OPEN ACCESS EC PHARMACOLOGY AND TOXICOLOGY ...Drug delivery not only involves the use of engineered particles as carrier, but also the nanoscale formulation of the drug itself as its

CroniconO P E N A C C E S S EC PHARMACOLOGY AND TOXICOLOGY

Review Article

Medical Application of Engineered Nanoparticles

Reshma VG, Nathiya Krishnan and Mohanan PV*

Toxicology Division, Biomedical Technology Wing, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, Kerala, India

*Corresponding Author: Mohanan PV, Scientist and Head, Toxicology Division, Biomedical Technology Wing, Sree Chitra TirunalInstitute for Medical Sciences and Technology, Thiruvananthapuram, Kerala, India.

Citation: Mohanan PV., et al. “Medical Application of Engineered Nanoparticles”. EC Pharmacology and Toxicology 6.3 (2018): 141-151.

Received: January 15, 2018; Published: February 27, 2018

AbstractNanoparticles (NPs) are the particles that exist on a nanometer scale i.e. at least one dimension must be below 100 nm. Due to

smaller size, they are highly reactive and show exceptional physical, chemical and optical properties compared to the bulk materials. These remarkable properties make them attractive candidate in various medical applications. Nowadays Nano medicine is a widely developing branch of science which deals with nanoparticle application in medical field. This review highlight the importance of engineered nanoparticles (ENPs) in various medical applications such as drug delivery, antimicrobial agents, photothermal therapy, magnetic hyperthermia, contrast agents in various imaging techniques and biosensors. Currently many NPs are under investigation for drug and gene delivery. Silver, quantum dots (QDs), nano-TiO2 etc. are used as biofilm therapeutic agents. ENPs like QDs act as theranostic agent i.e. they act as both diagnostic as well as therapeutic agent. ENPs have significant role in imaging techniques like MRI, CT scan etc. The risks related with the application of ENPs in various medical applications are not explored much and hence safety evaluation is mandatory before its clinical application.

Keywords: Nanoparticles; Safety; Medical Application; Bioimaging; Drug Delivery

Graphical Abstract

Figure

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IntroductionNanoparticles (NPs) are the materials having a size less than 100 nm at least in one dimension [1] and it differs from the bulk mate-

rial in chemical, physical and mechanical properties. High reactivity of nanomaterial compared to their parent material mainly because of their smaller size. As particle size decrease down to smaller nanoscale, increase their surface area to volume ratio give rise to novel nanomaterial. On the basis of their origin, nanoparticles can be classified into two categories, natural and anthropogenic. Engineered nanoparticles (ENPs) come under the anthropogenic category, which is produced intentionally owing to their nanospecific properties [2]. Exceptional properties of nanomaterial such as smaller size, large surface area, quantum confinement, thermal and electrical conductivity makes them suitable for various medical applications such as drug delivery, antibacterial agents, hyperthermia, photodynamic therapy, MRI contrast enhancement, cancer therapy and so on [3]. This review aims to explore the medical application of various engineered nanoparticles such as liposomes, dendrimers, silver (Ag) NPs, gold (Au) NPs, PLGA NPs, silicon dioxide (SiO2) NPs, iron oxide (Fe3O4) NPs and quantum dots (QDs).

Drug carriers

Drug delivery not only involves the use of engineered particles as carrier, but also the nanoscale formulation of the drug itself as its own ‘carrier’ [4]. Although vast sources with biological origin like phospholipids, lipids, lactic acid, dextran, chitosan, or “chemical” char-acteristics like various polymers, carbon, silica, and metals have been employed, there is an immense area of potential for the chemical composition of polymer origin.

As drug delivery vehicles, magnetic nanoparticles have the one of a kind favorable position of directing the nanoparticles to a desir-able area and keeping them localized at the site using an external magnet. Owing to its hypothermia effect, magnetic nanoparticles with a diameter of 10 nm were used in cancer therapy [5]. SiO2 magnetic nanoparticles were used to kill pathogenic bacteria [6].

