Dalton Review (1)

Dalton TransactionsAn international journal of inorganic chemistrywww.rsc.org/dalton Volume 40 | Number 24 | 28 June 2011 | Pages 63016576

ISSN 1477-9226

COVER ARTICLE Tremel et al. Synthesis and bio-functionalization of magnetic nanoparticles for medical diagnosis and treatment

Dalton TransactionsCite this: Dalton Trans., 2011, 40, 6315 www.rsc.org/dalton

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Synthesis and bio-functionalization of magnetic nanoparticles for medical diagnosis and treatmentDownloaded on 20 June 2011 Published on 01 March 2011 on http://pubs.rsc.org | doi:10.1039/C0DT00689K

Thomas D. Schladt,a Kerstin Schneider,a Hansj rg Schildb and Wolfgang Tremel*a oReceived 21st June 2010, Accepted 13th January 2011 DOI: 10.1039/c0dt00689k The synthesis of multifunctional magnetic nanoparticles (NPs) is a highly active area of current research located at the interface between materials science, biotechnology and medicine. By virtue of their unique physical properties magnetic nanoparticles are emerging as a new class of diagnostic probes for multimodal tracking and as contrast agents for MRI. Furthermore, they show great potential as carriers for targeted drug and gene delivery, since reactive agents, such as drug molecules or large biomolecules (including genes and antibodies), can easily be attached to their surface. On the other hand, the fate of the nanoparticles inside the body is mainly determined by the interactions with its local environment. These interactions strongly depend upon the size of the magnetic NPs but also on the individual surface characteristics, like charge, morphology and surface chemistry. This review not only summarizes the most common synthetic approaches for the generation of magnetic NPs, it also focuses on different surface modication strategies that are used today to enhance the biocompatibility of these NPs. Finally, key considerations for the application of magnetic NPs in biomedicine, as well as various examples for the utilization in multimodal imaging and targeted gene delivery are presented.

IntroductionToday, the development of nanomaterials has moved beyond the discovery of totally new materials and compositions. Instead the focus has shifted to the investigation of more complex, composite systems, in which the recombination of known materials into structures of higher complexity opens new possibilities of functionality.15 While scientic diligence of designing new composite or hybrid materials is speeding up, industrial producers have begun merchandising the earliest discovered nanomaterials, and, in fact, are developing novel applications for them to t the desired needs. Besides other commercial applications, magnetic nanoparticles (NPs) are intensively being investigated for utilization in many different scientic and industrial elds, ranging from catalysis to mass data storage.6,7 One of the fastest moving and most exciting research areas is the interface between nanotechnology, biology and medicine. It has been stated by numerous experts, that the application of nanotechnology in medicine, which is often referred to as nanomedicine, offers many exciting possibilities for healthcare in the future, and may revolutionize the areas of targeted drug delivery, disease detection and tissue engineering.811 An often used catch phrase in this context is theragnostics, which, as thisa Institut f r Anorganische Chemie und Analytische Chemie, Johannes u Gutenberg-Universit t, Duesbergweg 10-14, D-55099 Mainz, Germany. a E-mail: [email protected]; Fax: +49 6131 39-25605; Tel: +49 6131 39-25135 b Institut f r Institut f r Immunologie, Johannes Gutenberg-Universit t, u u a Obere Zahlbacher Str. 67, D-55131 Mainz, Germany

word construction implies, is the combination of both, therapy and diagnostics into one powerful tool. In fact, the concept of using magnetic nanoparticles to target tumor cells inside the human body, and applying them to treat cancer, was rst conceived in the late 1970s.12 The key idea was to attach common anticancer drugs to small magnetic spheres outside the body before administering them to the patient. After injection into the blood stream strong external magnetic elds should concentrate the drug-loaded particles inside the tumor tissue. The authors predicted that by this approach the drug payload would be reduced signicantly, and thereby the unwanted side effects associated with the systemic distribution of chemotherapeutic agents, including nausea, hair loss and a compromised immune system could be avoided. Although not yet fully in clinical use, nanomedicine has come a long way from these initial ideas, and it is proceeding with remarkable speed. Concerning diagnostics, the ability to accelerate the proton relaxation of water molecules in different tissues has been proposed to be one of the most promising features of magnetic NPs for nanomedicine, since it allows the development of novel contrast agents for magnetic resonance imaging (MRI). In fact, contrast agents based on superparamagnetic iron oxide NPs (SPIONs) have been in clinical use for almost two decades. Moreover, progress in the synthesis of magnetic NPs permits a precise tuning of their physical properties and, as a result, has led to tremendous improvements in their MRI performance. On the other hand, owing to their size, nanoparticles can penetrate cell walls13 and deliver biomolecules or drugs for therapeutic14 and diagnostic purposes.9 The use of Dalton Trans., 2011, 40, 63156343 | 6315

