Matijević, M., Popović, I., Stepić, M., Nešić, M., Radoičić, M., Stanković, M., Šaponjić, Z., Petković, M.: Inorganic nanoparticles in biology: drug carriers and auxiliary tools in bioimaging and bioanalytics. Biologica Nyssana, 9 (1). September, 2018: 1-19.


BIOLOGICA NYSSANA 9 (1) ⚫ September 2018: 1-19 Matijević et al. ⚫ Inorganic nanoparticles in biology: drug carriers… 

  

 1 

 

 

 

Review Article 

Received: 13 April 2018 

Revised: 27 June 2018 

Accepted: 22 August 2018  

 

Inorganic nanoparticles in biology: drug carriers and auxiliary 
tools in bioimaging and bioanalytics 

Milica Matijević1, Iva Popović1, Milutin Stepić1, Maja Nešić1, Marija Radoičić1, Maja 

Stanković2, Zoran Šaponjić1, Marijana Petković1 

1“Vinča” Institute of Nuclear Sciences, University of Belgrade, Belgrade, Serbia;  

2Faculty of Natural Sciences, University of Niš, Niš, Serbia 

* E-mail: milica.m@vin.bg.ac.rs 

 

 

 
 

Abstract:  

Matijević, M., Popović, I., Stepić, M., Nešić, M., Radoičić, M., Stanković, M., Šaponjić, Z., Petković, M.: 

Inorganic nanoparticles in biology: drug carriers and auxiliary tools in bioimaging and bioanalytics. 

Biologica Nyssana, 9 (1). September, 2018: 1-19. 

Among various nano-scaled materials composed from a spectrum of chemical compounds, inorganic 

nanoparticles are very attractive due to their physico-chemical properties, as well as their availability, 

simplicity, possibility of modifications, stability and biocompatibility. They are, on the one hand, an useful 

tool in advanced analytical chemistry, in particular for studying of biologically-relevant processes, but also 

important as functional parts of the systems designed for controlled and targeted delivery of medicaments for 

treatment of a variety of diseases and for imaging. So far, thousands of compounds and systems have been 

developed for the above-mentioned purposes, but there are only a few reviews dealing with these topics. The 

aim of this review is, thus, to summarize recent applications of nano-structured inorganic materials in the field 

of drug delivery, bioimaging and bioanalytics, and to give a prospective from the standpoint of biology-related 

applications. 

Key words: inorganic nanoparticles, photodynamic therapy, imaging 

 

Apstrakt: 

Matijević, M., Popović, I., Stepić, M., Nešić, M., Radoičić, M., Stanković, M., Šaponjić, Z., Petković, M.:: 

Neorganske nanočestice u biologiji: nosači lekova i pomoćni alat u bioimidžingu i bioanalitici. Biologica 

Nyssana, 9 (1). Septembar, 2018: 1-19. 

Među različitim nanomaterijalima, neorganske nanočestice privlače posebnu pažnju zbog svojih fizičko-

hemijskih osobina, kao i dostupnosti, jednostavnosti, mogućnosti modifikacije, stabilnosti i 

biokompatibilnosti. Neorganske nanočestice su korisna pomoćna sredstva u analitičkoj hemiji, posebno za 

ispitivanje biološki-relevantnih procesa, ali su i značajan funkcionalni deo sistema za kontrolisanu i ciljanu 

dostavu medikamenata za terapiju raznih oboljenja, kao i za medicinsku imidžing dijagnostiku. Do sada je 

razvijen veliki broj jedinjenja i sistema za gore-navedenu svrhu, ali se može naći samo nekoliko  preglednih 

članaka na ovu temu. Cilj ovog revijalnog rada je da dâ zbirni pregled primene nano-strukturnih neorganskih 

9 (1) • September 2018: 1-19 

 

DOI: 10.5281/zenodo.1470841 



 2 

materijala u oblasti dostave medikamenata, bioimidžinga i bioanalitike, kao i da pruži buduće smernice sa 

stanovišta primene u oblasti biologije. 

Ključne reči: neorganske nanočestice, fotodinamička terapija, imidžing 

 

 

Introduction 

Nanomaterials are attracting more and more 

attention for use in biological systems. The number 

of their potential applications in biology causes an 

expansion of new scientific discipline, so called 

nanobiology. This term refers not only to the 

application of nanomaterials for investigations of 

important biological processes in health and in 

pathological states but also to the utilization of 

various nanomaterials as auxiliary tools in different 

analytical methods for investigations of biological 

systems and their components. 

In this work, we are focusing on the 

application of inorganic nanoparticles for drug 

delivery, imaging and analytical chemistry, to cover 

the units which are interconnected and can be merged 

in practical work. Apart from those, there are also 

other numerous applications of nanoparticles, which 

are important from the standpoint of advances in 

technology, medicine and science in general. For 

instance, nanoparticles are widely used in diagnostics 

(imaging diagnostics, laboratory diagnostics, genetic 

diseases` and tumor diagnostics), radiosensitization, 

tissue engineering, drug delivery, therapeutic drugs, 

to the specific medical and other instrumentations 

such are nanoprobes, nanosensors and nanorobots 

(Su H. et all., 2017). Other application areas that are 

not covered in this review, but should be mentioned 

are the areas of the molecular biology as a bio-labels 

(Kumar & Sophia, 2018), surface chemistry, protein 

corona and intracellular nanoparticles pathways.  

The literature data suggest that term “nano” in 

biology mostly refers to the particles smaller than 5 

 

 

Fig. 1. Trajectory of peptide-conjugated gold NPs (GNPs) through the cell. A, Schematic of a 

functionalized GNP used in the study B. Trajectory of peptide-conjugated GNPs through the cell. C-F, 

Path of the NPs was captured using TEM images and is as follows: C, GNP-Peptide complex bound to the 

plasma membrane for entry into the cell via the endocytosis process, D, Internalized NPs were localized 

in vesicles, such as, endosomes and lysosomes, E, Escaping of NPs from vesicles into the cytoplasm, F, 

Entering the nucleus through nuclear pore complex (NPC) (scale bars = 100nm). Reproduced with 

permission from Yang et al. (2014). 



