Biophysicochemical Perspective of Nanoparticle Compatibility: A Critically Ignored Parameter in...

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Nanoscienceand Nanotechnology

Vol. 14, 1–13, 2014www.aspbs.com/jnn

Biophysicochemical Perspective of NanoparticleCompatibility: A Critically Ignored

Parameter in NanomedicineShabir Hassan1 and Ajay Vikram Singh2!3!!

1Institute of Physical Chemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland2Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180-3590, USA3Center for Biotechnology and Interdisciplinary Studies, Room 2127, Rensselaer Polytechnic Institute,

Troy, NY 12180, USA

Engineered nanomaterials are increasingly used in domestic and commercial products due to therapid growth and increasing public and industrial interests in nanotechnology. Undoubtedly therewill be more exposure of living organisms and the environment to nanomaterials. Therefore, under-standing the biophysicochemical interactions of nanoparticles with proteins, membranes, cells, DNA,and organelles at the nano-biointerface will help to control fundamental biological and dynamiccolloidal forces to promote the biocompatibility of the particles. In this article, we review how bio-and physicochemical surface characteristics at nanoscale govern particle biocompatibility for in vivoand in vitro models. We also revisit the promise and predictions gained from this understanding todesign special types of nanoparticles, such as quantum dots (QDs) and superparamagnetic ironoxide nanoparticles (SPIONs), for biomedical applications. This knowledge is essential not onlyfrom the perspective of safe use of nanomaterials, but also in paving the way for nontoxic interac-tions with biological systems. It paves the route for safe implementation of the materials in novelbiomedical diagnostics and therapeutics. We also put forward an outlook and future perspective,which are largely “ignored parameters” in nanomedicine. In conclusion, emphasis on the system-atic evaluation of nanomaterial toxicity in primary cells derived from vital organs and the need todevelop an international consortium for a materialomics database is encouraged.

Keywords: Nanoparticle, Biomedical Applications, Theranostic, Oxidative Stress,Nanomedicine.

CONTENTS1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12. Physical Properties of Metal Nanoparticles . . . . . . . . . . . . . . . . 33. What Makes Nanoparticles Biocompatible . . . . . . . . . . . . . . . . 44. Properties That Make Nanoparticles Lethal for Cells . . . . . . . . 45. Surface Composition and Lethality . . . . . . . . . . . . . . . . . . . . . . 56. Surface Chemistry Also Plays a Role . . . . . . . . . . . . . . . . . . . . 67. Nanoparticles for Biomedical Applications . . . . . . . . . . . . . . . . 68. Quantum Dots: Qubit Exploring Bionano-Interactions . . . . . . . . 79. Superparamagnetic Iron Oxide Nanoparticles (SPIONs) . . . . . . 710. The Role of Nanoparticles in Biophysics: Studying

Energy Transport in Peptide Models . . . . . . . . . . . . . . . . . . . . . 1011. Concluding Remarks and Future Perspective . . . . . . . . . . . . . . 11

Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12References and Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

!Author to whom correspondence should be addressed.

1. INTRODUCTIONFrom a broad perspective, ‘nano-biotechnology’ refers tothe interactions of cellular and molecular components andengineered materials at the interface between materialsand biological systems. Nanomaterials typically compriseclusters of atoms, molecules, and molecular fragments—at the most elemental level.108 Such nanoscale objects—typically, though not exclusively, with dimensions smallerthan 100 nanometers—can be useful by themselves oras part of larger devices containing multiple nanoscaleobjects. Concerning the applications of material science atthe nano-biointerface, nature made and synthetic worldsmerge into a new science where a complex interplayof dynamic physicochemical interactions, kinetics, andthermodynamic exchanges between nanomaterial surfaces

J. Nanosci. Nanotechnol. 2014, Vol. 14, No. xx 1533-4880/2014/14/001/013 doi:10.1166/jnn.2014.8747 1

Biophysicochemical Perspective of Nanoparticle Compatibility: A Critically Ignored Parameter in Nanomedicine Hassan and Singh

and the surfaces of biological components take place.The increasing promise in electronics,1 the clinical real-ity that nanomaterial science and technology holds forfuture nanomedicine, and in biotechnology for use in tar-geted drug delivery,2 makes it essential to understandthe forces governing the toxicity and biocompatibility ofthe nanoparticles based upon assembled knowledge, pro-viding a conceptual framework to guide its promisingfuture exploration. The emerging interest in nanomaterialsspanning different industrial sectors, from textiles3 to thenanoengineering of dental and wound-healing materials,4

makes nanomaterials a hot bed for investment and com-mercial diversifications. However, in this review, wefocus on advances in nanotechnology that have enablednanomedicine to target the disease-specific modules withnanoparticles having therapeutic and diagnostic (imaging)components. The newly emerging multipartite theranos-tic (thera(py)+ (diag)nostics) approach puts forth strongimplications for medical care and the cure of differentdisorders.5 We highlight the understanding of bio- andphysicochemical modulation of a particulate system whichis utilized in the current nano-theranostics tamed drugvehicles. The system commonly contains the cargo-carrierdoublet: targeting ligands (cargo), and imaging labels fordelivery to specific tissues, cells, or subcellular compo-nents on multipartite nanoparticles (carrier).6

The synthesis of inorganic nanomaterials has beendemonstrated by several methods involving physical,chemical, and biological routes (Fig. 1). Some of thephysical methods leading to the successful synthesis ofnanomaterials, especially the noble metal nanoparticles,include vapor deposition, thermal decomposition, spray

Shabir Hassan received his bachelor’s degree in Biology and Chemistry from the Univer-sity of Kashmir and moved to University of Pune for his master’s degree in Biotechnology.In Pune, he did his summer training at the National Centre for Cell Science (NCCS Pune,India) and worked on nanoparticles in tissue engineering. He finished his degree with athesis project from the National Chemical Laboratory (NCL Pune, India) in the biocom-patibility of various types of nanoparticles. After a year of research training in cancerbiology, he moved into the Department of Chemistry at the University of Zurich and ispresently in his fourth year of a Ph.D. in ultrafast spectroscopy and biophysics.