This journal is The Royal Society of Chemistry 2011

Downloaded on 20 June 2011 Published on 01 March 2011 on http://pubs.rsc.org | doi:10.1039/C0DT00689K

nanoparticulate (polymeric or inorganic) carriers allows the transport of hydrophobic low molecular weight drugs, to enhance their efciency. Additionally, a feature that proves to be benecial for the application of nanoparticulate systems is the fact that the blood vessels sustaining tumor tissue exhibit comparatively large fenestrations, and the lymph system of tumors is poorly operational. Therefore, macromolecules and nanoparticles leaking from these blood vessels can accumulate inside the tumor tissue, a phenomenon known as the EPR (enhanced permeability and retention) effect (see Fig. 1).15,16 However, one of the most prevailing issues associated with the application of these NP systems, is their behavior in vivo. For instance, the recognition and clearance by the reticuloendothelial system (RES) is a major obstacle since it reduces the circulation times of the NPs within the blood stream, and therefore, obstructs a site specic accumulation of the administered NP probes at designated areas (see Fig. 1).17 The enhanced uptake in the liver, spleen, and bone marrow is largely attributed to the macrophages residing in the tissues, which are responsible for clearing particulates and macromolecules circulating in the blood. When nanoparticles are administered intravenously, a variety of serum proteins bind to the surface of the nanoparticles, which are recognized by the scavenger receptor on the macrophage cell surface and internalized, leading to a signicant loss of nanoparticles from the circulation.18 The serum proteins binding on the nanoparticles are termed opsonins, and the macrophages contributing the major loss of injected dose are constituents of the RES or mononuclear phagocyte system (MPS). Minimizing protein binding is the key point for developing a long circulation nanoparticle formulation.

their surface properties, including morphology, charge and surface chemistry. As a consequence, efcient strategies for the synthesis of magnetic nanoparticles and their subsequent surface modication are necessary to meet the challenges of a later application in biomedicine. This review article summarizes some recent achievements in the rapidly evolving elds of nano-biotechnology and nanomedicine. It consists of three parts; in the rst section the properties and synthesis of magnetic NPs will be discussed briey before in the second part some of the most common surface modication strategies are presented. Finally, the last section addresses the application of magnetic NPs in biomedicine.

1. Magnetic propertiesMagnetic nanoparticles are among the most investigated nanomaterial systems, owing to the fact that their magnetic properties dramatically depend upon their size and their morphology. Several issues are responsible for these unique properties: nite size effects, which result from the quantum connement of the electrons inside the material, and surface effects caused by symmetry breaking of the crystal structure at the boundaries of the particles.2023 Concerning nite-size effects, the magnetic properties of (ferro-) magnetic nanoparticles are dominated by two key features: (1) The single domain limit and (2) the superparamagnetic limit, which both lead to individual material-dependent length scales, i.e. the single domain size and the superparamagnetic size. Both features will be discussed briey. 1.1. Single-domain-limit A ferromagnetic bulk material usually consists of many separate areas, in which all magnetic moments of the constituent atoms are pinned in the same direction. The reason for such an arrangement arises from the fact that the magnetostatic energy (DE MS ) of the materials is lowered once a large domain is broken up into several smaller domains. However, the formation of new domain walls requires energy (E D ), and therefore, there is a size limit, below which the energy needed for the creation of a smaller domain exceeds the amount of energy gained from decreasing the magnetostatic energy. Consequently, this means that a magnetic nanoparticle with a diameter comparable to, or lower than the size of the smallest possible magnetic domain, could only consist of a single domain, which, in turn, results in a narrowing of the magnetic hysteresis curve compared to the bulk material (see Fig. 2).22,24,25 1.2. Superparamagnetic limit To understand the super-paramagnetic effect the magnetic anisotropy energy per particle (E(H)) which pins the magnetic moments of a single domain particle in a certain direction, has to be considered. E(H) is proportional to K a V (V is the particle volume), the energy barrier which stops the magnetic moment ipping from one direction to the opposite. K a V is usually much higher than the thermal energy kB T, however, with decreasing particle size K a V decreases to values equal to, or below kB T. As a result, the magnetic moments are able to overcome the energy barrier and freely ip in any direction, i.e. for kB T K a V the This journal is The Royal Society of Chemistry 2011

