Inorganic Nanoparticles for Image-Guided Therapy - ACS Publications

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Inorganic nanoparticles for image-guided therapy Hong Yeol Yoon, Sangmin Jeon, Dong Gil You, Jae Hyung Park, Ick Chan Kwon, Heebeom Koo, and Kwangmeyung Kim Bioconjugate Chem., Just Accepted Manuscript • DOI: 10.1021/acs.bioconjchem.6b00512 • Publication Date (Web): 27 Oct 2016 Downloaded from http://pubs.acs.org on October 29, 2016

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Bioconjugate Chemistry

Inorganic Nanoparticles for Image-guided Therapy

†

†,‡

Hong Yeol Yoon, Sangmin Jeon, Kwon,

†

†,§

ǁ,*

Heebeom Koo,

†,‡

Dong Gil You,

‡

Jae Hyung Park, Ick Chan

†,*

,and Kwangmeyung Kim

Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, 5, Hwarang-ro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea

‡

School of Chemical Engineering, Sungkyunkwan University, 2066, Seobu-ro, Jangangu, Suwon 16419, Republic of Korea

§

KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul, 02841, Republic of Korea

ǁ

Department of Medical Lifescience, College of Medicine, The Catholic University of Korea 222, Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea

*To whom correspondence should be addressed: E-mail: [email protected] or [email protected].

ACS Paragon Plus Environment


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Abstract Recently, nanotechnology has provided significant advances in biomedical applications including diagnosis and therapy. Particularly, nanoparticles have been emerged as valuable outcomes of nanotechnology due to their unique physicochemical properties based on size, shape and surface properties. Among them, large amount of researches has reported imaging and therapeutic applications using inorganic nanoparticles with special properties. Inorganic nanoparticles developed for imaging and therapy contain metal (Au), metal oxide (Fe3O4, WO3, WO2.9), semiconductor nanocrystal (quantum dots (QDs)) and lanthanide-doped upconversion nanoparticles (UCNPs). Based on their intrinsic properties, they can generate heat, reactive oxygen species (ROS), or energy transfer, so that they can be used for both imaging and therapy. In this review, we introduce biocompatible inorganic nanoparticles for image-guided thermal and photodynamic therapy, and discuss about their promising results in vitro and in vivo studies for biomedical applications.

Keywords: Inorganic nanoparticle, image-guided therapy, theranostics, hyperthermia, photodynamic therapy


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1. Introduction Generally, clinical treatments of cancers are now mainly composed of surgery, radiation, and anticancer drugs. However, after all these treatments, many patients still suffer from unintended side effects or tumor recurrence. Therefore, various researches have focused to develop an alternative and complementary treatment strategy to completely eliminate tumor cells with safe and prevent cancer recurrence. Over the several decades, in combination with nanotechnology, multifunctional nanoparticles were developed and used platforms for cancer diagnosis, therapy and monitoring the therapeutic efficacy of cancer, which are useful in image-guided therapy (IGT).1-4 Based on the unique physicochemical properties of nanoparticle such as nanoscale size, high surface to volume ratio, and solubility, they have shown promising potential for modulating pharmacokinetic (PK) and pharmacodynamics profiles of therapeutic agents and imaging agents, resulting in improving their theranostic efficiency as platform technology.5-7 Various nanoparticles have been used for optical imaging, magnetic resonance imaging (MRI), computed tomography (CT) and positron emission tomography (PET) as well as drug delivery.8 To fabricate nanoparticles, researchers have used organic materials including phospholipids, polymers, or small molecule fluorophores for long time.9-11 They can be exactly characterized by simple methods such as nuclear magnetic resonance (NMR) or gel permeation chromatography (GPC), and are advantageous for the secretion from body. However, their functions are limited and researchers are always searching new materials for challenging and exciting trials. Recently, remarkable progress for IGT and the cancer theranosis has been achieved by inorganic nanoparticles in particular (Scheme 1). Inorganic nanoparticles have many favorable properties such as easy to fabrication, tunable size, generating heat or reactive



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oxygen species (ROS), X-ray absorption, and energy transfer properties.12-15 There properties have made them as promising candidates for IGT. In this review, we will introduce recent progress in biomedical applications of novel inorganic nanoparticles as IGT agents for cancer treatment. It is our hope that this review helps further progress in this research field and the progress results in both scientific and clinical outcomes in future.

