Review pubs.acs.org/CR
Nanomaterials for Theranostics: Recent Advances and Future Challenges Eun-Kyung Lim,†,‡,§ Taekhoon Kim,∥,⊥,§ Soonmyung Paik,#,∇ Seungjoo Haam,○ Yong-Min Huh,*,† and Kwangyeol Lee*,∥ ∥
Department of Chemistry, Korea University, Seoul 136-701, Korea Department of Radiology, Yonsei University, Seoul 120-752, Korea # Severance Biomedical Research Institute, Yonsei University College of Medicine, Seoul 120-749, Korea ∇ Division of Pathology, NSABP Foundation, Pittsburgh, Pennsylvania 15212, United States ○ Department of Chemical and Biomolecular Engineering, Yonsei University, Seoul 120-749, Korea ‡ BioNanotechnology Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Korea ⊥ Electronic Materials Laboratory, Samsung Advanced Institute of Technology, Mt. 14-1, Nongseo-Ri, Giheung-Eup, Yongin-Si, Gyeonggi-Do 449-712, Korea †
5.1.4. Magnetic Nanoparticles as Anticancer Drugs 5.2. Quantum Dots (QDs) 5.2.1. Strategies for Reduced RES Uptake 5.2.2. Anticancer Drug and Other Chemical Drug Delivery 5.2.3. Gene Delivery 5.3. Metal Nanoparticles 5.3.1. Metal Nanoparticle as Imaging Agent 5.3.2. Metal Nanoparticle as Photothermal Agent 5.3.3. Drug Release Triggered by Metal Nanoparticle-Based Hyperthermia 5.4. Upconversion Nanoparticles (UCNPs) 5.4.1. Imaging Agent 5.4.2. Photosensitizer Activator 5.5. Silica and Other Inorganic Nanomaterials 5.5.1. Silica 5.5.2. Calcium Phosphate 5.5.3. Apatite 5.5.4. Metal Organic Frameworks (MOFs) 5.6. Carbon-Based Nanomaterials 5.6.1. Carbon Nanomaterials as Carrier 5.6.2. Carbon Materials for Photothermal Therapy 6. Summary and Outlook Author Information Corresponding Authors Author Contributions Notes Biographies Acknowledgments Abbreviations References
CONTENTS 1. Introduction 1.1. What Are the Key Biological Processes Pertinent to Diseases, and How Can These Processes Be Monitored? 1.2. What Is the Core Advantage of in Vivo Imaging over in Vitro Assays? 1.3. What Are the Key Challenges That Need To Be Addressed To Overcome the Fundamental Limitations of in Vivo Imaging? 2. Major Cancer Signaling Pathways and the Concept of Targeted Delivery 3. Design of Theranostic Nanoparticles 3.1. Biomedical Payloads 3.1.1. Imaging 3.1.2. Therapeutics 3.2. Carrier 3.2.1. Polymers 3.2.2. Lipids 3.2.3. Dendrimers 3.2.4. Inorganic Nanocarriers 3.3. Surface Modifiers 4. Pharmacokinetic and Pharmacodynamic Properties of Nanomaterial-Based Therapy 5. Theranostic Nanomaterials 5.1. Magnetic Nanoparticles 5.1.1. Magnetic Nanoparticles as Imaging Agents 5.1.2. Magnetic Nanoparticles as Drug Delivery Vehicles 5.1.3. Magnetic Nanoparticles as Hyperthermal Agents © XXXX American Chemical Society
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1. INTRODUCTION In 2004, the U.S. Food and Drug Administration (FDA) released an important report entitled “Innovation/Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products”. This “Critical Path Initiative” directly reflects the FDA’s great interest to modernize the manufacturing process of FDAregulated products. In particular, the FDA reported the declining number of approved innovative medical products and strongly requested a concerted effort to modernize scientific tools.1−3 On the other hand, John Funkhouser, the Chief Executive Officer of PharmaNetics, used the term “Theranostics” for the first time in 1998 as a concept of “the ability to affect therapy or treatment of a disease state”. Accordingly, theranostics as a treatment strategy for individual patients encompasses a wide range of subjects, including personalized medicine, pharmacogenomics, and molecular imaging, in order to develop an efficient new targeted therapy and optimize drug selection via a better molecular understanding. Furthermore, theranostics aims to monitor the response to the treatment, to increase drug efficacy and safety, and to eliminate the unnecessary treatment of patients, resulting in significant cost savings for the overall healthcare system.2 Therefore, the emerging science of theranostics seems to provide a unique opportunity to pharmaceutical and diagnostics companies to meet the regulatory and financial constraints imposed by the FDA.1,2 Recently, theranostics, which is the combination of therapy and diagnosis, has become one of the core keywords in cancer research,6−19 based on the assumption that if cancer growth can be hampered during the diagnostic procedure, the subsequent cancer treatment would be much easier because cancer growth is retarded or cancer burden is reduced. Cancer is often regarded as a disease site that needs to be eliminated. Because the fastgrowing cancer tissues form leaky vasculatures around themselves,20,21 researchers can use the enhanced permeability and retention (EPR) effect20−28 for effective delivery