Fig. 1 Passive tumor targeting due to the EPR effect. Larger particles and agglomerates are rapidly attacked by phagocytes, whereas smaller particles can travel longer through the blood vessels to reach the target tissue. Once at the tumor site, the magnetic NPs accumulate inside the tumor tissue due to the EPR effect.

In addition to that, controlling the overall size of the NPs is crucial, since particles with a mean diameter below 5 nm are usually eliminated by renal excretion, whereas larger particles (>100 nm) are taken up easily by macrophages.19 Furthermore, the ultimate fate of nanoparticles within the body is determined by the interaction with the local environment inside biological systems, which depends not only on the particle size but also on6316 | Dalton Trans., 2011, 40, 63156343

existence of canted surface spins.21 Additionally, Bdker et al. reported, that the magnetic anisotropy K a of iron NPs increases with decreasing particle size, due to a higher contribution of the surface anisotropy K aS .26 As an example, antiferromagnetic NiO and MnO nanoparticles exhibit increasing net magnetization values and higher magnetic blocking temperatures with decreasing particle size, the reason being the larger number of uncompensated surface spins.20,27,28Downloaded on 20 June 2011 Published on 01 March 2011 on http://pubs.rsc.org | doi:10.1039/C0DT00689K

1.4. Magnetic NPs as contrast agents for MRI MR imaging is one of the most powerful non-invasive imaging techniques in clinical use today.29,30 Just as NMR spectroscopy, it is based on measuring the relaxation of protons in an external magnetic eld after they have been excited with a radio-frequency pulse. Basically, there are two different types of relaxation depending on the nature of the corresponding interactions: T 1 : Longitudinal relaxation. After excitation with a 90 radio frequency pulse the magnetization in the eld direction M z is zero and the perpendicular in-plane magnetization M xy is maximal. Over time, the magnetization returns into the eld direction and M xy decreases. This process is associated with a release of energy to the environment (the lattice), therefore, it is also called spinlattice (or longitudinal) relaxation. The time constant, at which the energy is depleted (and M z increases) T 1 , depends on different factors, including eld strength, or the nature of the observed tissue.30 T 2 : Transverse relaxation. The loss of the transverse magnetization M xy is also associated with a dephasing of the spins precessing in the xy-plane. Directly after excitation all spins are in phase and M xy is maximal. In principle, two components determine the dephasing process: On the one hand, an energy exchange between the spins induced by local magnetic eld interferences among the spins themselves (spinspin or transverse relaxation), leads to a faster and slower precession in the xy-plane. The time constant T 2 , with which M xy is depleted, is therefore independent of the applied magnetic eld. On the other hand, inhomogeneities of the external magnetic eld, arising from the magnetic coils of the MRI scanner itself or the body of the patient, lead to an additional dephasing and a faster decay of M xy with a time constant T 2 *.29,30 The contrast in MR images is mainly determined by three different features: the proton density, the T 1 time and the T 2 time of the regarding tissue. While the proton density is given by the chemical and physical nature of the tissue, the use of contrast agents can greatly enhance both T 1 and T 2 contrast. Basically it is desired to shorten the relaxation times because this leads to a greater difference in signal intensity and thus to a better contrast in the MR image. In T 1 -weighted images, the signal intensity relies on how fast M z is restored. After a given time period t following proton excitation, M z has only recovered to a value M z if no contrast agent is applied. On the other hand, in the presence of a paramagnetic substance the excess proton energy is released more efciently and therefore, the magnetization in eld direction reaches a higher value M z (M z >M z ). As a result, T 1 enhancement leads to a brighter (positive) contrast in the image. On the other hand, in T 2 -weighted images the signal intensity Dalton Trans., 2011, 40, 63156343 | 6317

Fig. 2

Illustration of the single domain limit.