BIOLOGICA NYSSANA 9 (1) ⚫ September 2018: 1-19 Matijević et al. ⚫ Inorganic nanoparticles in biology: drug carriers… 

  

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µm (Singh & Lillard, 2009), which can be, with 

minimum risk, administered into the blood 

circulation. Comparing with the smallest human 

cells, i.e. erythrocytes, the dimension of a typical 

nanoparticle is about 5 times smaller, whereas in 

comparison to oocytes, the largest nanoparticle could 

be more than 120 times smaller. That indicates that 

nanoparticles (NPs), speaking in physical terms, can 

be ingested by a cell, reach cellular interior and 

become available for the interaction with intracellular 

organelles or to target specific biomolecules. NPs can 

be ingested by a cell through utilizing the existing 

cellular pathways for ingestion, and/or diffusion 

through the membrane in the case of smaller NPs. 

Another way, i.e. endocytosis, or a receptor-mediated 

pathway is illustrated in Fig. 1, on the example of a 

peptide-bound to the NP (Yang et al., 2014). Based 

on that, NPs can be designed for intracellular 

imaging, to target particular biomolecule or an 

organelle and to interfere with the intracellular 

processes/signaling, either for the diagnostic or the 

therapeutic processes.  

In terms of a therapy, NPs as carriers for 

targeted and controlled drug delivery have attracted 

much attention. They have functions to preserve a 

drug until it reaches target tissue/organ and to secure 

targeted delivery and control a drug concentration 

(Pandey, 2017). After activation by various 

mechanisms, the drug is released and can act on 

desired site, thus minimizing side effects on healthy 

tissues. Although numerous medicaments have been 

designed to use intrinsic properties of diseased 

tissues, such as low intrinsic pH, due to a low oxygen 

concentration in tumor cells (Casciari et al., 1992), 

nanoparticle-based carriers are still attractive and 

promising approach for targeted therapy.  

In analytical (bio)chemistry, NPs are used as 

auxiliary tools in various techniques. Thanks to their 

properties, they enable better precision of the method 

(Frigerio et al., 2012; Will et al., 2006; Lucena et al., 

2011), and its increased selectivity and sensitivity 

(Ling et al., 1991; Arakawa & Kawasaki, 2010; 

Thompson et al., 2008). A waste amount of 

biologically important molecules are qualitatively 

and quantitatively analyzed with the assistance of 

NPs (Kawasaki et al., 2007; Chiang et al., 2010a; 

Popović et al., 2016; Popović et al., 2016a; Popović 

et al., 2016b). Some examples of methods which 

exploit the advantageous properties of NPs are mass 

spectrometry, chromatography, but also mass 

spectrometry imaging, and their application will be 

discussed in more details in this review.  

 

Physical and chemical properties of 
nanoparticles 

NPs can be fabricated from various materials, and 

coarse classification involves organic and inorganic, 

and commonly used types are shown at the Fig. 2. 

Based on their size and composition, there are several 

groups of nano-structured materials: NPs (1-100 nm), 

nanocapsules (nanoscale shells made of a polymer), 

 

 
 

Fig. 2. Types of NPs commonly used for biomedical applications: (a) polymer, (b) liposomes, (c) 

amphiphilic cyclodextrines, (d) dendrimers, (e) gold NPs, (f) micelles, (g) carbon nanotubes and (h) 

Quantum dots (QDs), modified form (McCarthy et al., 2014). 



 4 

fullerenes (made of a carbon and with various 

shapes), dendrimers (repetitively branched 

molecule), quantum dots (QDs), (a semiconductor 

nanostructures), nanostructures (size between 

intermediate and microscopic particles) and 

nanopores (with tiny hole in a thin membrane) 

(Akeson et al., 1999). In line with the topic of this 

review, the following part will summarize some 

biologically-relevant properties of organic vs. 

inorganic NPs.  

Each of them, organic and inorganic, has its 

own advantages and disadvantages. Organic 

materials are made mostly from biodegradable 

materials, and they can be metabolized in the 

organism, finally resulting with CO2 and water. As 

disadvantage, there is always a risk of premature 

degradation, which leaves the medicament exposed 

to enzymes and immunological system, causing too 

early activation of a medicament, which leads to the 

expressed side effects. This disadvantage could be 

avoided, or minimized, through the encapsulation of 

a medicament in the NPs (Dobrovolskaia & McNeil, 

2007; Singh & Lillard, 2009).  

Monitoring of the destiny/biodistribution of 

organic NPs in organism is sometimes difficult, due 

to limited possibilities to distinguish them in the 

surrounding organic milieu. The labeling techniques, 

for instance by some voluminous fluorescence dyes, 

might prevent the interaction with target 

molecules/tissue leading to the misinterpretation of 

the data. The application of inorganic materials for 

fabrication of NPs gives much more possibilities for 

surface functionalization, and much broader 

spectrum of methods which can be used for the 

monitoring of NPs` biodistribution. Modification of 

NPs allows controlled changes of the interface 

properties, which affects the dissolution and 

degradation rates, catalytic activity and possibility of 

stabilization through the adsorption of 

macromolecules (Stark, 2011). On the other hand, 

precaution is needed because inorganic material must 

be selected by making a compromise between 

biological inertness, availability and potential of 

surface modification. For biological applications, 

selection of inorganic materials for fabrication of 

NPs should be based on the information of their 

potential biological role. For instance, selected 

material should not contain a metal which might be a 

co-factor for any enzyme in the cells. In other case, 

the final concentration of metal should be under the 

enzyme-activating level (Chen et al., 2012; Lee & 

Yeo, 2015). The presence of higher concentrations of 

the enzyme cofactors, might lead to the enzyme 

activation and the interference with the intracellular 

signaling processes.  

Inorganic materials made of non-biological 

metals enable also easier detection by instrumental 

methods, which utilize either properties of their 

atoms (magnetic or paramagnetic properties, for 

instance) or intrinsic fluorescence, i.e. optical 

properties. For example, titanium is not biologically 

abundant, and it can be detected with methods which 

differentiate inorganic from organic materials, i.e. 

NMR (Padro et al., 2000), or other approaches. Some 

of most frequently used NPs in medicine are those 

made of gold, which could be visualized by 

microscopy, or fluorescence labeling, or other 

method (Gonciar, 2014). Having in mind that the 

inorganic NPs are the focus of this review, the 

summarized list of the different types of inorganic 

NPs that are relevant for this review, is shown in the 

Tab. 1. 

 

Metal oxide semiconductor-based 
nanoparticles 

A number of metals can form oxides that can conduct 

an electrical current, and NPs made of them are used 

as drug carriers, for imaging purposes and in 

analytical chemistry. The most commonly used are 

ZnO, CuO, TiO2, ZrO2 or MgO. Besides electro-

conductivity, properties which are advantageous for 

the variety of applications are photo-responsivity, 

magnetism, possibility of surface modification, etc. 