of anticancer agents. Thus, chemical research efforts pertaining to cancer research have been mainly focused on synthesis of anticancer drugs and design of vehicles (e.g., polymer particles, liposomes), which can be loaded with a large amount of anticancer drugs and deliver them specifically to cancer tissues. At the early stage of theranostics, i.e., before 2005, an imaging function was simply added to these delivery vehicles loaded with therapeutic agents by attaching imaging contrast agents for use in methods such as computed tomography (CT), positron emission tomography (PET), and magnetic resonance imaging (MRI). Furthermore, until 2005, very slow progress was made with regard to application of nanomaterials for fabrication of theranostic systems. Cancer research has undergone a great paradigm shift in the past few decades.20 Cancer is no longer viewed from a reductionist point,20 where the focus is only on cancer cells and genes they contain. As beautifully outlined by Prof. Robert A. Weinberg,29,30 cancer cells interact with a complex mixture of surrounding immune cells, endothelial cells, neovasculature, and fibroblasts. Furthermore, cancer can acquire various survival strategies such as self-sufficiency in growth signals, evasion of apoptosis, development of insensitivity to antigrowth signals, sustained angiogenesis, metastasis, and unlimited replication, which are considered the six hallmarks of cancer.29,30 This list of hallmarks was recently further extended to include two additional hallmarks, i.e., deregulation of cellular energetics and escape from immune destruction.31−34 Cancer also exhibits the enabling
characteristics of genome instability and mutation and tumorpromoting inflammation.31−34 A better understanding of cancer biology will eventually lead to development of targeted therapeutic strategies that are designed to attack a single or a few targets governing the survival and proliferation of genetically distinct subpopulations of cancer cells. In general, these targets are associated with genetic aberrations including mutations (single-base substitutions), amplifications, translocations (e.g., gene fusion), deletions, and insertions/deletions.35 For example, according to the “oncogene addition” theory, ErbB2 (amplification) and BCR-ABL (gene fusion) as target oncogenes govern the oncogenic potential of breast cancer cells and chronic myelogenous leukemia cells, respectively. On the other hand, cancer cells can become dependent on nononcogenes which do not have oncogenic mutations and/or functionally relevant genomic aberration in tumors. This nononcogene addiction contributes greatly to cellular survival and proliferation under stress condition.36−38 Highly characteristic and nonrandom mutation patterns are found in well-studied oncogenes and tumor suppressor genes. Oncogenes are recurrently mutated at the same amino acid positions, leading to increased activity of the corresponding proteins.35,39 For example, in the case of nonsmall cell lung cancer, the epidermal growth factor receptor (EGFR) is mutated to an active form; the mutant L858R EGFR can be imaged with the PET/CT technique, complimenting the existing gene sequencing,40 immunohistochemical,41 and fluorescence in situ hybridization analyses.39,42 Noninvasive imaging techniques seem to provide advantages over repetitive biopsies of multiple tumor lesions in patients, because biopsies can cause severe trauma. Furthermore, with noninvasive imaging techniques it is possible to assess the varying EGFR activities within the individual tumor lesions, which are genetically heterogeneous, thereby allowing prediction of the outcome of EGFR inhibitors inhibitor treatment even before the inhibitor-based therapy. It is well known that cancer shows high resistance under very adverse conditions. Even with intensive chemo- and radiotherapy, complete cancer eradication is an evasive goal; in many cases, cancer that acquired resistance to previous treatment recurs.43−46 This is because cancer can quickly adapt and survive through a series of mutations and/or redundancy of signaling pathways of both cancer cells and surrounding stromal cells. This implies that it is possible to cure cancer completely by simply combining a therapeutic drug with an imaging agent. Various nanomaterials have been developed in attempts to address these problems. Nanomedicines, coined by the National Institutes of Health (NIH),3 are nanoparticle-based therapeutics composed of a variety of organic or inorganic nanomaterials for treatment, diagnosis, monitoring, and control of biological systems. Nanomaterials can be loaded with multiple types of drugs or possess multiple inherent anticancer therapeutic abilities. They can target surface-bound molecules on cancer cells and be further loaded with multimodal imaging contrast agents. The formulation of theranostic nanoparticles enables us to monitor the response to treatment and to increase drug efficacy and safety.4,5 Recently, new advances in the bioapplication of nanomaterials are being reported. These advances include significant MRI contrast enhancement using superparamagnetic nanoparticles with high magnetization values,47−52 photoacoustic imaging with carbon nanotubes (CNTs),43−56 the photothermal effect of CNTs and other carbon nanomaterials such as graphene,57−59 the photothermal effect of polymer nanoparticles,60 nanoparticle-based effective gene-delivery veB