system behaves like a paramagnet. Since the individual atomic moments add up to one (super) moment for every particle, this phenomenon is called superparamagnetism. On the other hand, when the temperature is lowered for a given superparamagnetic particle, the thermal energy of the particle decreases until kB T is lower than the energy barrier K a V (kB T K a V ), i.e. the particle undergoes a magnetic transition from a superparamagnetic to a blocked state, in which the magnetic moments cannot ip freely. The temperature at which kB T = K a V is therefore called the magnetic blocking temperature T B .22,25 Experimentally, T B can be determined by measuring the magnetization of a nanoparticle sample versus increasing temperature under an applied external magnetic eld. More precisely, in a so called zero-eld-cooled/eld-cooled (ZFC/FC) experiment, the sample is rst cooled down to a temperature well below the expected blocking temperature (usually 5 K). Then, an external eld (generally 100 Oe) is applied and the sample is slowly heated up while simultaneously measuring the magnetization. Since the particles were frozen from room temperature, their magnetic moments are distributed homogeneously, and therefore, the net magnetization is zero. However, as the temperature, increases the particles are able to move their moments in the direction of the external eld. As a result, the net magnetization rises. As mentioned before, above T B the thermal energy exceeds K a V , leading to a decline of the magnetization. As a result, the ZFC curve passes a maximum at T B . 1.3. Surface effects

Surface effects depend directly on the ratio of surface spins to bulk spins. Therefore, surface effects become more pronounced with increasing surface to volume ratio, i.e. decreasing particle size. The symmetry breaking at the particle boundary can lead to variations in the electronic band structure, lattice constant, and atom coordination and, as a direct result, change the magnetic properties.25 Furthermore, surface effects can lead to a decrease of the magnetization of small particles, for instance ferromagnetic oxide nanoparticles, with respect to the bulk value. This reduction has been associated with different mechanisms, such as the existence of a magnetic dead layer on the particle surface, or the This journal is The Royal Society of Chemistry 2011

is determined by the decrease of M xy . Here, the presence of a contrast agent leads to a faster dephasing of the spins that precess in the xy-plane. Consequently, M xy drops faster (M xy 200 nm are easily sequestered by the spleen and eventually removed by the cells of the phagocyte system, resulting in decreased blood circulation times. Small particles with diameters less than 5.5 nm are rapidly removed through extravasations and renal clearance. Magnetic NPs are usually within this suitable size range. Reduced liver metabolism and renal clearance of drugs encapsulated in the nanoparticles often result in prolonged blood circulation with an increased chance of accumulation in the target tissue. Opsonization is a major issue that induces MPS uptake of NPs, and therefore the surface characteristics and surface functionalization greatly determine their pharmacokinetic prole. In general, NPs with diameters of between 5 and 100 nm and a neutral and hydrophilic polymer extended surface exhibit prolonged blood circulation, moderate liver uptake and an increased level of drug delivery as determined by radiolabeling (PET/MR).360 This journal is The Royal Society of Chemistry 2011

4.7.

Magnetic NPs for immunotherapy


With the development of DNA technology, especially recombination technology, gene therapy, which transfers DNA or RNA into target cells, has become a novel approach for disease therapy.361 Finding effective transfection methods is a major objective in gene therapy research due to rapid degradation of DNA and RNA by enzymes and their poor diffusion across cell membranes.362 In addition, functionalized nanoparticles represent a promising tool for immunotherapy of tumors. Tumor cells express a wide variety of proteins that can be recognized by the immune system. They comprise tumor-specic proteins containing mutations or fusions and also tumor-associated proteins normally expressed in a developmentally or tissue-restricted fashion. These proteins represent ideal targets for therapeutic interventions as they allow the specic detection by cells or components of the immune system. Established cancer therapies employ a variety of manipulations to activate antitumor immunity. These include (i) passive immunization with monoclonal antibodies, (ii) active immunization by the application of adjuvants alone or in combination with tumor antigens, and (iii) the systemic or local delivery of cytokines. A variety of novel strategies have been developed based on fundamental advances in our understanding of the interactions between tumors and the immune system. Collectively, these strategies attempt to augment protective antitumor immunity and to disrupt the immune-regulatory circuits that are critical for maintaining tumor tolerance. Antibodies. Antibodies play an essential role in providing protective immunity to several pathogens, and the administration of tumor-targeting monoclonal antibodies has proven to be one of the most successful forms of immune therapy for cancer at the moment. The infusion of manufactured monoclonal antibodies can generate an immediate immune response while bypassing many of the limitations that impede endogenous immunity. Monoclonal antibodies have been approved for the treatment of several solid and non-solid tumors (see Table 1). The conjugation of antibodies to nanoparticles now generates a new product that combines the physico-chemical properties of nanoparticles like thermal, imaging, drug carrier, or magnetic characteristics with the ability of antibodies to specically recognize antigens on the surface of tumor cells.363 The possible applications of antibody-conjugated nanoparticles are numerous and can be divided in therapy and diagnosis. Therapeutic applications include targeted drug delivery, gene delivery, magnetic hyperthermia,