Metal NPs have large surface-to-volume ratio and 

due to their high density and limited size of corner or 

edge on the surface site, metal oxide NPs exhibit 

unique chemical and physical properties. For 

instance, for the application in anticancer drug 

delivery systems, the size of metal NPs should be 

larger than 10 nm in order not to be cleared by the 

kidney excretion and captured by macrophages (Lee 

& Yeo, 2008), and on the other hand, to be smaller 

than 100 nm to reach the tumor tissue and enter the 

cell (Cho et al., 2008). Even within the range of 10-

100 nm, small alteration in size of NPs makes a big 

difference regarding their properties, i.e., as the size 

decreases, the number of surface and interface atoms 

generates strain or stress and concomitant structural 

perturbations (Gleiter, 1995; Trudeau & Ying, 1996; 

Valden et al., 1998; Rodriguez et al., 2002; Song et 

al., 2003; Schoiswohl et al., 2004). In terms of the 

NPs uptake by mammalian cells, oxides of zinc, iron, 

manganese, and cobalt exhibit nonclassical 

interaction – the Trojan-horse-type, which enables 

diffusion of the toxins by packing it in the small 

particles (Stark, 2011). 

Surface of inorganic NPs can be easily 

modified, and thanks to that property, they are often 

considered for drug discovery and therapy 

development. They can be modified for targeted drug 



BIOLOGICA NYSSANA 9 (1) ⚫ September 2018: 1-19 Matijević et al. ⚫ Inorganic nanoparticles in biology: drug carriers… 

  

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delivery for various significant biomolecules (nucleic 

acids, proteins or peptides) or for specific tissues. 

Such targeted nanocarriers decrease overal drug 

toxicity and offer more effective biodistribution, as 

discussed above. The conjugate of a drug and 

nanocarrier can pass some natural body barriers, such 

as blood or brain barriers (Rawat et al., 2006) and 

deliver drug to the target tissue. There are several 

external activators, which employ inner properties of 

inorganic nanoparticle as a carrier, eventually leading 

to cytotoxic effects at the target tissue, which will be 

discussed more in the next chapter. Stimulus or 

activators can be high magnetic field or ultrasound 

applied locally, which increase the temperature of 

diseased tissue, due to the accumulated NPs in the 

tissue (Arruebo et al., 2007; Singh & Lillard, 2009; 

Lee and Yeo, 2015). Light as activator attracted much 

attention in later decades, because it can be easily 

Table 1. Overview of different types of inorganic NPs from cited literature in this review 

System Structure Characteristics References 

AuNPs 
 

Semiconductor NPs: 

CdSe or CdTe 

Doped oxide materials, 

Y2O3 

Fe2O3, CoNPs 

Colloidal Effective phototermal destruction of 

cancer cells and tissues 

Photoluminiscence in the form of 

fluorescence 

Phosphorescence 

 

Magnetic moment 

Sperling & Parak, 2010 

Feridex Colloid with low molecular 

weight dextran coating, 

with a particle size of 120-

180 nm 

Magnetic moment 

Diagnostic agent in use 

Cherukuri et al., 2010 

Cobalt ferrite, CoFe2O4  Magnetic moment 

Binding to serum albumin proteins 

Amiri et al., 2017 

Fe3O4 NPs 

 

 

Fe3O4-PEG NPs 

Naked, 80±5 nm 

 

 

Functionalization with 

polyethylene glycol 600 

diacid, 46±0,6 nm 

Magnetic moment 

Higher accumulation in the lungs due 

to their in vivo agglomeration 

Magnetic moment 

Potential in Hyperthermia based 

cancer treatmens 

Radović et al., 2015 

Platinum-tethered gold 

NPs-PEG 

Au NPs functionalized with 

thiolated poly(ethylene 

glycol) (PEG monolayer 

capped with a carboxylate 

group of [Pt(R,R-dach)] 

NPs functionalized with PEG do not 

make aggregate 

Higher uptake than Pt(R,R-dach) 

NPs are capable of delivering 

[Pt(R,R-dach)] to the cell and then 

releasing it 

Brown et al., 2010 

Scg8-AuAg nanoroads Gold-silver-(AuAg-) 

nanoroads labeled with 

molecular aptamers 

Higher hyperthermia efficiency and 

selectivity to CEM cells than aptamer 

alone 

Conde et al., 2012 

Carbon nanotubes Carbon cylinders composed 

of benzene ring linked to 

the methotrexate attached to 

medicament-methotrexate 

Water-soluble and biocompatible 

through chemical modification 

Pastorin et al., 2006 

S1MPs, S2MPs Mesoporous SiO2 NPs, 

S1MPs which large pores 

are loaded with S2MPs 

High biocompatibility 

High surface areas and pore volumes 

Controlled release dynamic of 

medicament 

Tasciotti et al., 2008 

TiO2 NPs Colloidal TiO2 NPs attached 

to potentional medicament – 

Ru bis-bipyrydil complex 

Minimal dark cytotoxicity 

High surface to volumes relation 

The surface of TiO2 can be modified 

Controlled release dynamic of 

medicament 

Nešić et al., 2016, 2017 

 

 

 

 



 6 

controlled and focused to minimize influence on the 

healthy tissue. Light can be used in a combination of 

photo-responsive drugs or nanoparticle/drug system, 

which is then called a photosensitizer.  

Among inorganic NPs, we have selected for 

our investigations, those made of TiO2, due to their 

availability, stability, non-toxicity, potential to 

modify particles surface, but also photo-responsivity, 

and its properties will be discussed in the next 

paragraph, with the focus on the photodynamic 

therapy.  

The inorganic NPs, which are photo-

responsive, can serve as a source of photogenerated 

charges that interact with the electronic properties of 

the biomolecules. The linking of inorganic NPs with 

(bio)molecules facilitate hole transfer across the 

interface, establishing efficient crosstalk between the 

(bio)molecule and metal oxide NPs. These 

photoactive bioinorganic conjugates have properties 

that make them good for light induced manipulation 

of biomolecules and their switching functions (Rajh 

et al., 2004). 

TiO2, which will be presented also later in this 

review, is typical n-type semiconductor material, 

with many good properties, such as cost-

effectiveness, chemical and photo-stability, and 

excellent biocompatibility in the dark. Besides photo 

catalysis, energy storage system development and 

energy conversion, sun screening and sensor 

research, TiO2 has a wide application in medical 

fields, too. It can be applied as anti-cancer agent, 

implant and a substrate for stem cell expansion 

(Hamidi et al., 2017; Oliveira et al., 2017; Sims et al., 

2017). 