Dr. Ajay Vikram Singh received a Master of Science degree in Biotechnology from PuneUniversity, India, in 2005 and a Ph.D. in Medical Nanotechnology from the EuropeanSchool of Molecular Medicine (SEMM) in Milan, Italy, in 2011. He is currently workingas a postdoctoral scientist at the Department of Biomedical Engineering at the RensselaerPolytechnic Institute in Troy, New York. His research interests include understanding thebio-physicochemical interactions at the nano-bio interface that regulate protein adsorptionand are instrumental in the development of drug and gene delivery vectors, scaffolds fortissue engineering, smart prosthetics, and lab-on-a-chip devices. Within this realm, theidea is to pattern and apply micro/nano-hybrid features as topography and chemical cuesto device protein as a molecular switch to on-off stem cell differentiations.

Figure 1. Schematics summarizing different synthesis routes fornanoparticles.

pyrolysis, photoirradiation, laser ablation, ultrasonication,radiolysis, and solvated metal atom dispersion. However,chemical methods for the synthesis of metal nanopar-ticles have been more popular and have gained wideacceptance. Some of the common chemical routes includethe sol–gel method, solvothermal synthesis, micelles-basedsynthesis, and galvanic replacement reaction. Chemicalreduction has been the most popular route toward thesynthesis of metal nanostructures due to easy protocolsand the fine shape and size control that this methodprovides.

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Hassan and Singh Biophysicochemical Perspective of Nanoparticle Compatibility: A Critically Ignored Parameter in Nanomedicine

The control over size, shape, stability, and the assem-bly of nanoparticles is achieved by incorporating differentcapping agents, solvents, and templates. Capping agentsthat have been used range from simple ions to polymericmolecules and even biomolecules. Ever since the firstreport by Brust et al.7 for the synthesis of monolayer-protected clusters (MPCs), several advances have beenmade in the field and a variety of capping agents have beenused to prepare MPCs soluble in non-polar organic as wellas polar solvents. Although the majority of the synthe-sis reactions are carried out in an aquous medium; basedon our need and use, organic solvents,8–12 ionic liquids,13

and supercritical fluids14–16 as the media of choice havealso been reported. Similarly, in order to gain control overthe formation, assembly, and specificity of nanoparticles,many reviews and reports have been published on theuse of soft and rigid templates such as micelles, poly-meric molecules, DNA, viral nanoparticles, and preformednanoparticles.17–26

Although over the past several decades, physical andchemical methods have dominated the synthesis of nano-structures, recently considerable attention has focused onthe use of biological systems. Biological systems havebeen known to fabricate intricate structures at the micro-and nanoscales under normal environmental conditionswith precise control over the shape and size of the synthe-sized nanomaterials. The exquisite siliceous exoskeletonsof the diatoms and radilarians, and calcareous structuressynthesized by the coccoliths are microscale materials,which have attracted tremendous interest. In addition,magnetite particles found in the magnetosomes of the mag-netic bacteria are a wonderful example of functional nano-materials that help the microorganism in navigation andorientation with regard to the earth’s geomagnetic field.This fact has lured scientists to understand the underly-ing mechanisms used by the biological systems and thusexplore the biomimetic approach toward the synthesis ofnanomaterials. One of the reports that opened up the gatesfor the use of biological systems for the synthesis of nano-materials was by Klaus et al. on the synthesis of sil-ver nanoparticles in the periplasmic space of the bacteriaPseudomonas stutzeri AG259.27 To date, several bacteria,S-layer bacteria, fungi, algae, and plant systems have beenused for the synthesis of nanomaterials of different shapes,sizes, and compositions.28–30

2. PHYSICAL PROPERTIES OFMETAL NANOPARTICLES

As the size of any material approaches the nanometerscale, the fundamental properties of matter change. Theproperties of atoms and molecules are not governed bythe same physical laws as those for larger objects or evenlarger particles. The physical and chemical properties ofnanoparticles can therefore be quite different from thoseof larger particles of the same substance and composition.

The following section briefly discusses the changes in theproperties of the metals at a nanometer scale.It is well known that with a decrease in the size of par-

ticles for a given volume of material, the number of atomsat the surface (surface area) increases tremendously. Forexample a 3-nm particle would have 45% of its atomson the surface, and a 1-nm particle would have 76% ofthe atoms on its surface. So the surface area is greatlyincreased as the material approaches lower nanometerdimensions due to which nanoparticles become greatlyadvantageous for promoting the rates of chemical reac-tions. Thus, the reduction in the size of particles rendersthem excellent catalysts. For example, gold is consideredto be a noble metal in bulk state, but the nanoparticles ofgold dispersed in alumina or iron oxide were found to beexcellent catalysts for carbon monoxide oxidation.31!32

Mechanical properties of a material depend stronglyon the density of dislocations, grain size, and thesurface/interface-to-volume ratio. The strength and hard-ness of the material could be severely affected by anydecrease in grain size. As compared to the bulk, a nanopar-ticle has more defects due to the high surface-to-volumeratio hence altered mechanical properties. Sometimes thealteration in these properties leads to the generation ofsuperplastic nanomaterials.107