Scheme 1. Inorganic nanoparticles for tumor imaging and therapy

1. Image-guided thermal therapy Hyperthermia can induce apoptotic cell death in the tumor tissues, so that it has been used to improve therapeutic efficacy and survival rate in combination with radiotherapy or chemotherapy of tumors.16, 17 With heat generation, apoptotic signals in tumor cells were activated in the range of 41 oC to 47 oC.17 In addition, increasing of the temperature above 50 oC leads cell necrosis via instant denaturation of proteins.14 This technique enables less invasive treatment of cancer, and it requires the delivery of heatgenerating probes into the tumor tissues or cells for improved specificity. Recently,


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targeted hyperthermia based on inorganic nanoparticles has shown promising results in tumor-targeted thermal therapy. Targeted hyperthermia can be controlled by heat generation in the tumor tissues using inorganic nanoparticles such as gold nanoparticles, iron oxide nanoparticles, and tungsten nanoparticles in accordance with laser irradiation, short wave radiofrequency (RF), microwaves or ultrasound.

1.1 Gold nanoparticles Gold nanoparticles (AuNPs) are one of the most widely used inorganic nanoparticles in many fields because of their advantageous properties such as biocompatibility and facile modification. Their surface can be easily modified with other agents, such as polymers, drugs, contrast agents, antibodies and proteins, so that they has gathered much attention as delivery carriers. According to the size, shape and structure of AuNPs, they also have controllable surface plasmon resonance (SPR). Consequently, AuNPs have strong fluorescence absorption occurred by resonance energy transfer (FRET) and nonradiative energy dissipation properties, which can generate heat energy by electron excitation and relaxation.18 These particular properties of AuNPs provide promising potential as multifunctional platforms for diagnostic and therapeutic agents. In case of bare AuNPs, there are limitations for in vivo applications due to the low stability and deficiency of targeting ability. To overcome these limitations, the surface of AuNPs has been modified with biocompatible materials such as polyethylene glycols (PEGs) and glycol chitosan (GC) for enhanced stability. In addition, when NIR fluorescence probe is attached on surface of AuNPs, there is quenching effect by surface resonance of AuNPs, which is useful for simultaneous optical diagnosis and therapy. Among the various imaging techniques for diagnosis, computed cosmography (CT) was



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frequently used in studies with gold nanoparticles. Due to the unlimited penetration depth and high spatial resolution, CT has been used as powerful tool in clinic. Although low molecular iodine-based CT contrast agents are generally used in CT imaging, they have limitation such as renal toxicity and fast excretion.19,

20

To overcome these

drawbacks of conventional CT contrast agent, AuNPs have received substantial attention for CT imaging over the past few decades. In this point of view, Sun et al. modified AuNPs with heparin, glycol chitosan, and tumor-specific peptide probe.21-24 The outer space of AuNPs were coated with hydrophobically modified glycol chitosan polymer (hGC) to enhance the stability and tumor-targeting ability. These GC-coated AuNPs (GC-AuNPs) can generate CT signals, and matrix metalloproteinase (MMP)-activatable peptide probes were also chemically conjugated on the surface of GC-coated AuNPs. These MMP-GC-AuNPs have high stability in both distilled water and PBS, and were not toxic in cell viability test in vitro. The high stability of MMP-GC-AuNPs enables long circulation of them in the body, which promoted tumor-targeting ability by the enhanced permeation and retention (EPR) effect in fenestrated tumor vessels.24 In addition, they measured X-ray absorption of GC-AuNPs and MMP-GC-AuNPs in comparison with commercial iodine-based contrast agent (eXIATM160) in CT phantom images, where polymer-coated AuNPs showed higher absorption than eXIATM160 at the same elemental concentration. In vivo study of MMP-GC-AuNPs was performed using MMP-2 positive HT-29 tumor-bearing mouse model, and in vivo CT and optical dual imaging were tried. Although bare AuNPs showed aggregations when injected intravenously into the mice at high concentration (200 µL, 300 mg/kg), polymer-coated AuNPs showed excellent biocompatibility and stability at the same concentration. MMP-GC-AuNPs marked the


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tumor tissue through CT and optical imaging at the same region of tumor-bearing mouse model. These results indicate that polymer-coated AuNPs have promising potential as CT contrast agent for cancer imaging. AuNPs have been also used on therapeutic purposes such as photothermal therapy (PTT), radio therapy, and drug delivery. Particularly, AuNPs are useful for imageguided thermal therapy after proper modification. For many years, diverse types of AuNPs including nano-spheres, nanorods (AuNR), nano-stars, or nano-cubics have been developed for imaging and therapy.3, 25-28 Most AuNPs can absorb laser irradiation and converted the energy into heat source, and the wavelength of excitation light is changed by the size and shape of AuNPs. Particularly, the wavelength can be easily tuned by changing aspect ratio in case of AuNR, which makes AuNR more useful for photothermal therapy.22,