photodynamic therapy and the delivery of encapsulated molecules in vaccination strategies. An example for a therapeutic application is the use of AuFe3 O4 hetero-nanoparticles coupled with Herceptin and a platinum complex as target-specic nanocarriers for delivery of platinum into Her2-positive breast cancer cells.364 In diagnosis, the applications can be divided into those using in vivo and those using in vitro experimentation, and include contrast agents for magnetic resonance imaging (MRI), sensing, cell sorting, bioseparation, enzyme immobilization, immunoassays, transfection (gene delivery), purication, and so forth. Lee et al.33 showed that Herceptin-functionalized MFe2 O4 nanoparticles (M = Mn, Fe, Co or Ni) showed enhanced sensitivity for cancer cell detection and also made the in vivo imaging of small tumors possible. This suggests that by using appropriate cancer targeting molecules, the ultra-sensitive MR detection of various types of cancers should be possible. The improved sensitivity of assays using antibody-coated nanoparticles has also recently been shown by Thaxton et al. for the detection of the prostate specic antigen (PSA) in the serum of patients after radical prostatectomy).365,366 Here, sensitivity could be improved about 300-fold in comparison to the commercially available immunoassay used so far and allowed the prediction of disease relapse followed by adjuvant and salvage therapies at a much earlier time. Immune adjuvants. During the initial phase of infection, pathogen sensing by the immune system is based on recognition of a limited number of microbial molecular signatures, the pathogen associated molecular patterns (PAMPs) as summarized in Fig. 20.368,367 PAMPs are produced only by pathogens and not by host cells allowing the early distinction between self and microbial nonself. Many known PAMPs are typical nucleic acids or conserved components of cell wall structure from microorganisms. Their detection is mediated by a limited number of pattern recognition receptors (PRRs), which include membrane-bound receptors in the cell surface or in intracellular compartments, or soluble proteins secreted into the blood stream and tissue uids. Toll-like receptors (TLRs) represent a group of pattern recognition receptors with a great variety of different ligand specicities. Their discovery in 1997 by cloning and characterization of TLR4369 gave new impulses in the eld of innate immunity and in the understanding how innate and adaptive immunity are tightly interwoven. TLRs are type I transmembrane glycoproteins characterized by an extracellular leucine-rich repeat domain and a conserved intracellular domain, which is homologous to the cytosolic domain of the IL-1 receptor and therefore named Toll/IL-1 receptor (TIR) domain. Today, eleven different mammalian TLRs

Table 1 Monoclonal antibodies approved for tumor therapy in humans Product Rituximab (Rituxan) Trastuzumab (Herceptin R ) Gemtuzumab Ozogamicin (Mylotarg) Alemtuzumab (Campath) Cetuximab (Erbitux) Panimumab (Vectibix) Company Genentech Inc. Genentech Inc. Wyeth Averst Millennium/Ilex Partners LP ImClone Systems/Bristol-Myers Squibb/Merck KgaA Amgen Specicity Chimeric Ig anti-CD20 Humanized IgG anti-HER2 Humanized Ig anti CD33 Humanized Ig anti CD52 IgG1 , anti EGFR Human anti EGFR Disease Non-Hodgkin lymphomas breast cancer acute myeloid leukaemia chronic lymphocitic leukaemia colorectal tumor Metastatic colorectal carcinoma