The magnetic properties of nanoparticles differ fromthose of the bulk in two ways. The large surface-to-volumeratio results in a different local environment for the surfaceatoms in their magnetic coupling/interaction with neigh-boring atoms, leading to the mixed volume and surfacemagnetic characteristics. Unlike bulk ferromagnetic mate-rials, which usually form multiple magnetic domains, sev-eral small ferromagnetic particles could consist of only asingle magnetic domain.In the case of a single particle being a single domain,

superparamagnetism occurs,33!34 in which the magnetiza-tions of the particles are randomly distributed, aligningonly under an applied magnetic field. The alignment dis-appears once the external field is withdrawn. These couldhave important implications, for example, in ultra-compactinformation storage where the size of the domain deter-mines the limit of storage density.Metal nanoparticles when embedded between metal-

insulator-metal junctions, or between the tip of STM andan electrode, show a differential capacitance or chargingat low temperatures even at zero bias.35 It was realizedthat this behavior is caused by the extremely small capac-itance of the metal nanoparticles.36 These particles canstore charge by the addition or removal of electrons. Dueto their low capacitance, nanometer-sized metallic particlesare extremely sensitive to neighboring charges and there-fore, could be useful as sensor materials including vaporsensors.37!38

The optical properties of these nanoparticles are spectac-ular and, therefore, have stimulated a great deal of excite-ment during the last few decades in many applications

J. Nanosci. Nanotechnol. 14, 1–13, 2014 3


related to biology.39 The color variations arising fromchanges in the composition, size, and shape of nanoparti-cles, the surrounding medium, and the very high absorp-tion cross-section promoted these materials as inorganicchromophores from the visible to near-infrared region. Dueto this reason they find applications as optical sensors andimaging agents.40

The optical effects that metal nanoparticles exhibit aredue to a phenomenon called “surface plasmon resonance”(SPR). SPR is the frequency at which conduction electronsoscillate in response to the alternating electric field of inci-dent electromagnetic radiation.41!42 This phenomenon wasexplained by Mie and is based on the Maxwell equationson scattering.43 However, only gold, silver, and coppernanoparticles possess plasmon resonances in the visiblespectrum, which give rise to such intense colors.44 SPRcharacteristics of nanoparticles have been shown to beused in cancer diagnostics.45 Nanoparticle is a complicatedmulti-electron system, where the confinement of electronicmotion due to the reduction in size leads to fascinat-ing new effects, potentially tunable with particle size andshape.

3. WHAT MAKES NANOPARTICLESBIOCOMPATIBLE

A primary interest in the idea of nanobiotechnologycomes from the association of nanoscience with biol-ogy. An ideal nanomaterial for biological purposes shouldbe biocompatible. Nanoparticles have been used for var-ious biological applications in both in vivo and in vitrocontext.3–5!46 Thus it becomes important to study the short-and long-term effects of size, shape, and surface func-tional groups on the bioavailability, uptake, subcellulardistribution, metabolism, and degradation of these differ-ent nanostructures. Reports on the surface properties ofnanoparticles, both physical and chemical, stress the factthat nanoparticles differ from bulk materials. Their prop-erties depend heavily on the particle size and the cappingagent(s). Therefore, nanoparticles are not merely smallcrystals but an intermediate state of matter placed betweenbulk and molecular material. Hence, the biocompatibilityof nanomaterials cannot be compared with the same mate-rial in bulk. Since there are numerous recipes for the syn-thesis of nanoparticles and synthesized nanoparticles aresurface functionalized with different capping agents, eachtype of nanoparticle must be considered unique and testedfor its biocompatibility. Attempts have been made towardthis goal, and studies have been undertaken to addressthese issues with carbon nanostructures, CdSe QDs, andmetal nanoparticles in vivo and in vitro.47 The toxicity ofgold and silver nanoparticles inside the biological systemhas always been an issue of concern. Despite the scientificliterature available on cytotoxicity and immunotoxicologyof gold (I)/(III) and Iron (II)/(III) complexes and recentreports on cytotoxicity of various gold nanoparticles,48!49

little attention has been focused on the immunologicalresponse of cells to gold nanoparticles.

4. PROPERTIES THAT MAKENANOPARTICLES LETHAL FOR CELLS

Particle size and surface area are important material char-acteristics from a toxicological perspective. As the size ofa particle decreases, its surface area increases and allowsa greater proportion of its atoms or molecules to be dis-played on the surface rather than the interior of the mate-rial. This can be explained by the example given in Table Iwhere it is shown that as particle size for a group ofairborne particles with fixed mass (10 "g/m3# and unitdensity (1 g/cm3# decreases, their number increases expo-nentially along with the surface area. The increase in thesurface area in turn determines the potential number ofreactive groups on the particle surface.50

Much of the current knowledge of size-dependent toxic-ity of nanoparticles comes from the studies on the effect ofair pollutant ultrafine particles (UFPs) on pulmonary toxi-city. The human body displays a type of defense reactionin response to ultrafine nanoparticles that is called inflam-mation and is characterized by tissue injury, infection, orirritation which in turn leads to swelling, redness, heat,and pain at the affected area.51 An immune response isthen normally stimulated where usually a healing processgradually follows. However, a persistent or high inflam-matory response may damage the cell layer at the sur-face of the tissue and other cells (such as macrophageswhich are used for particle clearance of the lungs), whichcan result in tissue damage and loss of function.52 Thereis a correlation between a decrease in particle size andan increase in toxicity.53 The studies on rodents demon-strate that UFPs administered to the lung cause a greaterinflammatory response than do larger particles, per givenmass; i.e., the UFPS made of low-solubility, low-toxicitymaterials are more inflammatory in the rat lung than fine,respirable particles made from the same material.54 Forexample, in the case of nickel, it has been shown thatthe extent of lung injury was greater with ultrafine nickel(20 nm) than standard nickel (5 "m) suggesting that UFPshave a much more toxic effect than fine particles of thesame material. Although, this is a well established corre-lation, the mechanisms behind this are poorly understood.