 

Quantum dots 

QDs are semiconductors nanocrystals with size 

between 1-10 nm, which have unique and tunable 

absorption and emission properties, depending on 

their size and shape. For instance, they have large 

transition dipole moment, so can be precisely tuned 

from the UV to the infrared region (Lucky et al., 

2015). Some of them exhibit photoluminescence or 

fluorescence (semiconductor quantum dots, e.g., 

CdSe, CdTe, CdTeSe/ZnS) (Gozuacik et al., 2014). 

Structurally, QDs consist of a metalloid 

crystalline core and a “cap” or “shell” that shields the 

core, and further assignation of coatings or functional 

groups to the QD core–shell can give QDs a desired 

bioactivity. QDs` core consists of the metal complex 

which defines the structure group that particular QD 

presents. For example, the group III–V series QDs 

are composed of indium phosphate (InP), indium 

arsenate (InAs), gallium arsenate (GaAs) and gallium 

nitride (GaN) metalloid cores, and group II–IV series 

QDs, of zinc sulfide (ZnS), zinc–selenium (ZnSe), 

cadmium–selenium (CdSe), cadmium–tellurium 

(CdTe) cores and heavier structures such are 

CdTe/CdSe, CdSe/ZnTe) and hybrids composed of 

lead–selenium (PbSe). Regarding QD toxicity, it 

depends on multiple factors: QD size, charge, 

concentration, outer coating bioactivity (capping 

material, functional groups), and oxidative, 

photolytic, and mechanical stability have each been 

shown to be determining factors in QD toxicity 

(Hardman, 2006). 

In biological systems, QDs have been 

investigated for the application mostly in cancer 

treatment, theranostics, cancer drug delivery, 

photothermal and photodynamic therapy. The ability 

of fluorescence emission of QDs, make some of them 

good imaging agents. Furthermore, 

photoluminescent properties of QDs have been 

exploited in the other fields of application, such as in 

analytical chemistry in environmental monitoring, 

pharmaceutical and clinical analysis and food quality 

control (Frigerio et al., 2012).  

 

Magnetic nanoparticles 

The advances in the synthesis of biocompatible 

magnetic NPs in a reproducible way, allowed 

extensive research and further development of drug 

delivery systems based on magnetic field as an 

external driving and control force. Applications of 

magnetic NPs in biomedical areas, on the other hand, 

require the use of magnetic colloids, which consist of 

a suspension of magnetic particles of nano sizes in a 

carrier liquid like water, with usual particle 

concentrations in the range of 1021-1023 particles/m3 

(Goya et al., 2008). 

Magnetic iron oxide NPs are the most widely 

used NPs with magnetic properties, and there are 

various trade names for super oxide and ultra-small 

super oxide variations in structure (Shadab et al., 

2015). Usually, inorganic nanoparticle core is coated 

by a suitable coating material, which increases the 

stability and solubility of the nano-drug conjugate, 

leading to higher rates of biocompatibility and 

aqueous stability in the saline environment of 

biological tissues. Feridex is an example of this 

commercially available iron NPs, which are coated 

with sugars (e.g. dextran) (Cherukuri et al., 2010). 

The enrichment of magnetic NP surface, for instance 

with SiO2, can allow direct functionalization making 

it more suitable for biomedical application (Radović 

et al., 2015). 

The other group of compounds with magnetic 

properties, facile synthesis and chemical stability, are 

ferrites of the general formula MFe2O4 where 

M = Fe, Mn and Co. Some ferrites exhibit additional 



BIOLOGICA NYSSANA 9 (1) ⚫ September 2018: 1-19 Matijević et al. ⚫ Inorganic nanoparticles in biology: drug carriers… 

  

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properties making them even more suitable for 

application in the biological systems, for instance, 

cobalt ferrite, CoFe2O4 binds strongly to serum 

albumin proteins (Amiri et al., 2017). 

 

Inorganic nanoparticles controlled drug 
delivery systems: Applications for anti-
cancer therapy 

In recent years, a combined nanotechnology – drug 

delivery systems have been developed by two 

components within the general formulation, 

nanocarrier/drug complex. The purpose of the nano-

drug conjugation is to allow modification of the 

pharmacokinetics and metabolism of the drugs, 

particularly regarding reducing the side effects, such 

as non-selective toxicity to tumor cells and inactivity 

against drug-resistant cell lines (Llevot & Astruc, 

2012). The drug delivery system with nanocarrier has 

even more advantageous properties, such as better 

encapsulation, bioavailability, lower toxic effects to 

the healthy tissues and possibility for controlled 

release (Pandey, 2017). In such manner, some of 

these features are related to each other. As instance, 

the encapsulation of the drug in the nanocarrier 

prevents quick elimination by the reticuloendothelial 

system, which consequently leads to higher levels of 

blood circulation and to increased 

rates of the transport through 

biological barriers. The final 

outcomes of these processes are 

better availability of drug at the 

targeted tissue and lower toxic 

effects to the healthy tissues. 

Moreover, in the focus of the 

researches is to develop the drug 

delivery system which is capable of 

maintaining constant concentration 

gradients by continuous and 

controlled release of therapeutic 

drugs. 

These unique chemical and 

biological properties of the 

nanocarriers are linked to the NPs 

large surface area-to-volume ratio, as 

discussed above. This property 

allows them to combine, absorb and 

hold other compounds like drugs 

molecules, DNA, RNA, proteins 

(Shadab et al., 2015). Additionally, 

surface modification can enable the 

increase of the circulation time in the 

body, cell specific targeting and 

membrane permeability. By 

interacting with biomolecules placed 

on the cells surface and inside the 

cells, penetration into the tissues is promoted with the 

higher levels of specificity. Furthermore, it is 

possible to develop the advanced NPs drug delivery 

systems for the spatially and temporally controlled 

release of drugs in response to specific stimuli within 

the tumor microenvironment (Yin et al., 2013). 

A stimuli-responsive delivery system 

improves the efficacy of the drug, and can be 

designed to react to the disease specific property (pH 

level, redox property or enzyme levels). Drug 

accumulation and release at the tumor site can be 

additionally intensified by external forces like 

magnetic field (Arruebo et al., 2007; Shadab et al., 

2015), light (Mari et al., 2014; El-Hussein et al., 

2015; Nešić et al., 2017) and/or heat (Cherukuri et al., 

2010). 