Liposomes are making its beginning entry as delivery vehicle to make an impact on the nanomedicine scene. Liposomes being small, flexible and biocompatible have the advantage to pass along the smallest arterioles and endothelial fenestrations without clot formation [7-9]. Liposomes have been reported to improve the pharmacokinetic properties of drugs such as the therapeutic index, metabolism, re-duction of harmful side effects and increase of in vitro and in vivo anticancer activity [10]. Turkova., et al. [11] conducted a meta-analysis in order to evaluate the efficacy and safety of deoxycholate and lipid (liposomal) amphotericin B formulations (AMBF) in the treatment of invasive fungal disease (IFD) in neonates. Safdar and co-workers showed that nephrotoxicity is generally similar for ABLC and L-AmB in patients receiving antifungal therapy and prophylaxis. Recent studies have reported the clinical outcomes of drug examples in liposomal formulations such as anticancer drugs [10], neurotransmitters (serotonin) [12], antibiotics [13], anti-inflammatory and anti-rheumatic drugs [14].

Unpredictable side effects in cells other than the target site is the major obstacle arising during drug delivery. Studies proved the suc-cessful application of modified liposomes instead of bare liposomes which markedly reduced the undesirable side effects [15]. Now also other materials including various co-polymers and dendrimers at the nanosize range have become available to alter the distribution of encapsulated or attached drugs. Multifunctional liposomes are a promising approach containing the specific proteins, antigens, or other biological substances which act selectively on particular tissue [16]. Biswas., et al. [17] investigated the reversible model ligands by presenting hydrazine-functionalized poly- (ethylene glycol)-phosphatidylethanolamine (PEG-PE)-based amphiphilic polymer which can conjugate a variety of ligands. The reversible ligand model successfully performs the function of targeting at the specific site. Polyethylene glycol (PEG) molecules have got hydrophilic ‘stealth’ properties thus providing longer circulation times as a carrier.

Unlike bio conjugates, monoclonal antibodies are good targeting vehicles for drug delivery. One of the ultimate goals is to create ap-tamers that mimic antibodies which bind practically with any antigen in an in vitro system. The mechanisms behind the action of antibod-ies include receptor ligand binding competition; interference with receptor function; cell-mediated cytotoxicity; complement-dependent cellular cytotoxicity. The aptamers, generally nucleic acid ligands are generated by evolutionary methods in vitro, targeting antigens of higher affinity in vivo.

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Various researchers have used paclitaxel as a model drug and studied them for their toxicity, mitochondrial targeting and efficacy in delivering. Danhier and co-workers [18] demonstrated the use of PEO-modified poly(ε-caprolactone) (PCL) nanoparticles as a multi-drug-delivery system for the apoptosis modulator ceramide and the chemotherapeutic drug paclitaxel. Their results indicated that the dual-drug-delivery system could greatly improve chemosensitivity of ovarian cancer cells exhibiting Multi Drug Resistance by bypassing P-gp drug efflux. Win and Fen [19] demonstrated enhanced cytotoxicity for tumor cells in vivo, wherein the drug paclitaxel encapsulated in vitamin E TPGS-emulsified poly (D,L-lactic-co-glycolic acid) (PLGA) nanoparticles, resulted in higher and prolonged level above the effec-tive concentration in vivo. Biswas., et al. [17] examined polyethylene glycol-phosphatidylethanolamine (PEG-PE) conjugated with the TPP group as drug carriers. Danhier., et al. [18] reviewed the beneficial usage of PLGA-based nanoparticles both in vitro and in vivo for targeted and untargeted drug delivery. Owing to its slow degradation rate, PLA (Poly lactic acid) polymers have been replaced by PLGA polymers in drug delivery. PLA modified microspheres poly (hydroxyethyl methacrylate) showed a better anti-tumor effect as well as increased loading capacity than the unmodified one.

Nano medicinal methods have been a good chance of cancer immunotherapy with much less damage to normal tissue than exist-ing therapeutic protocols. The existing are chemotherapeutic methods with major drawbacks including the destruction of surrounding healthy tissues in deep, underlying tumors. To overcome this problem, methods have been developed to selectively heat the tumors using near-infrared–absorbing gold nanoparticles called nanoshells.

Another promising and perhaps, complementary approach is the use of oligonucleotides for tumor destruction. Nano liposomes when coupled with oligonucleotides target and deliver the nucleic acids to the cancer cells and blocks α-folate receptor production decreasing survival rate by 5-fold to doxorubicin in breast cancer cell lines. [20]. Ongoing clinical trials include prostate, breast, pancreatic, lung, colorectal, melanoma, and brain cancers. This is a good example of how antisense technology involving the use oligonucleotides can be used to increase the effectiveness of existing drugs even at lower dosages.