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hicles,61−74 nanocomposites applicable to multiple therapies,75−78 elucidation of the removal process of nanomaterials from the body,79−81 activatable therapeutic nanomaterials,75,77,82−126 and a better understanding of nanotoxicology.127−137 The most encouraging aspect of these new developments is that some of the current research efforts start to implement the latest concepts of cancer, that is, theranostics is evolving to incorporate aspects of both molecular imaging78,130−137 as well as personalized cancer therapy.77 This review mainly describes the theranostic research with nanomaterials since 2006, when nanomaterials started to be used extensively in the development of theranostic systems. First, a brief history of molecular imaging and personalized cancer therapy and an introduction of cancer biology are provided to give an overall perspective of modern theranostic research and to set the standard for the future design concept of theranostic nanomaterials. Then, an anatomical description of theranostic nanomaterials is given, followed by a detailed description of research results of the application of theranostic nanomaterials in biomedical research. A simple comparison of the ideal future theranostic system, including all desired properties, with the current state of theranostic research would clearly point out the technical areas that need to be further improved. Finally, we conclude this review by pointing out the limitations of nanotheranostics and suggesting some future research directions in theranostics. The first application of molecular imaging was in vivo measurement of the level of reporter gene expression.138,139 The main challenge was development of a suitable probe to enable in vivo imaging of a biological event that could be conventionally assessed only by in vitro assays. Soon thereafter, molecular imaging was defined as the “in vivo characterization and measurement” of biologic processes at the cellular and molecular levels.140 The three outstanding questions in current molecular imaging are as follows: (1) What are the key biological processes pertinent to diseases and how can these processes be monitored, (2) what is the core advantage of in vivo imaging over in vitro assays, and (3) what are the key challenges that need to be addressed to overcome the fundamental limitations of in vivo imaging?
assessment of the presence of certain genes with nanoprobes is very challenging because of, in part, the difficulty in delivering nanoprobes into the nucleus. Quantification of genes with nanoprobes is not possible yet. Nonetheless, continuous research efforts are being made to utilize nanoprobes as gene carriers.66,67,71,72,146−148 It is envisaged that successful utilization of nanoprobes as gene carriers would lead to further development of indirect molecular imaging. 1.2. What Is the Core Advantage of in Vivo Imaging over in Vitro Assays?
In vitro assays provide a comprehensive “snapshot” of biological indicators or biomarkers of cancer. However, molecular imaging can take this information a step further, revealing the “in vivo” activity of these markers and how their location changes over time.103,149−153 Although detailed and quantitative information cannot be collected from molecular imaging at the current stage, studies using this technique should, ideally, be able to describe the progress of a disease in a spatially resolved and time-resolved manner. Furthermore, compared to in vitro assays, molecular imaging is minimally invasive. This is of paramount importance in cases of advanced diseases involving anatomical locations such as the brain or lung, which are difficult to be biopsied. Therefore, the current challenge in molecular imaging lies in providing as detailed information as in vitro assays do. However, it should be noted that the current molecular imaging methods cannot compete with the state-of-the-art of in vitro assays. 1.3. What Are the Key Challenges That Need To Be Addressed To Overcome the Fundamental Limitations of in Vivo Imaging?