To date, there are only a few clinically 

approved nanocarriers that incorporate molecules to 

selectively bind and target cancer cells, and these 

drug delivery systems are mostly based on organic 

nanocarriers, such as liposomes and polymers, free or 

attached to proteins (López-Dávila et al., 2012). 

Inorganic nanocarriers, on the other hand, are much 

smaller, and the active form is usually simple metal 

based structure with gold (Brown et al., 2010), silver 

(Conde et al., 2012), carbon (Pastorin et al., 2006; 

Cho et al., 2008), oxides (mesoporous SiO2, TiO2, 

Fe2O3, graphene oxide) (Goya et al., 2008; Tasciotti 

 

 

Fig. 3. Schematic representation of various stages involved in PDT. 

Reproduced with permission from the authors Avirah et al. (2012) 



 8 

et al., 2008; Nešić et al., 2016; Nešić et al., 2017), or 

in the form of QDs (selenides, sulfides or tellurides 

of metals like cadmium, lead or zinc) (Sperling & 

Parak, 2010; Chen et al., 2014). Different designs 

varying in size, shape, and porosity allow easy 

conjugation with drugs for cancer therapy 

(Bhattacharyya et al., 2011) and they are more stable 

over large ranges of pH and temperature (Shadab et 

al., 2015). 

 

Photo-sensitive systems for drug delivery 

Optical energy can trigger a variety of photochemical 

processes useful for therapies. It is the raising field in 

the development of new therapeutic approaches in 

the last decades. Photodynamic therapy (PDT) 

involves the administration of a tumor-localizing 

photosensitizer (PS), usually NP, which undergoes 

reversible changes upon light exposure of a specific 

wavelength. The induced changes in such manner, 

can lead to the release of therapeutic drugs, thereby 

providing spatio-temporal control of drug release 

(Shadab et al., 2015), or the excited PS can transfer 

its energy to molecular oxygen, thus generating 

cytotoxic reactive oxygen species (ROS) and singlet 

oxygen, which can modify cellular macromolecules 

leading to tumor cell ablation (Lucky et al., 2015). 

Simplified schematic representation of the stages 

involved in PDT, is shown in Fig. 3. 

Inorganic, metallic, or composite NPs have 

been investigated as multifunctional carriers for PDT 

due to their unique characteristics such as optical 

properties and tunability in its shape, size, porosity, 

and that they may not degrade readily in the 

biological systems. It is also reported that the degree 

of drug resistance is far less than those encountered 

in chemotherapy, and that there is no cross-resistance 

between PDT and chemotherapy (Kim et al., 2015) 

The most promising PSs are nanosized oxides, 

which exhibit distinctive optical absorption 

properties, transparency of the matrix to light 

absorption and chemical inertness. They can be easily 

attached to therapeutic medicament in the form of 

nanocomposite system, which can exhibit greater 

cytotoxicity (Nešić et al., 2017) and higher 

therapeutic effectiveness for cancer than the 

corresponding free drugs (Chen et al., 2011; Wang, 

Y. et al., 2015). 

The most investigated NPs/metal oxides are 

mesoporous silica (Teng et al., 2013), titanium 

dioxide (Nešić et al., 2016) and zinc oxide (Zhang et 

al., 2014). 

TiO2 NPs are specially interesting as, upon 

ultraviolet (UV) light excitation, they absorb the 

energy higher than its own band gap energy (3.2 eV), 

which leads to excitation of the electrons from the 

valence to the conduction band, creating the 

electron/hole pairs and further generating active free 

radicals, thus allowing oxidation/reduction of species 

in surrounded medium. TiO2 itself was reported to 

have a good anticancer effect in response to the light, 

owing to the production of active free radicals under 

UV irradiation (Wang, T. et al., 2015). In addition, 

the incomplete coordination sphere of the surface 

metal atoms exhibits the high affinity of TiO2 NPs for 

linking with biomolecules and oxygen-containing 

ligands (Rajh et al., 2004). 

While TiO2 NPs with the anatase crystalline 

phase absorb UV light and consequently generate 

ROS, great chemical stability and minimal 

cytotoxicity of TiO2 NPs are detected in the dark. In 

comparison with traditional organic photosensitizers, 

TiO2 NPs can be maintained for a longer time in the 

body. Even TiO2 NPs possess high photosensitization 

activity toward various cancer cell lines, for the 

suppression of in vivo tumors there are characteristics 

that need to be improved, as low penetration into 

tissue and the damage to normal tissue (Hou et al., 

2015). 

In the study of nanocomposite system based on 

TiO2 NPs and daunorubicin, MTT assay have 

confirmed significant cytotoxicity when leukemia 

cell line, K562, was treated with the nanocomposite 

system, while low cytotoxicity was shown when 

K562 cells were treated solely with TiO2 NPs, and 

thus TiO2 NPs demonstrated important properties of 

a drug carrier and showed good potential for the 

applications in cancer therapy (Zhang et al., 2012). 

In a similar study, it was demonstrated that the 

nanocomposite system made of Pt(NH3)4Cl2 

transitional metal complex and TiO2 NPs, as well as 

individual components, lead to a significant decrease 

in C6 glioma cell proliferation; the reduction in the 

tumor volume was also confirmed (López et al., 

2008). 

In our previous work we studied in vitro light 

stimuli-responsive properties of nanocomposite 

system based on the colloidal TiO2 NPs and 

transitional metal complex, cis-dichlorobis(2,2′-

bipyridyl-4,4′-dicarboxylic acid)ruthenium(II). The 

system had the light controlled release properties, as 

the release of the complex was facilitated upon 

illumination with UV light, and sustained upon 

illumination with visible light. Results obtained by 

the investigation of the nanocomposite system 

cellular cytotoxicity towards melanoma cancer cells 

line A375 were in agreement with in vitro drug 

release test: while the nanocomposite system and its 

components exhibited the significant decrease of the 

cell viability upon UV irradiation, red light 

irradiation showed an extremely low anti-cancer 

effect (Nešić et al., 2017). 