Conjugation of the antigens to the nanobeads provides a major breakthrough in cancer therapy and the effectiveness of vaccines in general. Surface area and charge density of nanotubes are considered to be critical in determining their electrostatic complex formation with DNA. Gamvrellis [21] in his study, coupled the antigens to solid-core nanobeads (40 nm to 50 nm), allowing them to localize dendritic cells in the draining lymph nodes. A single dose of the antigen-coated beads cause rapid clearance of established tumors in 2 different mice model.

Gene-specific silencing agents will be an essential component of the new wave of cancer treatments. Small interfering” RNAs or siR-NAs found in most eukaryotes, act as effector molecules of the RNA interference (RNAi) pathways [22]. The siRNAs being a small double stranded molecule of about 21 nucleotides in length makes it an attractive candidate as nanodrugs. Instability in the blood and poor up-take of drugs into the target cells has been rectified when nanoparticles are being coupled with siRNAs. They result in specific degradation of mRNAs containing the complementary sequence that directs the complex to the tumor site [10].

Drug delivery

A number of issues remain to be addressed when designing effective drug delivery vehicles. The basic prerequisites for design of new materials include;

1. Drug incorporation,

2. Formulation stability and shelf life,

3. Biocompatibility,

4. Bio distribution and target release and

5. Functionality.

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Therapeutic selectivity of nanoparticles is critical including their instability during blood circulation, low renal clearance, limited ac-cumulation in cancer tissues, and inadequate uptake. Unique properties of nanoparticles like mono-distribution, thermal and magnetic properties have fascinated substantial attention [23].

Antibiotic property

Antibiotic resistance is a growing problem, especially among the public health care responsible for some 2 million infections each year that lead to approximately 23,000 deaths of individuals. Rapidly accelerating drug resistance further deteriorates this threat to human health. The rise of multidrug resistance (MDR) specifically is a consequence of the different types of drug resistant genes by the same bacterial cell [24]. The significant groups of antibiotics that are presently being used have bacterial focuses on: the cell wall synthesis, translational, as well as DNA replication machinery (Wang., et al. 2017). Unfortunately, it is significantly hard to distinguish novel bacterial targets on the growing new classes of efficient antimicrobial agents (Silver, 2011). Beyond the global efforts to limit overuse and abuse of antibiotic drugs, a new tool has emerged in fighting drug resistant microorganisms. Innovative research conducted over the past 50 years has inspired the current diversity in nanoparticle research. Conversely, more in-depth understanding of interactions between the biology of microorganisms and the physical chemistry of nanoparticles is required to overcome the antibiotic resistance. Concurrent with this chemistry is a necessary in order to ultimately target bacteria, and overcome their colossal arsenal of defences.

The toxic nature of metallic nanoparticles speaks to a powerful answer for whipping bacterial protection. Recent investigations have demonstrated that combining nanoparticles with antimicrobials not just diminishes the harmfulness of the two agents towards human cells by lessening the prerequisite for high measurements, yet in addition upgrades their bactericidal properties. Combining antibiotics with nanoparticles additionally ascertain their capacity to wreck microbes that have obtained protection from them. Nanoparticles la-beled with antibiotics have been appeared to build the centralization of antimicrobials at the site of bacterium-antibiotic interaction, and to encourage binding of antibacterials to microscopic organisms [25]. Likewise, synergistic nature has been seen within nanoparticles and antimicrobial peptides, as well as essential oils against bacterial resistance.

Interaction with bacteria

While dispersed (planktonic) bacteria represent a therapeutic challenge to acute illness, bacterial biofilms present major hurdles for both diagnosis and treatment altering the community level of resistance [26,27]. Bacterial biofilms are structured communities of bacteria embedded in a matrix of extracellular polymeric substances (EPS) that can be formed on variety of surfaces, such as tissues and medical devices [28]. Biofilms are a serious health threat as they can produce superantigens to evade the immune system [29].

Figure 1: Interaction of nanoparticles.