Various imaging techniques such as CT, MRI, PET, and fluorescence molecular tomography (FMT) are available for clinical applications. Because each technology has its unique strengths and limitations, hybrid imaging platforms such as PETCT, FMT-CT, FMT-MRI, and PET-MRI are being developed to improve data reconstruction and visualization. While imaging probes for each specific imaging modality are currently available, it is imperative to develop a single nanoprobe that can be used for multiple imaging modalities to take full advantage of the potential benefits of hybrid imaging techniques. Furthermore, multimodal imaging should allow in-depth analysis of clinically relevant biological phenomena. There are a number of examples where it was demonstrated that suitably designed nanoprobes can be utilized as multi-imaging probes.110,112,154−162 There are multitudes of nanoprobes with superior imaging abilities that surpass the abilities of conventional molecule-based imaging probes by far; the most successful developments have been made with regard to MRI contrast agents. Nanoprobes can be further designed to incorporate suitable therapeutic agents such as genes or drugs, leading to the genesis of nanotheranostics. However, because nanoprobes are larger than conventional molecular imaging probes, addressing the intrinsic problems associated with the penetration of physiological barriers is further complicated. Therefore, it is very important to develop methods for delivery of nanoprobes through physiological barriers for both molecular imaging as well as therapeutic purposes. Furthermore, the delivery efficiency of nanoprobes needs to be greatly enhanced. The current level of delivery loss due to uptake by the reticuloendothelial system (RES) and nanoprobe instability during circulation is not acceptable for practical applications. Most recent advances in theranostics have started to address these important questions. For example, MRI nanoprobes with
1.1. What Are the Key Biological Processes Pertinent to Diseases, and How Can These Processes Be Monitored?
There are many plausible answers to this question depending on the type of disease and biological field. In this review, we will limit our discussion to personalized cancer therapy. The type of gene mutation and level of gene expression represented as the amount of specific proteins vary depending on the type of cancer.141,142 Molecular imaging strives to identify the type of gene mutation and assess the level of gene expression in cancer cells. The three principal strategies adopted for molecular imaging are as follows: (1) encoding with genetic reporters (e.g., photoproteins or PETand MRI-detectable reporter genes),143 (2) radiotracers, fluorochromes, or magnetically tagged affinity molecules (e.g., labeled antibodies or small molecules),144 and (3) biorthogonal reporter strategies.145,146 Nanoprobes, in general, rely on the attachment of affinity molecules on the nanoprobe to overexpressed proteins, especially on cell membranes. For example, the overexpressed EGFR/ErbB receptor moieties on the cell membrane of breast cancer cells are efficiently targeted by nanoprobes, enabling quantitative assessment of tumor progression. However, direct C
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Figure 1. Schematic representation of targeting the major cancer-signaling pathways. Modified with permission from ref 169. Copyright 2013 American Society of Clinical Oncology.