Table I. Particle number and particle surface area for 10 "g/m3 airborneparticles.

Particle surface areaParticle diameter ("m) Particles/ml of Air ("m2/ml of air)

2 2 300.5 153 1200.02 2!390!000 3000

Source: Adapted with permission from [56], A. Nel, et al., Science 311, 622 (2006).© 2006, American Association for the Advancement of Science.



The theories that try to explain the mechanisms behindthe increased toxicity of UFPs are many. The most well-established theory is that it has to do with the increasedsurface area for the UFPs and/or combination with theincreasing number of particles/unit volume. The increasein particle surface area is believed to be linked to lung can-cer, lung fibrosis, and inflammation in the lung.55 There isa considerable body of epidemiological studies suggestingthat an increase in ambient particle concentration is relatedto an increase in mortality and diseases in the exposedpopulation. The strongest associations are seen for respi-ratory and cardiac deaths, particularly among the elderlyand particulate air pollution is also associated with asthmaexacerbations, increased respiratory symptoms, decreasedlung function and increased medication use. Table II sum-marizes the possible adverse effects of nanomaterials onhuman health at the cellular level and their possible patho-physiological outcomes.56 It is not established yet whatmakes nanomaterials so adverse to respiratory tissues but

Table II. Nanomaterial effects as the basis for pathophysiology andtoxicity. Effects supported by limited experimental evidence are markedwith asterisks; effects supported by limited clinical evidence are markedwith daggers.

Experimental NM effects Possible pathophysiological outcomes

ROS generation! Protein, DNA and membrane injury,!

oxidative stressOxidative stress! Phase II enzyme induction, inflamma-

tion, mitochondrial perturbation!

Mitochondrial perturbation! Inner membrane damage,!

permeability transition (PT) poreopening,! energy failure,!

apoptosis,! apo-necrosis,cytotoxicity

Inflammation! Tissue infiltration with inflammatorycells, fibrosis, granulomas,atherogenesis, acute phase proteinexpression (e.g., C-reactive protein)

Uptake by reticulo-endothelialsystem!

Asymptomatic sequestration andstorage in liver,! spleen, lymphnodes, possible organ enlargementand dysfunction

Protein denaturation,degradation!

Loss of enzyme activity,!

auto-antigenicityNuclear uptake! DNA damage, nucleoprotein

clumping,! autoantigensUptake in neuronal tissue! Brain and peripheral nervous system

injuryPerturbation of phagocytic

function,! “particleoverload,” mediator release!

Chronic inflammation, fibrosis,granulomas, interference inclearance of infectious agents

Endothelial dysfunction,effects on blood clotting!

Endothelial dysfunction, effects onblood clotting!

Generation of neoantigens,breakdown in immunetolerance

Autoimmunity, adjuvant effects

DNA damage Mutagenesis, metaplasia,carcinogenesis

Source: Adapted with permission from [56], A. Nel, et al., Science 311, 622 (2006).© 2006, American Association for the Advancement of Science.

a theory is that the increase in particle concentration inthe air may overload the lungs and the phagocytes that areresponsible for eliminating those particles. However, so farno direct relationship between manufactured nanomateri-als and disease has been established due to the scarcityof data. Tissue and cell culture analysis point out therole of oxidative stress in the production of inflamma-tory cytokines and cytotoxicity in response to nanoparticleexposure.Recently, Nel and coworkers compared the effects of

ambient UFPs with manufactured titanium dioxide (TiO2#,carbon black, fullerol, and polystyrene (PS) nanoparticlesin a cell culture system.57–59 The study was conductedin a phagocytic cell line (RAW 264.7) that represents alung target for nanoparticles. Physicochemical characteri-zation of the nanoparticles showed a dramatic change intheir state of aggregation, dispersibility, and charge duringtransfer from a buffered aqueous solution to a cell culturemedium. Particles differed with respect to cellular uptake,subcellular localization, and ability to catalyze the produc-tion of reactive oxygen species (ROS) under cellular andcell-free conditions.60 Spontaneous ROS production wascompared by using an ROS quencher (furfuryl alcohol) aswell as an NADPH peroxidase bio-electrode platform.61!62

Among the particles tested, ambient UFPs and cationic PSnanospheres were capable of inducing cellular ROS pro-duction, glutathione (GSH) depletion, and toxic oxidativestress. This toxicity involved mitochondrial injury throughincreased calcium uptake and structural organellar damage.Although active under abiotic conditions, TiO2 and fulleroldid not induce toxic oxidative stress. While increasedTNF-alpha production could be seen to accompany UFP-induced oxidant injury, cationic PS nanospheres inducedmitochondrial damage and cell death without inflamma-tion. They concluded that ROS generation and oxidativestress are a valid test paradigm to compare nanoparticletoxicity. Although not all materials have electronic config-urations or surface properties to allow spontaneous ROSgeneration, particle interactions with cellular componentsare capable of generating oxidative stress (Table II).