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Generation of NP-based antimicrobial systems requires engineering at the initial stage of nanomaterial- biofilm matrix interaction itself. It’s not the first time that nanoparticles have been used to combat bacteria. Previous research has shown that metal nanoparticles are effective against antibiotic-resistant infections, but at a cost: indiscriminate damage caused to surrounding cells in addition to the infection. Silver nanoparticles are effective antimicrobial reagents to a certain extent that block infections associated with implanted bio-medical devices [30]. Previous study reported that AgNPs interfere with biofilm integrity of drug-resistant strains of Escherichia coli and Klebsiella pneumonia [31]. Similar result has been observed by Mohanta [32] on AgNPs produced from silver nitrate (AgNO3). In contrast, silver nanoparticles have adverse effects on cells such as the production of reactive oxygen species (ROS) which are toxic to both bacteria and eukaryotic cells [33,34]. It was also observed that the bacteria B. subtilis in the center of biofilm not only can survive but also can resist foreign substances. It’s because when a biofilm grows to a certain extent, the edge will periodically stop growing allowing the nutrients to flow further into the center of the biofilm [16]. Deposition of nanoparticles inside the biofilm is directly proportional to the electrostatic interaction as well as the homogeneity of the charges on the biofilm surface. The penetration and deposition of NPs are taken into account while designing biofilm therapeutics.

Microbial resistance

Contemplating the methods that MDR bacteria have taken to inactivate or evade all classes of β-lactam antibiotics, studies were per-formed to explore connection of ampicillin to nanoparticles. Spherical silver (AgNP) and gold nanoparticles (AuNP) were constructed and functionalized them with ampicillin to serve as an alternative for drug delivery system [35]. AgNP coupled with ligands such as polyeth-yleneimines, chitosan and glucosamine have increased antibacterial activity as these ligands tend to increase the binding of the nanopar-ticles to bacterial cells and, augment uptake [36-38]. AuNP of specific physiochemical characteristics are proven to be non-cytotoxic and biocompatible paving its way functional into therapeutic drug delivery vehicles [39,40]. Tom., et al. [41] found that the reactive portion of the molecule ciprofloxacin was surface exposed when bound to AuNP. Although, these studies supports the idea that other antibiotics bound to AuNP in order to retain their activity, the potency of antibiotics was still questionable. However, reports demonstrated the de-cline rates of bacterial adhesion and biofilm formation by NPs, their specific mechanism is not yet fully understood.

One of the foremost roles of the cell membrane in communication has a close relationship with apoptosis. The disruptive effect of TiO2 NPs on a fluorescence microscope showed changes in the fluorescence intensity of the cytoplasm when altering the potential of the cell membrane. Certain researchers similarly believe that the mechanism through which NPs cause bacterial death is dependent on the components and structure of the bacterial cell [42]. The components of the cell membrane of both Gram-positive and Gram-negative bac-teria produce different adsorption pathways. Many studies have shown that NPs have greater activity against Gram-positive bacteria than against Gram-negative bacteria, because of its cell wall components. LPS, a unique structure of the cell wall of Gram-negative bacteria, with its negatively charged region forms a penetration barrier that allows the entrance of only macromolecules attracting NPs [43]. In contrast, teichoic acid and a thin layer of peptidoglycan and abundant pores in Gram positive bacteria allow foreign molecules to pen-etrate, resulting in cell membrane damage and cell death [44].

Recent advent of nanotechnology offers new opportunities to reshape the landscape of the pharmaceutical industry in developing for-mulations based metallic nanoparticles against these superbugs. Similarly, Kelkar [45] and his co-workers demonstrated that nanomate-rial can be fine-tuned through appropriate surface functionalization which in turn provided a promising synergy arising from multivalent interactions with bacteria. Triggered release of antimicrobials from these nanocarriers can be an alternative strategy to diminish their undesirable side effects.

A group of researchers at the University of Colorado, developed nanoscale quantum dots with specific light-absorption properties to help understand how an antibiotic is effective against bacteria. Quantum dots (QDs) are a heterogeneous group of nanocrystals with size ranges from 2.5 to 100 nm, depending on coating thickness. Moreover, they have broad absorption spectra and narrow emission spectra; their fluorescence (each with a unique color emission) is much dependent on their chemical composition and size. The activated quan-tum dots upset the balance of chemical processes, called “reduction-oxidation” that kill drug-resistant superbugs without harming the

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surrounding healthy tissue. Studies have been conducted on some of the most dangerous drug-resistant infectious agents: methicillin-resistant Staphylococcus aureus; extended-spectrum β-lactamase-producing Klebsiella pneumoniae and Salmonella typhimurium; multi-drug-resistant Escherichia coli; and carbapenem-resistant Escherichia coli [46]. Koole and co-workers [47] demonstrated the penetration and deposition of QDs within the biofilms. The relatively larger surface area of QDs aids for attachment of peptides/antibodies which in turn precisely target cell types or tissues. Their study revealed that cationic QDs with hydrophobic terminal groups were found through-out the biofilm, whereas their hydrophilic counterparts, neutral and anionic QDs remained in the EPS matrix of the biofilm.