production of the lipid second messenger phosphatidylinositol (3,4,5)-trisphosphate (PIP3) found on the cell membrane.171−175 The PI3K pathway regulates various cellular processes, such as proliferation, growth, apoptosis, and cytoskeletal rearrangement. PI3K and PIP3 levels are barely detectable in mammalian cells under unstimulated growth conditions and tightly controlled, owing to the combined effects of stringent PI3K regulation and the action of several PIP3 phosphatases (phosphatase and tensin homologue [PTEN], SH2-containing inositol phosphatase, SH2-containing inositol phosphatase 2).172,176,177 Among them, PTEN acts as a tumor suppressor gene through the action of its phosphatase protein product and has subsequently been implicated more broadly in various human cancers.173,174 PIP3 in turn contributes to the recruitment and activation of a wide range of downstream targets, including the serine-threonin protein kinase Akt, which can indirectly promote cell survival.176,177 The PI3K/Akt pathway interacts with molecular mechanisms controlling cellular energy control and glucose metabolism that also controls angiogenesis, growth proliferation, senescence, and other processes.178−181 In contrast to p53, a tumor suppressor protein, and other tumor suppressor pathways, the PI3K/Akt pathway is activated in cancer, making it an optimal target for therapy as it is easier to inhibit activation events than to replace lost tumor suppressor functions.171,172,175−177,182−185 Therefore, hyperactivation of the PI3K/Akt pathway is often genetically selected during tumorigenesis, and the normal cellular functions regulated by this pathway are recruited to promote proliferation and survival suppressor function. Through reciprocal regulation of the PI3K/Akt pathway and the tumor suppressor protein p53, Akt can promote p53 degradation by phosphorylating and activation of murine double minute 2 (MDM2), an important negative regulator of the p53 tumor suppressor.182 Therefore, blocking this pathway could simultaneously inhibit the proliferation of tumor cells and sensitize them
an unprecedented ability to provide anatomical details can be conjugated with aptamers or antibodies with which the amount of pathologically important molecules such as ErbB2 can be directly assessed. More specifically, the expression levels of proteins such as ErbB2 provide guidance as to which therapy should be used. Therefore, improving the MRI image with an ErbB2-specific antibody-conjugated nanoprobe can be classified as “true” molecular imaging. Furthermore, therapeutic agents can be delivered to the target tumor site with the ErbB2-specific nanoprobe, completing the theranostics approach. In addition, recently developed nanoprobes that respond specifically to the cancer microenvironment are another example of theranostics. Cancerous tissues are very different from normal tissues in that they are more acidic due to aerobic glycolysis (Warburg effect).163−168 For imaging or drug unloading purposes, nanoprobes or drug-delivery vehicles can be designed to be selectively activated under this acidic condition. Potential side effects could be significantly reduced with activatable nanoprobes or drug-delivery vehicles conjugated with suitable targeting moieties. We believe that the main thrust of future theranostic research lies in the convergence of three cornerstone technologies, i.e., imaging technology, nanoprobes, and personalized cancer therapy.
2. MAJOR CANCER SIGNALING PATHWAYS AND THE CONCEPT OF TARGETED DELIVERY Normal cells rely on the integrity of regulatory circuits that control cell proliferation and maintenance. The regulatory circuits are disrupted in cancer cells, and the type and behavior of the cancer cell vary depending on the type of damage caused to the regulatory circuits. The major cancer signaling pathways are shown in Figure 1.169 Phosphatidylinositol 3-kinase (PI3K) is the major signaling component in the downstream of growth factor receptor tyrosine kinases (RTKs).167−170 The heterodimeric lipid kinase PI3K, composed of regulatory and catalytic subunits, catalyzes D
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Figure 2. (A) Therapeutic targeting of the hallmarks of cancer. (B) Examples of nononcogene addictions in cancer cells. Modified with permission from refs 29 and 30. Copyright 2009 Elsevier Ltd.
of the PI3K pathway is likely to result in optimal efficacy when combined with other signal transduction inhibitors, chemotherapy, or radiation therapy.170−172,196 Inhibitors of RTKs have been actively developed. In particular, trastuzumab, a humanized monoclonal antibody (mAb) directed against the HER2 RTK protein, shows high efficacy in HER2amplified breast cancer in adjuvant and metastatic settings when combined with chemotherapy. We demonstrated the synergistic therapeutic efficacy of a theranostic magnetic nanocluster that combined trastuzumab with doxorubicin (DOX).78 However, functional downregulation of PI3K/Akt is essential for trastuzumab activity. Therefore, tumor cells can become resistant to RTK inhibitors by mutations or gene amplifications affecting downstream signaling components or by loss of negative regulators. Indeed, it has been recently shown that loss of PTEN in tumor cells can result in resistance to Iressa, an EGFR RTK inhibitor, by setting a high threshold of Akt activation.201−205 Therefore, when developing RTK inhibitors as therapeutic agents, it is essential to monitor the activity of downstream PI3K/Akt pathway effectors in response to the targeted therapy for both selecting patients who are likely to respond and rapidly identifying nonresponders in order to allow triage to other therapeutic approaches.171,172,175,176,189,196,207−210 Discovery of the direct effector of Ras and Raf kinases family (A-Raf, B-Raf, and C-Raf)207 linked Ras to the extracellularsignal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway and increased interest in inhibitors of Ras-