BIOLOGICA NYSSANA 9 (1) ⚫ September 2018: 1-19 Matijević et al. ⚫ Inorganic nanoparticles in biology: drug carriers… 

  

 9 

Inorganic nanoparticles and tissue 
imaging 

Inorganic NPs including semiconductor QDs, iron 

oxide NPs, and gold NPs have been developed as 

contrast agents for diagnostics by molecular imaging 

(Huang et al., 2011; Yu & Zheng, 2015). Compared 

to traditional contrast agents, NPs offer several 

advantages: their optical and magnetic properties can 

be tailored by engineering the composition, structure, 

size, and shape; their surfaces can be modified with 

ligands to target specific biomarkers of disease, as 

mentioned in the Introduction section. The contrast 

enhancement provided can be equivalent to millions 

of molecular counterparts; and they can be integrated 

with a combination of different functions for multi-

modal imaging (Cho et al., 2010). 

Broadly, the field of biomedical imaging can 

be divided into categories based upon the 

electromagnetic spectrum as shown in Fig. 4. 

Molecular imaging is a new frontier of biomedical 

research for visualizing, characterizing, and 

monitoring biological processes in cells, tissues, and 

organisms using sensitive instrumentation and 

contrast mechanisms. Molecular imaging differs 

from traditional imaging in that way in which the 

contrast agents are typically utilized to help identify 

particular biomarkers or pathways with high 

sensitivity and selectivity (Cho et al., 2010), and for 

that purposes, inorganic NPs is an actively explored 

technology for the development of contrast agents. 

This imaging function based on interrogation of 

biological processes to report on and reveal the 

molecular abnormalities that might point to a disease, 

being thus a powerful tool for the diagnosis of cancer, 

cardiovascular syndrome, or neurological disorders.  

Imaging based on ionizing radiation generally 

refers to the detection of high frequency emissions 

from radioactive elements such as the gamma ray 

emitters 111In or 99mTc (metastable nuclear isomer of 

technetium-99) or the passage of X-rays through the 

body. The main technologies involved are positron 

emission tomography (PET), single-photon emission 

computed tomography (SPECT), and X-ray 

computed tomography (CT). Magnetic resonance 

imaging (MRI) tends to operate on the other end of 

the spectrum in the MHz frequency range, relying 

upon contrast agents such as gadolinium or 

superparamagnetic iron oxide to modify the 

relaxivity of water molecules to provide soft tissue 

contrast (Pansare et al., 2012). 

Compared with other imaging approaches, 

optical imaging is a versatile, economic and efficient 

modality for bio-imaging with high sensitivity, great 

choice for probe selection and it does not require 

precaution, like in the case of application of X-rays 

or other ionizing radiation. Various fluorescent 

molecules or nanomaterials, such as conventional 

organic fluorescein, semiconductor QDs, rare-earth 

co-doped up-conversion nanophosphors, etc., have 

been explored to label and image cancer cells both in 

vitro and in vivo. Integrating mesoporous silica with 

fluorescent materials towards multifunctionalization 

could endow them with simultaneous optical bio-

imaging and drug transport capabilities (Chen et al., 

2013). 

There are numerous efforts to combine the 

unique advantages which nanoprobes have in cancer 

imaging, and to create a “universal” nanoprobe. Such 

nanoprobe should be multimodal, have a strong EPR 

(Electron Paramagnetic Resonance) effect, able to 

circulate in a body for a long time (Bouccara et al., 

2015), be stable in physiological 

conditions, specific for target 

tissue, and not to interfere with 

physiological processes. Most 

inorganic NPs can meet some 

criteria, but one of the most 

challenging is the avoidance of 

renal clearance, which enables the 

prolonged blood circulation, and 

afterwards, accumulation in 

target, or tumor tissues. Some 

examples of inorganic NPs for 

various molecular imaging 

purposes are given below in the 

text, classified according to their 

purpose, i.e. imaging technique 

(Yu & Zheng, 2015).  

 

 

 

 

 

Fig. 4. Types of medical imaging: ionizing radiation (X-ray and CT), 

magnetic resonance imaging (MRI), ultrasound and optical imaging 



 10 

Major inorganic nanoparticles for 
molecular imaging 

Contrast agents for various imaging purposes should 

be easy to design but it is required for them to have 

particular electrical, magnetic and optical properties. 

Their properties can be fine-tuned by tailoring NPs` 

composition, geometry and structure. Therefore, 

particles can be composed of metals, metal oxides, 

semiconductors, they can vary in size and shape, and 

be solid, or hollow. Some of NPs used in imaging 

techniques are iron oxide NPs, QDs, gold NPs, and 

others, which can be used in different imaging 

approaches (Cho et al., 2010; Huang et al., 2011; 

Chen et al., 2013; Bouccara et al., 2015; Yoon et al., 

2017), and most inorganic NPs possess great 

potential for noninvasive and real-time in vivo 

diagnosis of disease (Chen et al., 2013). 

In terms of magnetic resonance imaging 

(MRI), both, magnetic or superparamagnetic NPs can 

be used as contrast agents. Among them, iron/based 

NPs are routinely applied because they were 

approved by FDA for human use (Yoon et al., 2017). 

However, a caution is needed regarding the size of 

NPs for MRI. In general, reducing a size of ferro- or 

ferrimagnetic particles below critical, could lead to 

randomization of the magnetic dipoles in a short 

period of time, as a thermal energy becomes 

comparable to what is needed for spins to flip. Those 

NPs are superparamagnetic, because they do not have 

permanent magnetic moments in the absence of an 

external field, but they can quickly respond to it when 

applied (Cho et al., 2010). 

QDs are currently replacing fluorescence dyes, 

because they have high absorption coefficients and 

broad emission range in visible and near infrared 

region (Cho et al., 2010). Gold NPs are also utilized 

in optical imaging, thanks to their optical properties, 

i.e. presence of strong extinction peaks in visible and 

near IR region (Pansare et al., 2012). Those 

extinction peaks are caused by the collective 

oscillations of conduction electrons in the presence of 

an incident light. This phenomenon is known as 

localized surface plasmon resonance. In addition, 

gold NPs can be used as contrast agents for CT 

imaging, due to their absorption coefficient for the X-

rays, but also, they are capable of 

photoluminescence. Finally, gold NPs can enhance 

the intensity of Raman-active molecules and be used 

for the surface-enhanced Raman spectroscopy (Cho 

et al., 2010; Huang et al., 2011). 

A particular class of NPs are rare-earth doped 

NPs, which exhibit sharp emission peaks, long 

fluorescence lifetimes, high quantum yields, and 

excellent photostability (Cho et al., 2010; Bouccara 

et al., 2015). 