Doping modification is also one of the most effective methods to prevent the aggregation of NPs and to disperse NPs in hydrophilic environments. Nano-TiO2 with antibacterial activity that can reduce the formation of biofilms is widely applied in orthopedic, dental im-plants. The doped form in comparison with unmodified nano-TiO2, can effectively extend the active spectrum to the visible light region by increased valence bandwidth.

Imaging and diagnostic applications

A considerable thrust of recent research has been envisioned on imaging capabilities that cater basic and clinical pulmonary research and disease diagnosis through the application of nanotechnology. X-ray computed tomography (CT), is widely used diagnostic imaging tool offering broad availability at modest cost. X-ray CT is used to visualize tissue density differences between normal and cancerous tissue. At present, highly water-soluble small organic iodinated molecules were used as CT contrast enhancers which suffer from very short imaging times. Therefore, the development of functionalized nanoparticles that specifically enhance contrast of diseased tissue has received considerable attention. At the same tune, in recent years many researchers have been focused on development of new imaging agents with an ability to anchor a large number of the same or different molecules.

With their strong surface plasmon absorption properties, gold nanoparticles (Au NPs) attracted interest in the medical imaging areas like computed tomography (CT), photoacoustics and Surface-Enhanced Raman Spectroscopy (SERS) [48]. Gold nanoparticles have also emerged as colorimetric biosensors based on the change in the plasmon resonance frequency. Zhang and co-workers [49] developed DNA-gold sensors. They demonstrated the interaction of a cross linker with a receptor molecule between nanoparticles when an anti-receptor is added.

Nano-sized blood pool contrast agents of high diagnostic relevance for many diseases, including vascular inflammation like athero-sclerosis and arthritis, tumor angiogenesis, thrombosis, chronic venous insufficiency, and cancer have also been developed [50]. Nanoma-terials combined with imaging provide a breakthrough for high throughput diagnostic assays and improved tumor biopsies. Theranostic nanoparticles are a novel concept currently at the preclinical stage and may provide the opportunity for real-time imaging of tumors as patients are undergoing therapy. They are multifunctional nanosystems. Peptide-modified ferritin nanocage is yet another attrac-tive biocompatible nanoplatform. It comprises of a protein-based nanoparticle made of 24 subunits, which can be self-assembled into a cagelike nanostructure. It may be used for the targeted delivery of imaging agents (e.g., radiometal isotopes and fluorescent dyes) and therapeutic agents (e.g. photosensitizers and doxorubicin) to tumors that overexpress integrin αvβ3. To date, few examples of theranostic nanoparticles that actively target tumor in vivo have been reported. This trajectory strategies guide certain nanoparticles into a new era of theranostics approaches including nucleic acid delivery, chemotherapy, photothermal ablation, photodynamic, and radiation therapy in combination with one or more imaging functionalities both in vitro and in vivo.

Multiple imaging modalities (e.g. MR/CT, MR/PET, optical imaging, and others) allow complementary information in a single nano-platform [51]. Mulder., et al. [52] lead the way to the use of lipid-based nanoparticles for contrast-enhanced MRI and molecular imaging applications. FDA approved safe MRI contrast agents i.e., nanoconstructs using iron oxide nanoparticles especially because of concerns over the safety while increasing contrast enhancement and imaging efficacy in MRI imaging.

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More importantly, with advancements in imaging capabilities, researchers have QDs paired with fluorescent organic dyes (Fluores-cence Resonance Energy Transfer (FRET) pairs) in monitoring polyplex trafficking in vitro [45]. Quantum dots are also being used in ex vivo diagnostics where bio-compatibility is not a requirement. Koole., et al. [47] developed paramagnetic lipid-coated silica quantum dot core as a contrast agent of αvβ3-integrin expression on cultured endothelial cells for multi imaging purpose. A significant area of increas-ing application is in the development of new x-ray sources from nanoparticles.