5. SURFACE COMPOSITION ANDLETHALITY

Nanoparticles may overcome solubility and stability issuesfor the drug and minimize drug-induced side effects. Butthere could be significant toxicity issues associated withthe composition of nano-carrier themselves. Although,there is evidence that small size and high surface areaof nanoparticles are the major determinants of toxicity,there are very few reports on the toxicity of nanomateri-als due to their composition. Recently Warheit’s group hasshown that the toxicity of different types of titania particleswas not dependent on particle size and surface area.63!64

Smaller nanoparticulate materials had effects compara-ble to larger nanoparticulate material. What did correlate



strongly to cytotoxicity was the phase composition of thenanoscale titania. Anatase TiO2 was 100 times more toxicthan an equivalent sample of rutile TiO2.

6. SURFACE CHEMISTRYALSO PLAYS A ROLE

Nanoparticles interacting with the cell mainly affect pro-teins, membranes, cells, DNA, and organelles via twoprominent interfaces: the solid–liquid interface at thenanoparticle surface and the nano-bio interface at thecell membrane65 (Fig. 2). When nanoparticles are intro-duced to cell culture conditions, colloidal forces emergingfrom culture media and dynamic biophysicochemical inter-actions between the cell membarne and nanoparticlesestablish biocompatibility. Thus, understanding the majorbio-physicochemical factors between nanomaterials andbiological systems is instrumental for compatibility ofnanomaterials in vivo and in vitro (Table III). In this con-text, the surface chemistry of nanoparticles is a decisivefactor. For example, polycationic macromolecules show astrong interaction with cell membranes in vitro. Biocom-patibility studies revealed that the cytotoxicity of polyca-tionic materials such as DEAE-dextran and poly-L-lysine(PLL), dendrimers and polyethylenimine (PEI) increaseswith the increase in their molecular weight.66 Rotelloand co-workers have also demonstrated that the cationic

Figure 2. Understanding biophysicochemical interactions at the nano-bio interface. The main effects stem from material properties, modifica-tion of the surface properties of those materials through interactions withthe suspending medium, and the dynamic interactions of the solid–liquidinterface with biological molecules and cellular compartments. Reprintedwith permission from [65], A. E. Nel, et al., Nature Mater. 8, 543 (2009),© 2009, Nature Publishing Group, a division of Macmillan Publisherslimited.

gold nanoparticles are cytotoxic to the mammalian andprokaryotic cells while anionic nanoparticles are inert.67!68

Furthermore, the arrangement of cationic charges overnanoparticles depends on the three-dimensional structureand flexibility of the surface macromolecules and deter-mines the accessibility of their charges to the cell surface.For example, branched molecules were found to be moreefficient in neutralizing the cell surface charge than poly-mers with linear or globular structure, as rigid moleculeshave more difficulties in attaching to the membranes thanflexible molecules. Therefore, high cationic charge densi-ties and highly flexible polymers should cause higher cyto-toxic effects than those with low cationic charge densities.Globular polycationic macromolecules (cationized HumanSerum Albumin (cHSA)69!70 and ethylenediamine-corepoly (amidoamine) dendrimers (PAMAM)) were found tobe polymers with a good biocompatibility (low cytotoxic-ity), whereas polymers with a more linear or branched andflexible structure (e.g., poly-diallyl-dimethyl-ammoniumchloride (DADMAC), PLL, PEI) showed higher cell-damaging effects.71!72

Gaschen et al. studied the influence of the particle sur-face chemistry on its interaction with the lung surface lin-ing layer.73 They found that regardless of the nature oftheir surfaces, particles submersed into the lining layerafter their deposition in small airways and alveoli. Thisdisplacement was promoted by the surfactant film itself,whose surface tension falls temporarily to relatively lowvalues. On the other hand, reactive groups on a particlesurface certainly modify the biological effects. For silica,it has been shown that the surface modification of quartzaffects its cytotoxicity, inflammogenicity, and fibrogenic-ity. These differences are mainly due to particle surfacecharacteristics. Specific cytotoxicity of silica is stronglycorrelated to the appearance of surface radicals and ROS,which is considered to be the key event in the developmentof fibrosis and lung cancer by this compound.74 In thecase of silica it is demonstrated that the reactive groupson nanoparticles influence their interaction with the cells.As shown in Figure 3, the surface chemistry and proteincorona are the primary nano-bio interface which the cellrecognizes and further intiates the interactions.75

7. NANOPARTICLES FOR BIOMEDICALAPPLICATIONS

Nanotechnology offers unique approaches to probe andcontrol cell-protein-surface interactions that occur atnanometer scales not only in eucaryotes but also, latelyexplored, in procaryotes.76–78 It is expected that nanotech-nologoy will have a revolutionary impact on biomedicinedue to the development of tools and techniques thatprovide precise control in context with top-down andbottom-up approaches in nanoscale design.79 Among theapproaches for exploiting nanotechnology in medicine,80

nanoparticles offer some unique advantages as sensing,



Table III. Major bio-physicochemical actors between nanomaterials and biological systems.