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Fig. 20 Signalling through TLR3, TLR7, TLR8 and TLR9 in response to endosomal nucleic acids of viral origin. The Toll-like receptors (TLRs) that sense nucleic acids can operate in non-infected cells of many types to detect the production of infection in other cells. Following the recognition of viral double-stranded RNA (dsRNA), single-stranded RNA (ssRNA) or CpG-containing DNA by TLR3 or TLR7, TLR8 and TLR9 that are expressed in the endosome, signalling proceeds through TIR (Toll/interleukin-1 receptor (IL-1R))-domain-containing adaptor protein inducing interferon-b (TRIF) or myeloid differentiation primary-response gene 88 (MyD88), respectively. UNC93B is a multiple-transmembrane-spanning protein that is predominantly located in the endoplasmic reticulum (ER), but is known to associate with these endosomal TLRs and to be required for them to signal. TRIF, through the recruitment of tumour-necrosis factor receptor (TNFR)-associated factor 6 (TRAF6) and receptor-interacting protein 1 (RIP1), as well as TANK-binding kinase 1 (TBK1) and inducible IkB (inhibitor of nuclear factor-kB (NF-kB)) kinase (IKKi) activate interferon (IFN)-regulatory factor 3 (IRF3) and NF-kB. MyD88 recruits TRAF6 and IL-1R-associated kinase (IRAK) and activates IRF7 and NF-kB. TLR4 (not shown) also detects viruses, signalling in response to specic virally encoded proteins through MyD88, TRIF and/or TRAM (TRIF-related adaptor molecule). NF-kB, IRF7 and IRF3 translocate to the nucleus to induce the transcription of genes encoding cytokines such as TNF, IL-6 and type I IFNs (with permission from ref. 367).

have been identied, with their genes dispersed throughout the genome. They recognize a wide range of pathogen associated molecular patterns (PAMPs) derived from microbes and viruses such as ds-RNA, ss-DNA, and lipopolysaccharides (LPS) as well as intrinsic stress proteins. Upon ligand binding TLRs dimerize, thereby undergoing conformational changes required for the recruitment of the adaptor molecule MyD88 (myeloid differentiation primary-response protein 88). MyD88 consists of a C-terminal TIR domain, which interacts with the TIR domain of the receptor, and ultimately results in the activation of several kinases inducing phosphorylation, followed by ubiquitylation and subsequent degradation of IkB, thereby releasing NF-kB (nuclear factor-kB). NF-kB is consequently free to translocate into the nucleus and induce the expression of its target genes. Besides this MyD88-dependent signalling cascade, additional receptorproximal adaptor proteins have been described. They contribute6336 | Dalton Trans., 2011, 40, 63156343

to a MyD88-independent activation of the NF-kB pathway and include: TIRAP (TIR-domain containing adaptor protein, also known as MyD88-adaptor-like protein, MAL),370,371 TRIF (TIRdomain-containing adaptor protein inducing IFN-b; also known as TIR-domain-containing molecule 1; TICAM1)372 and TRAM (TRIF-related adaptor molecule, also known as TIR-domaincontaining molecule 2; TICAM2)373377 In an orchestrated interplay pathogen recognition by TLRs links innate and adaptive immune responses by inducing the expression of diffusible chemotactic factors and cell surface adhesion molecules attracting innate immune cells, such as monocytes, neutrophils, basophils, eosinophils and NK cells as well as adaptive immune cells, and facilitating their migration to the inamed tissue.378 TLR triggered activation of DCs having captured microbial antigens does not only lead to the upregulation of co-stimulatory and MHC molecules but also to a switch in This journal is The Royal Society of Chemistry 2011


Fig. 21 Modication of manganese oxide nanoparticles with a multifunctional polymeric ligand and linkage to ssDNA. The ssDNA conjugated nanoparticled trigger the immune cascade by activating NF-kB (reproduced with permission from ref. 387).

chemokine receptor expression and to the secretion of cytokines and chemokines nally resulting in the generation of effector responses including T helper cell and CTL responses. Because of these features, TLR ligands represent a group of molecules ideally suited for the use as immune adjuvants. For example, synthetic oligodeoxynucleotides (ODNs) that contain unmethylated CpG motifs, which are present at a much higher frequency in the genomes of prokaryotes than of eukaryotes379,380 stimulate a powerful innate immune responses by interacting with TLR9.381384 Therefore, ODNs are currently evaluated for the immunotherapy of cancer, including the treatment of kidney, skin, breast, uterine and immune malignancies. Because cancer cells often express a variety of abnormal proteins that can serve as targets for an immune response (antigens) local administration of adjuvants can induce tumor-associated inammation and protective immunity. To further improve the use of TLR ligands as adjuvants immobilization on nanoparticles represents a very attractive approach and provides a tool to limit the systemic release of proinammatory cytokines associated with TLR ligand application in solution. This has been demonstrated for siRNA molecules complexed to polyethylenimine-based nanoparticles triggering DC activation in a TLR5-dependent manner,385 for CpG oligonucleotides386,387 encapsulated within liposomal nanoparticles.177 These different nanoparticles efciently activated the TLR9 signaling pathway (Fig. 21). This journal is The Royal Society of Chemistry 2011