Unlike soft nanoparticles, metal-based nanoparticles can also engender tremendous contrast for imaging. Polyelectrolyte complex nanoparticles have been established as potential materials for gene delivery and imaging because of their relatively efficient transfection efficiency and simple formulation. These nanocarriers have proved effectiveness against entrapping and delivering peptides, proteins, and RNA. MRI studies on Gadolinium incorporated PEC nanoparticles by means of Gd-DTPA grafting to chitosan and ionic trapping of Gd ions revealed that contrast-enhanced PECs rapidly accumulated in the rat kidney and liver [53]. In recent years, Perfluorocarbon nanoparticles (PFCNP) have also received considerable attention in molecular imaging [35,54,55]. PFC core of PFCNPs are an encapsu-lated lipid monolayer which has been relatively non-volatile, inert, non-toxic and non-degradable material [56]. They act as a platform to carry contrast-enhancing agents or chemotherapeutic drugs in MRI assessments of tumor angiogenesis [57], cellular tracking [58] and atherosclerosis [59].

Application of lipid-based nanoparticles such as liposomes and micelles as contrast agents for bioimaging has been performed. These lipids acts as a shell to contrast enhancers like QDs, metal based nanoparticles and so on. Cressman., et al. [60] developed RGD-labeled liposomal nanoparticles and studied trafficking in cultured endothelial cells. Furthermore, Senarath-Yapa., et al. [61] reported the use of poly (lipid)-coated, fluorophore-doped silica nanoparticles for bio-labeling and cellular imaging applications.

Therapeutic delivery vehicles goes hand in hand with fluorescent markers (organic dyes and inorganic quantum dots), different con-trast agent probes for MRI imaging, (T1 and T2 agents), and nuclear imaging agents (PET/ SPECT/CT agents) in order to facilitate easi-ness in trafficking pathway, kinetics, and therapeutic efficacy. Labeling polymers with “classical” fluorescent types of labels alters the physiochemical properties of these polymers. To overcome these, researchers have demonstrated the use of Fluorescence Correlation Spectroscopy (FCS). It was found that the cationic diblock polyethyleneglycol-polyethyleneimine (PEG-PEI) copolymers when labeled with a fluorescent cyanine dye Cy5 lose their ability to bind to nucleic acids [62]. The development of nanoprobes for molecular imaging of disease pathways, and the development of better contrast agents that will classify tumor subtypes based on identifying genetic or epi-genetic markers with in vivo and ex vivo diagnostics leading to personalized therapies are forthcoming.

Theranostics

Engineering of various kinds of theranostic nanoparticles for simultaneous cancer imaging and therapy has been developing past few years. The term “Theranostics” is a combination of two words that are used for simultaneous diagnosis and treatment. Active tumor targeting of theranostic nanoparticles is very crucial for both diagnosis and therapy. An ideal theranostic process needs the following requirements (Figure 2).

Figure 2: Theranostic requirements.

• Route of administration.

• Formulation of nano-drug carrier contains therapeutic agent, imaging agent, targeting agent, cell penetrating ligand, stimuli-sensitive antennae etc.

• Escape from clearance of reticuloendothelial system (liver, spleen, and bone marrow) and hemocompatibility.

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• Target specific cells (tumor cells).

• Cell penetration and intracellular drug delivery.

• Real time monitoring of effect of treatment in both diseased cells and normal cells with the help of a diagnostic agent (imaging, magnetic or optical) [63-65].

Conclusion

Reports indicated that ENPs have been integrated into every aspects of our life in the form of drugs, chemicals, cosmetics and in sev-eral other consumer products. The safety of nanoparticles is still remains a debate, how they evade immune recognition and their fate remains unclear. Anxiety rising from the undesirable toxic effects of nanoparticles substantially reduces their potential use. Thus it is vital to assess the safety of nanoparticles before implementing their use in order to avoid unintentional health hazard and to ensure a risk free safer technology. The present review highlights the importance of engineered nanoparticles (ENPs) in various medical applications such as drug delivery, antimicrobial agents, photothermal therapy, magnetic hyperthermia, imaging and biosensors.

Acknowledgements

The authors wish to express their sincere thanks to the Director and Head, Biomedical Technology Wing, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum for their encouragements and support for this study.

Conflict of Interest

The authors declare that they have no conflict of interests.

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