Applications of inorganic nanomaterials 
in analytical (bio)chemistry 

NPs have been used as an auxiliary tool to increase 

sensitivity and specificity of standard analytical 

methods. One of earlier applications of inorganic 

particles, was the use of magnetic particles (beads) in 

the affinity chromatography, in which the antigen 

was bound to the surface of a particle, and after 

specific and selective interaction with a component 

from a complex solution magnetic NPs could be 

easily collected and separated from the mixture 

(Chen & Chen, 2005). Also, NPs are used as the 

stationary phase in several chromatographic 

techniques, where they increase the active surface 

available for the interaction with analytes. In this 

chapter, the overview of inorganic NPs and their 

application in chromatography and mass 

spectrometry will be given and discussed.  

 

Chromatography 

The application of NPs and nanomaterials in 

chromatography has been of great interest in recent 

years due to the unique physical properties of these 

substances, their large surface area-to-volume ratios, 

and their ability to be employed with a variety of 

surface chemistries (Guihen, 2013; Tang et al., 2014; 

Zhang & Qiu, 2015; Castillo-García et al., 2016). A 

number of carbon-based nanomaterials and inorganic 

nanomaterials have been considered for use in LC, 

some examples are: carbon nanotubes, fullerenes and 

nanodiamonds (Valcárcel et al., 2007; Scida et al., 

2011; Guihen, 2013; Pyrzynska, 2013; Speltini et al., 

2013; Zhang et al., 2013), metal NPs and 

nanostructures based on silica, because of their 

relatively high surface area, availability in various 

particle sizes and pore diameters, and the ease with 

which surface can be modified to contain a wide 

range of functional groups to increase specificity and 

sensitivity of detection and separation (Zhang et al., 

2006). These properties have led to the use of silica 

NPs and related materials (e.g., silica nanofibers) in 

making stationary phases or supports for such 

methods as reversed-phase chromatography, HILIC, 

and UTLC (Ge et al., 2006; Jim et al., 2011; 

Newsome & Olesik, 2014; Aydoğan & El Rassi, 

2016), alumina, zirconia and titanium dioxide (Zhang 

et al., 2006; Nesterenko et al., 2013). 

Application of these nanomaterials have 

included the reversed-phase, normal-phase, ion-

exchange, and affinity modes of LC, as well as 

related methods such as chiral separations, ion-pair 

chromatography and hydrophilic interaction liquid 

chromatography. 

 



BIOLOGICA NYSSANA 9 (1) ⚫ September 2018: 1-19 Matijević et al. ⚫ Inorganic nanoparticles in biology: drug carriers… 

  

 11 

Mass spectrometry 

Small molecules – metabolites (molecular mass less 

than 1000 Da) are significant for understanding of 

cellular processes and metabolism, and their 

importance is reflected in the development of 

relatively new discipline, called metabolomics. The 

metabolome represents the large scale qualitative and 

quantitative changes of all metabolites in a biological 

cell, tissue, organ or organism, which are the end 

products of cellular processes. This is of high 

importance for the understanding of biological 

processes. Metabolomics combine strategies for 

identification and quantification of metabolites with 

different analytical approaches and statistical 

methods, and the great efforts are made for their 

development. Metabolites are involved in different 

cell processes e.g. cell signaling which controls cell 

division, growth and differentiation. 

Another very important and diverse group of 

small molecules are drugs. Qualitative and 

quantitative analysis of drugs (especially their 

biodistribution) is essential for the drug discovery, 

monitoring and understanding of their mechanism of 

action and pharmacological and toxicological effects 

(Monro, 1994; Mizojiri et al., 1996). Method that is 

routinely applied for detection and analysis of drugs 

is autoradiography, which for qualitatively and 

quantitatively investigation of the drugs in the tissues 

requires radioactive materials, and the procedure is 

rather time consuming.  

Other methods that are in use for the detection 

of small molecules are: High-Performance Liquid 

Chromatography, HPLC (Araki & Sako, 1987; Rafii 

et al., 2007), capillary electrophoresis, СЕ (Caussé et 

al., 2000; Bayle et al., 2002), gas 

chromatography/mass spectrometry, GC/MS 

(Larsson & Lindgren, 2005), SERS (Pietzsch et al., 

1997) and fluorescence spectroscopy (Ling et al., 

1991). These techniques are time consuming, and 

additional methods for the sample preparation and 

additional derivatization are needed. Some of these 

methods have additional disadvantages such as low 

selectivity and low sensitivity for the detection of 

small molecules in biological samples. 

Matrix assisted laser desorption and ionization 

time of flight mass spectrometry (MALDI TOF MS) 

is powerful technique that is traditionally used for the 

analysis of large, non-volatile, and termolabile 

biomolecules and biopolymers (proteins, DNA, 

saccharides). In this method, organic matrices are 

traditionally in use, like 2,5-dihydroxybenzoic acid 

(DHB), 9-aminoacridine (9-AA), 2′,4′,6′-

trihydroxyacetophenone (THAP), α-cyano-4-

hydroxycinnamic acid (CHCA), sinapic acid (SA). In 

theory, MALDI TOF can be used for the semi-

quantitative mass analysis of all kind of molecules, 

but in practice that is not a case because of numerous 

disadvantages which are consequence of the use of 

organic matrices. Firstly, inhomogeneous 

distribution of samples molecules between matrix 

molecules (hot spots, cold spots) (Tholey et al., 2006; 

Jaskolla et al., 2009; Kuzema, 2011) lead to the mass 

spectra with poor quality, and eventually the 

reproducibility and the repeatability of a method is 

low. Second drawback refers to the analysis of small 

molecules; organic matrices have low molecular 

masses and the high number of signals in the low 

mass range (usually less than 500 Da) which interfere 

with sample signals. Matrices are usually organic 

acids and they have intensive signals in negative ion 

mode, so it is very difficult to detect the negative ions 

of samples (Petković et al., 2001a; Petković et al., 

2001b). Another disadvantage is that the organic 

matrices do not tolerate high concentrations of salts. 

Biological samples have high concentrations of 

inorganic salts, and because of that the great number 

of matrix signals are present in spectra and the signals 

arising from the analytes are with underestimated 

intensity if not completely suppressed. 