toward apoptosis. In addition, hyperactivation of the PI3K/Akt pathway is found in a wide range of tumors leading to tumor cell transformation and resistance to chemotherapeutic agents. Thus, blockage of these pathways might be sufficient to inhibit tumor growth. The available clinical evidence of PI3K pathways deregulating in various cancers and identification of downstream kinases that are involved in mediating the effects of PI3K (Akt and phosphoinositide-dependent kinase-1 (PDK1)) provides potential targets for development of small-molecule therapies.170−173,175−177,182,186−194 The lipid−protein interaction domains required for activation of PI3K targets provide another potential strategy for developing targeted therapies. PI3K/Akt anomalies in cancer, e.g., PTEN loss/downregulation, serve as an excellent diagnostic target to identify patients who are likely to respond to PI3K pathway inhibitors. There is strong evidence that PI3K/Akt signaling mediates resistance to both nonspecific and targeted cancer therapies.170−176 Therefore, there might be benefits in combining these cancer therapies with PI3K inhibitors, in particular, in the presence of genomic anomalies that activate the PI3K pathway. Selective kinase inhibitors of Akt kinases would also be effective at inhibiting these pathways by disrupting the binding of PIP3 to PH domains, thereby preventing membrane translocation and activation by phosphoinositide-dependent kinase-1 (PDK1).195−198 In particular, as the PI3K pathway is a crucial regulator of survival during cellular stress and given that tumors frequently exist in intrinsically stressful environments with limited nutrient and oxygen supply and low pH, inhibition E
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agents, etc.). Carrier should provide sufficient physical protection for the biological payloads under physiological conditions during delivery to the desired target site. Various organic-based and inorganic-based carriers have been developed. The carrier might be designed to become cancer-specifically disintegrated for better imaging or therapeutic efficacies. Finally, modifiers are attached to the surface of the carrier, which are expected to provide theranostic nanomaterials with additional properties, e.g., long circulation time, barrier-penetrating ability, and target-specific binding ability. The components for generating a theranostic nanoparticle along with material classifications and functions are listed in Table 1.
dependent tumors. Activating mutations in an isoform of Raf, BRaf, have been observed in a large (>60%) fraction of human malignant melanomas and other tumors that induce activation of downstream ERK signaling.208−210 Overall, selective kinase inhibitors targeting mutated forms of signaling proteins such as B-Raf or EGFR have emerged as an important class of anticancer agents with demonstrated clinical efficacy and favorable toxicity where conventional treatments have previously provided only modest benefit.34,178,179,190,195−197,199,200,206,211−217 In addition to the original and revised hallmarks described by Hanahan and Weinberg,29,30 Luo and Elledge outlined the stress phenotypes of cancer, i.e., DNA damage/replication stress, proteotoxic stress, mitotic stress, metabolic stress, and oxidative stress.36 For example, production of reactive oxygen species (ROS) is the defining characteristic of oxidative stress in cancer. ROS have been regarded as very sensitive stimuli while designing activatable nanotheranostic platforms.218,219 Moreover, ROS are highly linked to endogenous DNA damage events in cancer cells. Aerobic glycolysis, which is used for extensive proliferation, enables tumor cells to acidify their microenvironment (metabolic stress), leading to the escape from immune surveillance.164−168,171 Therefore, the acidic microenvironment of cancer cells provides excellent opportunities to optimally design multifunctional nanoplatforms for theranostic applications. Furthermore, phenotypic characteristics of cancer have proper nodes between classical and revised hallmarks of cancer, as denoted in Figure 2.29,30 It is known that cancer is recurrent in the majority of cases when the most appropriate treatments are applied separately. Therefore, various drug combination strategies such as the (i) reversal of resistance approach, (ii) sequential approach, (iii) addition approach, (iv) alternating approach, and (v) pulse dose approach have been proposed.169 It seems that the immediate challenge and opportunities of theranostics toward personalized cancer therapy lies in full exploitation of combinatorial approaches of various targeted toolkits.220−228 Design of multifunctional nanoplatforms must come from a better understanding of critical problems in cancer biology and new advantages/shortcomings in nanomaterials.