Nanoparticle Suspending media Solid–liquid interface Nano-bio interface

Size, shape and surface area Water molecules Surface hydration and dehydration Membrane interactions: specific andnonspecific forces

Surface charge, energy, roughnessand porosity

Acids and bases Surface reconstruction and release of freesurface energy

Receptor-ligand binding interactions

Valence and conductance states Salts and multivalent ions Ion adsorption and charge neutralization Membrane wrapping: resistive andpromotive forces

Functional groups Natural organic matter(humics, proteins, lipids)

Electrical double-layer formation, zetapotential, isoelectric point

Biomolecule interactions (lipids,proteins, DNA) leading tostructural and functional effects

Ligands Surfactants Sorption of steric molecules and toxins Free energy transfer to biomoleculesCrystallinity and defects Polymers Electrostatic, steric and electrosteric

interactionsConformational change in

biomoleculesHydrophobicity and

hydrophilicityPolyelectrolytes Aggregation, dispersion and dissolution Oxidant injury to biomolecules

Hydrophilic and hydrophobic interactions Mitochondrial and lysosomaldamage, decrease in ATP

Source: Adapted with permission from [65], A. E. Nel, et al., Nature Mater. 8, 543 (2009). © 2009, Nature Publishing Group, a division of Macmillan Publishers limited.

image enhancement, and delivery agents.81 In the past fewyears nanoparticles have attracted significant research andpractical attention. They are versatile agents with a varietyof biomedical applications, including contrast agents forhighly sensitive disease diagnostics and therapeutics,5!82

thermal ablation and radiotherapy enhancement, as wellas cancer diagnostics and therapeutics,83 and drug andgene delivery.84 To further the application of nanoparti-cles in disease diagnosis and therapy, it is important thatthe systems be biocompatible and capable of being func-tionalized for recognition of specific target sites in thebody after systemic administration. For biomedical appli-cations, surface functionalization of metal nanoparticlesis essential in order to target them to specific diseaseareas and allow them to selectively interact with cellsor biomolecules. Surface conjugation of antibodies, pep-tides, and other targeting moieties is usually achieved byadsorption of the ligand to the gold/polymer surface.80

Additionally, for systemic applications, long-circulatingnanoparticles are desired for passive targeting to tumorsand inflammatory sites. Figure 4 represents a simpleschematic design of multifunctional nanoparticles for drugdelivery and imaging applications.85 With the advancementof nanotechnology, a variety of nanostructures with dif-ferent shapes and structures of different composites havebeen developed including polymeric nanoparticles, metalnanoparticles, liposomes, micelles, QDs, dendrimers, andnano-assemblies.86

8. QUANTUM DOTS: QUBIT EXPLORINGBIONANO-INTERACTIONS

Nanoparticles of semiconductors (quantum dots) were the-orized in the 1970s and were initially created in theearly 1980s.87 For the first time, Dickson and co-workersreported the synthesis of highly fluorescent, water-solubleQDs of noble metals.88–90 If semiconductor particles are

made small enough, quantum effects come into play,which limit the energies at which electrons and holes (theabsence of an electron) can exist in the particles. QDstypically contain a CdSe or CdTe core and ZnS shell.87

QDs absorb white light and then re-emit it a couple ofnanoseconds later at a specific wavelength. By varying thesize and composition of QDs, the emission wavelengthcan be tuned from blue to near infrared. For example,2-nm QDs luminesce bright green, while 5-nm QDs lumi-nesce red. QDs have greater flexibility; when comparedto other organic fluorophores, QDs have bright fluores-cence, a narrow emission range, broad UV excitation, largemolar extinction coefficients, and a high photo stability.91

Recent advances in chemistry have resulted in the prepara-tion of monolayer-protected, high-quality, monodispersed,crystalline QDs as small as 2 nm in diameter, which canbe conveniently treated and processed as a typical chem-ical reagent.92 The above-mentioned qualities make themideal for use in building nanoscale computing applicationswhere light is used to process information. These struc-tures offer new capabilities for multicolor optical codingin gene expression studies and high-throughput screening.QDs have been covalently linked to various biomoleculessuch as antibodies, peptides, nucleic acids, and other lig-ands for fluorescence probing applications.106 Some of theapplications of QDs in biology along with their tremen-dous potential for imaging have already been exploredin vitro and in vivo.93 However, the biocompatibility ofQDs for in vivo applications is still a subject of debate.94

9. SUPERPARAMAGNETIC IRON OXIDENANOPARTICLES (SPIONs)

These entities are usually prepared by the alkaline co-precipitation of appropriate ratios of Fe2+ and Fe3+ saltsin water in the presence of suitable hydrophilic poly-mer such as dextran, and poly(ethylene glycol), Poly(vinyl



Figure 3. The effects of a protein corona surrounding a nanoparticle. The corona constitutes a primary nano-bio interface that determines the fate ofthe nanoparticle and can cause deleterious effects on the interactive proteins. (a) Pre-existing or initial material characteristics contribute to the formationof the corona in a biological environment. Characteristic protein attachment/detachment rates, competitive binding interactions, steric hindrance bydetergents and adsorbed polymers, and the protein profile of the body fluid lead to dynamic changes in the corona. The corona can change whenparticles move from one biological compartment to another. (b) Potential changes in protein structure and function as a result of interacting with thenanoparticle surface can lead to potential molecular mechanisms of injury that could contribute to disease pathogenesis. The colored symbols representvarious types of proteins, including charged, lipophilic, conformationally flexible proteins, catalytic enzymes with sensitive thiol groups, and proteinsthat crowd together or interact to form fibrils. Reprinted with permission from [65] A. E. Nel, et al., Nature Mater. 8, 543 (2009). © 2009 NaturePublishing Group, a division of Macmillan Publishers limited.