To overcome listed disadvantages of organic 

matrices, the inorganic matrices/substrates are much 

more in use. Wei et al. (1999), were synthesized 

porous nanostructures based on silicon (Desorption 

and ionization on silicon, DIOS). The term SALDI 

the first was used by Sunner et al. (1995), when 

replaced organic matrices with graphite, and refers to 

the techniques that use nanostructured substrates 

instead of organic matrices. Different inorganic 

materials which absorb ultraviolet light were used as 

substrates for SALDI: carbon (Chen & Chen, 2006; 

Kawasaki et al., 2009; Tang et al., 2009; Dong et al., 

2010), silicon (Hu et al., 2007; Northen et al., 2007; 

Teruyuki et al., 2007; Guénin et al., 2009; Walker et 

al., 2010; Cheng et al., 2012), nanomaterials based on 

metals and metal oxide (Chen & Chen, 2004; Chen & 

Chen, 2005; McLean et al., 2005; Okuno et al., 2005; 

Chen & Chen, 2006; Huang & Chang, 2006; Wu et 

al., 2007; Kailasa et al., 2008; Kawasaki et al., 2008; 

Sherrod et al., 2008; Chen et al., 2009; Chiang et al., 

2010b).  

Substrates based on metals and metal oxides 

have additional advantages compared to substrates 

based on silicon and carbon. These substrates are 

more chemically stable in the air and have high 

conductivity (Chen & Chen, 2004; Arakawa & 

Kawasaki, 2010), the samples are NPs based on Au, 

Pt, Ag, ZnO, Fe and MnO2/MnO3. Different 

inorganic NPs are in use in analytics of different 

biological molecules and samples: Sherrod et al. 

(2008) describe selective ionization of olefin 

compounds (cholesterol and carotenoids) direct from 



 12 

the mixture with silver NPs. Wu et al. (2007) were 

analyzed and quantified small, neutral carbohydrates 

from urine with gold NPs. Lee at al. (2007) found that 

ТiO2 NPs with diameter less than 20 nm interact with 

enediol compounds, which have an impact on 

increase of absorptivity in UV-Vis spectra of light. 

Chiu et al. (2008) analyzed urine samples for the 

detection of estrogen hormones – estrone, estradiol 

and estriol with silver NPs of a diameter (34 ± 3) nm. 

Watanabe et al. (2008) were used ZnO NPs that have 

anisotropic shapes, such as cubic or rectangular 

parallelepiped, for the detection of verapamil 

hydrochloride, testosterone, phospholipids, 

oligosaccharides and synthetic polymers. 

Semiconductor ZnS NPs with surface modification 

with different functional groups were used for the 

analysis of cyclodextrin and small proteins (Kailasa 

et al., 2008). Arakawa & Kawasaki, (2010) used 

oxidized graphitized carbon black (GCB) particles 

for the analysis of pharmaceutically active 

compounds. A common pharmaceutical compound, 

propranolol, was successfully extracted from Baltic 

Sea blue mussels and quantified using oxidized GCB.  

TiO2 is a good candidate for SALDI mass 

spectrometry, because it is readily available, non-

toxic and efficiently absorb UV light of N2 laser in 

MALDI instrument. It is first shown applicability of 

sol-gel TiO2 films (Chen & Chen, 2004), and then 

applicability of TiO2 NPs (Radisavljević et al., 2012), 

nanotubes (Lo et al., 2008) and nanowires (Kim et al., 

2014) in SALDI analysis of biomolecules. The 

example of positive ion spectra obtained by SALDI 

method in which TiO2 served as a substrate is shown 

in Fig. 5. 

Scarce data were found in literature about 

tolerance of substrate on high concentration of salts 

in samples solutions. Popović et al. (2015) have 

shown that the quality of mass spectra of transition 

metal complexes obtained with TiO2 NPs was 

idependent of the high concentration of sodium and 

potassium ions.  

Size and shape of nanocrystals have impact on 

analytical performances and ionization efficiency in 

SALDI mass spectrometry (Popović et al., 2016; 

Popović et al., 2016a; Popović et al., 2016b). TiO2 

nanocrystals with various shapes and sizes, such 

colloidal TiO2 NPs (NPs, average diameter ~ 5 nm), 

prolate nanospheroids (PNSs, length: 40–50 nm, the 

lateral dimension: 14–16 nm) and nanotubes (NTs, 

length: 100-150 nm, average diameter 11 nm), were 

investigated substrates for SALDI-TOF MS for 

quantitative analysis of small biomolecules such as 

various sex hormones (testosterone and 

progesterone), vitamins (vitamin A and E), 

carbohydrates and others (Popović et al., 2016; 

Popović et al., 2016a). In general, the best 

reproducibility was obtained with the larger 

nanocrystals, PNSs and NTs, making them good 

candidates for the quantitative 

determination of small molecules. 

However, for analysis of citric acid, 

dexasone, vitamins E and A, PNSs 

provided the highest sensitivity and 

reproducibility (Popović et al., 2016b). 

 

Future use of nanomaterials in 
analytics of (bio)molecules – a 
summary 

Inorganic particles often exhibit 

improved and some novel properties as 

their size approaches nanometer scale 

dimensions. The unique electronic and 

optical properties of nanocrystals may 

lead to future advances of analytical 

(bio)chemistry, biology, for 

investigation of biological processes 

and in medicine. Their additional and 

important application is the 

development of novel therapeutical 

approaches. In terms of therapy, novel 

NPs and activators are expected to be 

exploited. The challenge is to further 

minimize the side effects and involve 

 

 
Fig. 5. Positive ion SALDI TOF mass spectra of inorganic 

complexes: the upper spectrum represents the spectrum of Ru-

complex, whereas the bottom is the spectrum of Pt-complex. The 

spectra are acquired with the assistance of TiO2 NPs with diameter 

of 5 nm. Transmission electron micrograph of TiO2 NPs is given in 

the upper left corner of the figure. Reproduced with permission 

(Popović et al., 2016). 



BIOLOGICA NYSSANA 9 (1) ⚫ September 2018: 1-19 Matijević et al. ⚫ Inorganic nanoparticles in biology: drug carriers… 

  

 13 

light (and potentially other stimuli) in therapy of deep 

tumors.  

In terms of imaging, the future challenge is to 

target specifically a single molecule by a NP. One of 

advanced imaging approaches is mass spectrometry 

imagining which is a rapidly growing field, which 

uses nanotechnology (either for production of targets 

or for the interaction with molecules within the 

cell/tissue) for the visualization of molecules in 

tissues, based on the identification of molecules on 

ions generated. One of the problems with which is 

this approach facing is lateral resolution in cells and 

still, despite of the creativity of scientists, is not easy 

to visualize the intracellular content by this method. 

However, the potential of new materials and 

nanocomposites in those fields is yet expected to be 

exploited in the future. 

Acknowledgements. This work was funded by the 

Serbian Ministry of Education, Science and Technological 

Development, Grants OI 172011, OI 172056 and III 

45010. 

 
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