. Besides the mentioned advantages, most of the works are related only to the simple toxicity test such as MTT cell assay [60][61]. However, cancer cells usually have better activated survival systems than normal cells. MTT test has not shown non-specific interaction with blood components, tissue-specific toxicity, chronic toxicity, etc. Only some of the MNPs demonstrated acute toxic effects. However, most of them have chronic toxicity or can cause disorders such as inflammation, ulceration, metabolic disorders, immune response, decreases in growth rate, or changes in animal models [20][21][24]. MNPs accumulation in some organs may interfere with the physiological iron metabolism after the degradation with further mitochondria, membrane, and nucleic acid damage (somatic or inherited mutation). It is oblivious that the extended toxicity experiment is a laborious work of many researchers [24]. However, the simplest tests combinations as plasma stability, ROS formation, and several cell types (for MTT assay) are required for any research, which claims that their MNPs can be used for further clinical investigations.
Magnetochemistry 08 00013 g005
Figure 3. Schematic representation of possible biological responses to MNPs [2][21][62]. The preformed albumin coating inhibits MNPs sub effects.
Albumin coating usually results in very moderate particle uptake and low ROS production cytotoxicity, as many works on in vitro and cell experiments [23][37][63][64][50][58][65][66][67][68][69][70][71]. It should be noted that albumin coating has to be enough for the surface of the nanoparticles. If the nanoparticles’ Zeta potential has not changed to the negative or, perhaps, stayed positive, it is not such an incredible effect of protection can be obtained [72]. Albumin-coating improves the in vitro therapeutic outcome of drug-loaded MNPs, highlighting the potential for success in vivo studies [63][50][52][65]. Moreover, albumin coating could prevent cardiac effects of MNPs [73]. No changes in central hemodynamics, microcirculation, and endothelial integrity factors were detected [74]. The presented results show that albumin coating provides a stable and biocompatible shell and prevents cytotoxicity of magnetite core.
As mentioned above, albumin can bind with various receptors, which possess the targeted delivery of albumin-coated MNPs [75]. However, the possibility of surface functionalization provides the feasibility to accumulate or increase the accumulation at specific locations and organs using specific receptor-mediated targeting [13][29][76][77]. Some of the possible albumin surface functionalization chemistry is presented in Figure 2. For albumin surface modification, vitamin or vitamin-like derivatives (biotin, folate), carbohydrates (glucose, galactose, lactose, and mannose), and peptides (RGD or cell-penetrating peptides) are widely used [29][76][77]. For example, due to the interaction with specific receptors biotin modified HSA targets breast and cervical cancer [76]. Folic acid conjugated albumin–MNPs are effective for cell targeting and brain tumor MRI imaging [76][78][79]. The rare possibility is to conjugate the albumin–MNPs with antibodies (anti-EGFR and VEGF) [68][80]. However, anti-EGFR and VEGF antibody-conjugated HSA–MNPs effectively targeted breast tumor and brain glioma delivery in a mice model, respectively [68][80].

2.3. Albumin-Coated MNPs for MRI

MRI is a great non-invasive diagnostic tool. Various contrast agents can improve anatomic resolution and diseased tissue region. The contrast agents are usually divided into longitudinal T1 and transverse T2 contrast agents. Using T1 agents MRI image becomes brighter and T2 darker. The contrast ability of a contrast agent can be quantitatively characterized by relaxivity (r1 and r2), which is a proportionality coefficient between relaxation time T and contrast agent concentration. MNPs usually are T2 contrast agents with high r2. MNPs coating influences both T1 and T2 relaxation processes due to changes in the availability of water molecules near the magnetic core [81]. However, the universal recipe to obtain the best MRI agent is unknown [81]. The thin coating usually highly decreases r1 but does not influence r2 values due to the different relaxation mechanisms. Some layer is required to have relevant stability and biocompatibility effect. As expected, albumin absorption of the MNPs surface decreases r1 from 12 to 6 mM−1 s−1 and increases r2 from 480 to 600 mM−1 s−1 (magnetic field 1.5 T) [45]. Interestingly, the coated MNPs have about six times higher r2 value than the contrast agent Resovist® (coated Fe3O4), which is recommended to use only in low doses due to the sub effects [45]. Another example is that 30 nm HSA-coated MNPs have an r2 of 314 mM−1 s−1, 2.5 times higher than Feridex [37][82]. Some other works show the same tendencies on slightly or high enhancement of the r2 relaxivity, which is the feature of their magnetic nucleus formation procedure and size [26][37][45][47][65][80][82][83][84][85]. Enhanced r2 values and potential for MRI of albumin-coated iron oxide nanoparticles were previously reported in a number of in vitro and in vivo studies [37][45][68][75][80][82][84][85][86].