Figure 4. Schematic diagram of a multifunctional nano-assembly fordrug delivery, disease diagnosis and therapy.

alcohol). This yields an iron core that is hexagonallyshaped and surrounded by polymeric molecules. Theseparticles are called “superparamagnetic,” indicating thatthey are attracted to a magnetic field but retain no resid-ual magnetism after the field is removed. Therefore,suspended superparamagnetic particles tagged to the bio-material of interest can be removed from a matrix usinga magnetic field, but they do not agglomerate (i.e., theystay suspended) after removal of the field. Iron oxidenanoparticles are also amenable to surface functionaliza-tion with small surface functional groups or multivalentsmall molecules as well as by conjugating proteins, anti-bodies, and oligonucleotides for active targeting in vivo orfor in vitro diagnostic procedures.A common use of superparamagnetic nanoparticles is

for immunospecific cell separations.95 The process isknown as “magnetic activated cell sorting” (MACS). Typ-ically, the nanoparticles are dispersed within the pores oflarger microparticles. In the simplest (direct) method, themicroparticles are coated with a monoclonal antibody fora cell-surface antigen.96 The antibody-tagged, superparam-agnetic microparticles are then incubated with a solutioncontaining the cells of interest. The microparticles bind tothe surfaces of the desired cells, and these cells can thenbe collected in a magnetic field. Methods of this type havebeen used to isolate or remove numerous cell types, includ-ing lymphocytes, stem cells, and tumor cells. In additionto loading microparticles with superparamagnetic nanopar-ticles, other examples of tagging the desired biomate-rial with individual nanoparticles have been reported.97

This approach has numerous advantages over the tradionalmethods.98 Whereas bound microparticles can affect theviability of the selected cells, nanoparticles supposedly donot affect cell viability. In addition, nanoparticles do notaffect the extent of light scattering by the cell solution. Thedisadvantage of this approach is small magnetic momentsof individual nanoparticles; however, this problem can beovercome by using a high-gradient magnetic field.SPIONs are used in almost every biological applica-

tion of metallic nanoparticles because of their unique mag-netic advantages, ease of synthesis, and facile conjugatechemistry for targeting ligands/proteins99 (Fig. 5). SPI-ONs remains on the sidelines because of their propensity

Figure 5. The effect of surface coating on nano-immuno interactions.Uncoated nanoparticles are mainly taken up by macrophages. This prop-erty is important in magnetic resonance imaging (MRI) studies. Label-ing of nanoparticles with, for instance, immunoglobulin (IgG) allows forenhanced uptake by immune cells expressing the corresponding Fc recep-tor, and this is useful for the targeting of nanoparticles. The coating of par-ticles with poly(ethylene-glycol) (PEG) results in a prolonged circulationtime due to the avoidance of macrophage internalization of the particles,and this is important to consider when designing nanoparticles for targeteddrug delivery. The labeling of nanoparticles with the vitamin folic acidselectively targets tumor cells with high surface expression of the folatereceptor. This is an advantage in not only imaging tumors but also in tar-geted drug delivery, and several drugs based on this strategy are already inclinical trials. Reprinted with permission from [99], A. Kunzmann, et al.,Biochim. Biophys. Acta 1810, 361 (2011). © 2011, Elsevier B.V.



Figure 6. Pathways of cellular internalization of nanoparticles. Several different pathways are implicated in the cellular uptake of nanoparticles, andthe main determinants are thought to be the size and surface properties of the particles as well as the nature and activation status of the engulfingcell (macrophage, endothelial cell, etc). However, the details of the routes of nanoparticle uptake remain to be elucidated. (CNT—carbon nanotube;MSN—mesoporous silica nanoparticle; SPION—superparamagnetic iron oxide particle.) Reprinted with permission from [99], A. Kunzmann, et al.,Biochim. Biophys. Acta 1810, 361 (2011). © 2011, Elsevier B.V.

to oxidatively corrode and aggregate in electrolytic solu-tions. The oxidative corrosion and aggregation of SPIONnanoparticles can be effectively eliminated, however, withthe proper protective layer, allowing stable nanoparticlesolutions to exist at high NaCl concentrations and over awide range of pH. The labeling of targeting molecules suchas antibodies with magnetic nanoparticles truly revolution-ized the visualization of subcellular components throughMRI and medical scanners, exemplifying the utility of thisparticular noble metal element.100 During the last 10 years,several groups have prepared SPIONs linked with sugars,proteins, and DNA.101!102 These modifications offer intra-cellular uptake of particles for desired theranostic outputsas shown in Figure 6. These nanoparticles, along with newgenerations carbon nanotubes (CNTs) are being used forassembling new materials, developing bioassays, and asmultivalent systems for interaction studies.

10. THE ROLE OF NANOPARTICLES INBIOPHYSICS: STUDYING ENERGYTRANSPORT IN PEPTIDE MODELS

With the advent of using essentially AuNPs in the hyper-thermal treatment of cancer, studying the underlying mole-cuar mechanism for localized heat deposition on theaffected cancerous tissue is very important. Be it ther-mally destroying the target tissue/cell or stimulating drugrelease from the attached molecules on the nanoparticlesurface, nanobiotechnology relies heavily on the uniqueproperty of nanoparticles: surface plasmon resonance.Recently polycrystalline Au (111) and small gold nanopar-ticles (AuNPs) have been used as “heaters” to studyenergy transfer from surface to thiolate self-assembled

monolayers103 (SAMs) and into and out of an artificialpeptide layer104 respectively.Briefly, the peptide to be studied is functionalized