3.1. Biomedical Payloads
3.1.1. Imaging. The characteristics of various imaging modalities are briefly summarized (Table 2). 3.1.1.1. Optical Imaging. Organic fluorescent dyes such as cyanine 5.5 (Cy5.5) and fluorescein isothiocyanate (FITC) are widely used to monitor molecular events in biological systems. Visible or ultraviolet (UV) light used to excite organic dyes does not penetrate deeply into the tissue, which confines application of organic dyes in bioimaging mainly to cells. In addition, individual organic dyes are photobleachable and rather toxic. Therefore, methods have been developed by which organic dyes are protectively encapsulated in an SiO2 matrix232−236 or polymer161,237−248 has been developed to provide the required photostability and reduce loss during delivery, which would lead to lower imaging ability and increased toxicity. In this context, recently a developed two-photon dye utilizing NIR light shows great promise249−254 because NIR light is minimally absorbed by human tissues. Park and Kwon et al. synthesized chitosan-based nanoparticles (CNPs) for simultaneous cancer diagnosis and therapy.254 CNPs were labeled with Cy5.5, an NIRF dye, for imaging and loaded with anticancer drug paclitaxel (PTX). In addition, in a study by Perez et al., a water-soluble hyperbranched polyhydroxyl polymer was formulated with cytochrome c and amphiphilic fluorescent dye molecules (indocyanine green [ICG])255 and further conjugated with folic acid (FA) (Figure 4). Furthermore, NIR light is less toxic to cells than visible or UV light. For example, Cho et al. recently developed a series of twophoton dyes and elucidated some important signaling events in mammalian cells.253 UCNPs, which are made of inorganic materials, are comparable to two-photon dyes.156,215,256−269 As with organic two-photon dyes, UCNPs take up the energy of NIR light to emit light in the visible or UV range. Although UCNPs are much larger than organic dyes, UCNPs can be used to elucidate important cell events. Lee et al. recently visualized the action of a motor protein using UCNPs as imaging probes.260 One salient advantage of UCNP over organic dyes is their excellent stability in physiological systems. In particular, organic dyes could be linked to a fluorescence quenching moiety such as an Au nanoparticle via a peptide linker. In the presence of peptide-cleaving enzymes, the fluorescence of organic dyes is turned on due to the absence of a fluorescence resonance energy transfer (FRET) mechanism. Thus, in this case, the fluorescence signal of organic dyes could indicate the presence of the responsible enzyme in the studied biological system. Park and Choi et al. reported tumor-targeting hyaluronic acid nanoparticles (HANPs) as carrier of a hydrophobic photosensitizer, chlorin e6 (Ce6), for simultaneous photodynamic
3. DESIGN OF THERANOSTIC NANOPARTICLES The design concept of theranostic nanoparticles has been discussed in previous reports.4−19,229 By adopting Ferrari’s classification,20 a theranostic nanoparticle can be dissected into at least three components, i.e., biomedical payload, carrier, and surface modifier, depending on both their roles and their physical locations, as shown in Figure 3. Biomedical “payloads” include imaging agents (e.g., organic dyes, quantum dots [QDs], upconversion particles [UCNPs], MRI contrast agents, CT contrast agents, etc.) and therapeutic agents (anticancer drugs, DNA, small interfering RNA [siRNA], proteins, hyperthermia-inducing nanoparticles, ROS-generating
Figure 3. Schematic illustration of a multifunctional nanocomposite. F
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Table 1. Materials Used in Multifunctional Nanoparticles229 component biomedical payload
carrier
surface modifier
material
function
imaging agents for optical, CT, MRI, PET, ultrasonic imaging (organic dye, QDs, UCNPs, magnetic materials, metal nanoparticles with SPR, CNT) therapeutic agents (anticancer drugs, DNA, siRNA, hyperthermal/photodynamic materials) organic (lipid, natural/synthetic polymers) inorganic (hollow metal nanoparticles, hollow metal oxide nanoparticles, carbon nanostructures, porous Si or SiO2 nanoparticles) antibody aptamer peptide/protein small molecules charge-balancing molecules
imaging enhancement cancer cell death induction, gene up/downregulation monofunctional (protection of payloads, controlled release of drug/gene, biocompatibility, stimuli responsiveness) multifunctional (imaging ability added to above functions) molecular imaging target specific delivery uptake enhancement penetration of barrier signaling transduction stimuli responsiveness
Table 2. Characteristics of Imaging Modalities230,231 modality optical imaging MR imaging PET imaging ultrasound imaging CT imaging
energy source visible light or near-infrared radiofrequency magnetic field high-energy γ rays high-frequency sound X-ray
depth