However, optimal induction of adaptive immune responses does not only rely on efcient innate immune cell activation but requires the presentation of antigens at the same time. Nanoparticles represent an ideal tool to combine these two stimuli in newly developed vaccination protocols. This has been demonstrated for cationized gelatin nanoparticles carrying CpG oligonucleotides and the model antigen ovalbumin.388 A similar approach was taken by Uto and colleagues. Here CpG oligonucleotides and ovalbumin was immobilized using biodegradable glutamic acid nanoparticles.389 Potent induction of proinammatory cytokine release in a TRL9-dependent manner and activation of cytotoxic T cells was observed. In addition, nanoparticles have been used to activate the inammasome in an approach to induce potent immune responses. This was achieved by the incorporation of LPS on the surface of poly(lactic-co-glycolic acid) nanoparticles loaded recombinant West Nile envelope protein. Immunization of mice resulted in the protection against a murine model of West Nile encephalitis.390 However, most approaches so far immobilize TLR ligands and antigens in an unspecic manner by adsorption or encapsulation. This has the disadvantage that the exact composition of the nanoparticles is difcult to control especially when functionalization using several molecules is intended. A solution for this problem will be the development of nanoparticles carrying different functional groups on their surface and therefore allowing a controllable immobilization of TLR ligands for innate immune cell activation, antigens for adaptive immune cell activation and Dalton Trans., 2011, 40, 63156343 | 6337

molecules, like antibodies or lectins, that will allow the targeting of nanoparticles to certain cell subsets best suited for the induction of appropriate adaptive immune responses.

5.

Summary and Outlook

Functionalized nanoparticles are important platforms for multimodal imaging and targeted drug delivery. In this eld, materials scientists provide tailor-made tools for medical research, diagnosis and treatment. These tools are rationally designed to have dened functions. Still, the value of these tools can only be determined by the users in medical sciences that develop assays for applying these tools. The recent developments in the synthesis and functionalization of magnetic nanoparticles permit the use of those particles in diagnosis and therapy. The next generation of particles is expected to contain more potent uorophors, enhanced MRI contrast and various attachment sites for specialized drugs. Still, little is known about the impact of multifunctional particles that display intrinsic chemical and physical asymmetry which poses new challenges for cells associated with the amphiphilicity, dipole moments and chemical diversity/patchiness of the functionalized nanoparticles. Why is it important to study the impact of anisotropic multifunctional particles on biological cells extending the intricacy of the problem even further? Current nanotechnology projects that started during the few years focus more and more on the supramolecular weak binding of functionalized particles with the goal to form larger ensembles exhibiting novel functionalities. Thus one may anticipate new and so far untouched phenomena associated with the exposure of human tissue to the primary building blocks of these new materials. Therefore, in future work, several scientic questions need to be addressed: (i) How does multifunctionality, shape- and chemical anisotropy impact the interaction of particles with biomembranes? (ii) How do these particles enter cells? Do they exert curvature in cell membranes that inevitably leads to vesiculation due to longrange attraction as observed from viral endocytosis? (iii) What are the possible biochemical consequences for the uptake of multifunctional nanoparticles? Despite the challenges that have to met, multifunctional nanoparticles provide fascinating opportunities for tailoring properties that are not possible with other types of therapeutics. As more clinical data become available, the nanoparticle strategy may improve to such an extent that more sophisticated tools actually reach the clinic. Results from current trials are fuelling the enthusiasm of researchers.

AcknowledgementsWe are grateful to Center for Complex Matter (COMATT) for support. K.S. is a recipient of a fellowship through funding of the Excellence Initiative (DFG/GSC 266). T. D. Schladt is recipient of a Carl-Zeiss Fellowship.

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