2.4. Albumin-Coated Multimodal Imaging or Theranostics MNPs

Recently, albumin-coated MNPs were actively used for the multimodal imaging or theranostics production [63][64][50][52][55][56][57][59][67][70][75][78][79][85][87][88][89][90]. The albumin-coated MNPs surface was labeled by 64Cu-DOTA complex (for positron emission tomography, PET) and fluorescence dye (Cy5.5) to assess the possibility of multimodal imaging. Triple-imaging (PET, near-infrared fluorescence imaging, and MRI) was successfully tested on the glioma mouse model [82]. Another possibility is tumor-targeted folate delivery with simultaneous bimodal imaging by fluorescence and MRI [78]. A possible albumin surface labeling technique by the fluorescence reporter group is widely useful for simple cell uptake experiments or in vivo fluorescence imaging using NIR fluorescence dye [78][82][90].
An even more difficult goal is to obtain theranostic constructions based on albumin-coated MNPs [63][64][52][55][59][65][79][85][88][89]. Theranostics MNPs offer great potential in drug-resistance cancer treatment. However, the progress in the area is limited and has been raised in the last several years. Some potential for MRI and drug release was conducted with paclitaxel anticancer drug loading on albumin-coated MNPs [52]. The significant results were obtained using albumin-coated MNPs loaded with doxorubicin [89], methotrexate [59], curcumin [63][64][85], or synergistic delivery of curcumin with 5-fluorouracil [79], which was shown on the cell line model. An excellent therapeutic effect on rat models with gliosarcoma tumors was obtained [59]. Integrating hyperthermia and chemotherapy was shown in vitro on cell lines using paclitaxel [65] and etoposide (topoisomerase-II inhibitor) [88]. These results highlight the great potential of simultaneous imaging and therapy on one nanoparticle species. Several therapy strategies are preferable to solve the problem of the drug-resistance cancer problem.

3. Conclusions

Nanoparticles are a promising platform for creating new drugs for simultaneous therapy and diagnostics (theranostics). Such systems can take an important place in creating new generation drugs due to the possibility of manipulating their physicochemical and biological properties, targeted regulation of the composition, size, and surface functionalization. MNPs are a promising nucleus of theranostics due to possible MRI diagnostics, external field guiding, and hyperthermia effect. The main problem of the MNPs coating is to possess the biostability and targeted delivery to the tumor. It is vital to save and/or improve physical properties under the functionalization process. The biochemical and biophysical properties of albumin make it an ideal candidate for MNPs’ coating. Its excellent biocompatibility, biodegradability, and outstanding cancer tissue accumulation, due to the enhanced permeation and retention effect and specific receptor binding, have great proven potential. The possibility of albumin surface modification with reporter or address groups can simultaneously possess better tissue targeting and imaging procedures. Furthermore, the diversity in the preparation of covalent or binding an albumin-based drug delivery system gives numerous opportunities to include a wide range of therapeutic or theranostic agents. Combining the effects of MNPs, albumin coating, and albumin modification provides the resulting system with outstanding properties.

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Alexey Chubarov
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