onto the nanoparticle surface. Vibrational energy (heat) isdeposited locally via a laser pulse that matches its surfaceplasmon resonance frequency into the nanoparticle. Thisheat is transferred via phonon–phonon transfer105 in to theattached peptide. With another weak laser pulse (infrared),the corresponding heat transfer is studied by followingthe unique vibrational signature of the reporter groups orlabels, placed at specific sites in the primary sequence ofthe peptide to be studied. As an example, Figures 7 and 8demonstrate such an experiment. Hamm and co-workersused the C13 isotope label for the carbon of the amidecarbonyl group of alanine at different positions in the pri-mary sequence of an artificial peptide.104 Two octamericpeptides (differing in the number of $-aminoisobutyricacid units in the primary sequence of the peptide) withC13-labeled alanines at different positions in the peptidewere attached as a capping layer onto small gold nanopar-ticles (labeled 1 and 2 respectively in the figure). Car-bonyl groups at positions 1 and 9 (numbered according tothe position from the attachment of the peptide with thenanoparticle) belong to the urethane moeity and the ter-minal ester group of the peptides. Their position is fixedin both the samples. Upon excitation by a visible laserpulse (frequency near the SPR peak of the AuNPs), therespective “flow” of heat energy was studied by a sec-ond, ultrafast weak IR laser pulse for carbonyls with C13

at positions 3 and 5 in samples 1 and 2 respectively. Thetime-resolved spectra gives a detailed insight into the heattransport into and out of the capping layer, which in this



Figure 7. (a) Cartoon structure of the peptide-capped nanoparticles.The labels indicate the positions of the different C O thermometers inthe capping layer relative to the gold core at the N -terminus. In peptide1, the 13C O labeled Ala is situated at site #3; in peptide 2, the labelis placed at site #5. (b) FTIR and UV-vis (inset) spectra in acetonitrile-d3 recorded for nanoparticles 1 (black) and 2 (red) at equal effectivepeptide concentration. The spectrally resolved C O bands are labeledaccording to their positions in the peptide chain as shown above. In theUV-vis spectra the plasmon resonance appearing around 520 nm is morepronounced for nanoparticle 2 due to the bigger diameter of its goldcore. Reprinted with permission from [104], M. Schade, et al., Nano Lett.10, 3057 (2010). © 2010, American Chemical Society.

case is a peptide. The farther a carbonyl group is from theheater (small AuNP in this case), the later and lesser theheat comes to it, as can be seen with a lower absorbanceby the carbonyl at that specific position. This kind of studycan give us detailed information about the processes thatrely on the plasmonic property of nanoparticles as in theoptically activated drug delivery.

11. CONCLUDING REMARKS ANDFUTURE PERSPECTIVE

The current scenario of emerging applications ofnanomaterials puts forth a strong notion to under-stand the factors associated with multi-tier nanotoxicity:cytoto/immuno/genotoxicity and detailed evaluations ofcaricnogenic potential.All the levels of toxicity evaluation must be carried out

using the primary cells associated with organ systems sup-porting fundamental bodily functions: Nervous (neuron),digestive (colon), respiration (lung), excretory (kidney),

Figure 8. Time-resolved spectroscopy: Transient IR spectra in theC O stretching region for (a) 1 and (b) 2 recorded at various delaytimes (black, 1.5 ps; red, 3.0 ps; blue, 9 ps; green 15.0 ps; orange 20.0 ps;purple 400.0 ps) after excitation of the gold nanoparticles. (c) Timedependence of the bleach intensity of the main bands of 1 (black) and2 (red) with opposite sign as in (a) and (b), the inset shows the data atearly times. Second derivatives of the bleaches of sites (d) #1, #3, and#9 (measured in 1) and (f) #1, #5, and #9 (measured in 2). The C Obands are labeled as in Figure 7 (e) Transient vis spectra of the plasmonband at 520 nm of 1 (black) and 2 (red). Reprinted with permission from[104], M. Schade, et al., Nano Lett. 10, 3057 (2010). © 2010, AmericanChemical Society.

skin (epithelial), circulation (cardiac), corneal and auditorycapsule cells, and the muscular system.There is an immense need to develop an HTP sys-

tem to handle and examine multitudes of toxic poten-tial for in vitro assesment and subsequent mandatoryin vivo correlations regarding biocompatibility, biodistri-bution, and biodegradation of nanoparticles to be used innanomedicine.The National Center for Biotechnology Information

(NCBI) based consortium initiative is to develop a mate-rialomics database of detailed bio- and physicochemicalcharacteristics of each putative nanomaterials applicable toin vivo theranostics.More emphasis should be given to gas phase produc-

tions and immobilizations of nanoparticles/clusters80 inmicro- and nanodevice81 systems, to avoid circulation andreduce systemic toxicity.Nanomedicine largely considers the compatibility issues

related to cells and cell lines associated with mammalianorigin, though many advances in cell biology deal withanimal models of non-mammalian origin. While dealingwith this, cytocompatibility and selection should be madewith appropriate choices.



The in vivo environment includes mammalian cells,many cellular-friendly inhabitants that belong to “gut-fit”microflora, carrying important functions related to enzy-matic and vitamin synthesis. The in vitro biocompatibilityissue should also consider those factors, as there is lessdata available related to procaryotes and their interactionwith nanostructured materials.76–78

Acknowledgment: AVS gratefully acknowledges fund-ing support from the Department of BiomedicalEngineering (BME), Rensselaer Polytechnic Institute(RPI).

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Received: 4 July 2013. Accepted: 25 July 2013.


Biophysicochemical Perspective of Nanoparticle Compatibility: A Critically Ignored Parameter in...

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