29, 30

Therefore, AuNR has been frequently used to trigger

hyperthermia in combination with near-infrared (NIR) laser which is advantageous for tissue penetration than UV or visible light. For example, Yi et al. designed and developed MMP-sensitive AuNR as multifunctional platform for simultaneous diagnosis and therapy. NIR fluorescent dye, Cy5.5, was conjugated to MMP- sensitive peptide sequence which can be degraded by MMP enzyme, and attached the dyepeptide conjugate onto the surface of AuNRs. Due to the surface energy transfer of AuNR, the fluorescence of Cy5.5 is quenched when the dye is close to AuNR. However, after bond cleavage of the peptide substrate by MMP enzyme, the fluorescence is recovered because the distance between Cy5.5 and AuNR increase and the quenching effect disappear. Through this mechanism, these AuNRs could be used for analyzing the activity of MMP in vivo. In this report, the activation of NIR fluorescence was monitored in tumor site after intratumoral injection of MMP-AuNRs, while reduced



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fluorescence was observed at MMP-2 inhibitor-treated tumor site. In addition, MMPAuNRs showed photothermal effect in response to 671 nm laser irradiation time, which was observed in vivo using mice after subcutaneous injection of MMP-AuNR. The result of photothermal effect by MMP-AuNRs was also confirmed via dark field microscopy and H&E staining. Recently, Du et al. also showed that AuNRs can be used for optoacoustic imaging and PTT simultaneously. Optoacoustic imaging is a newly developed technique that can increase the spatial resolution and penetration depth of imaging while maintain the high sensitivity of optical imaging.31 Upon laser irradiation, several proteins including hemoglobin and melanin can generate acoustic signals which can be detectable. Analyzing these signals and reconstructing images with them can provide information about deeper tissue comparing to obtain emission light from fluorescent dyes. Traditional organic dyes like indocyanin green have been used as contrast agent for optoacoustic imaging. Particularly, surface plasmon resonance from gold nanoparticles also can generate strong optoacoustic signals, which makes them promising optoacoustic contrast agents. Du et al. developed triangular structures using M13mp18 genomic DNA scaffold strands and encapsulated AuNRs inside them.32 These structures can enhance stability of AuNR and its tumor-targeting ability by EPR effect. After accumulation in tumor tissue, the AuNRs in DNA-origami structure (D-AuNR) can generate optoacoustic signals upon NIR laser irradiation as well as result in photothermal effect (Figure 1a). The optoacoustic signals in tumor tissue were clearly observed after i.v. injection to mice, and the signals continued for longer time than the control AuNR without DNA structure (Figure 1b). Infrared thermal images showed that tumor tissue could be heated to 53.3 oC after i.v. injection of D-AuNR and this


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photothermal effect can result in improved survival rate in 4T1 tumor-bearing mice models (Figure 1c and 1d).

Figure 1. Gold nanoparticles for optoacoustic imaging and PTT. (a) Schematic illustration of DNA-prigami-gold-nanorod (D-AuNR)hybrid nanoprobe system. (b) Optoacoustic images of 4T1 tumor after i.v. injection of D-AuNR. (c) Infrared thermal images of tumor-bearing mice after i.v. injection of D-AuNR and 808 nm laser irradiation. (d) Survival rate of 4T1-fLuc tumor-bearing mice after PTT using AuNR. Reproduced with permission from Ref 32

1.2 Iron oxide nanoparticles Among many inorganic nanoparticles for cancer theranostics, superparamagnetic iron oxide nanoparticles (SPION) have special meaning because they were approved by



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FDA for human use and actually have been used in clinic.33, 34 For example, Feridex I.V.® is approved and used for liver and spleen imaging, and Combidex® is also used for detecting lymph node metastases. Because of the superparamagnetism of iron oxide, SPIONs can be used as contrast agents in magnetic resonance imaging (MRI) for disease diagnosis and treatment monitoring, where SPIONs provide strong T2 contrast effect induced by their magnetic inhomogeneity. In addition, the facile modification of SPION enables various surface modifications with andtibodies, peptide, and polymer to provide a long-circulation property and target-specific imaging in similar with AuNPs. Furthermore, iron oxide nanoparticles have negligible toxicity because they are degraded after long time and the resulting iron molecules are already abundant in body. However, wide clinical uses of the SPION-based T2 contrast agents were hampered by several disadvantages. The intrinsic dark contrast from SPION in T2-weighted MRI sometimes may mislead diagnosis in clinic because the labeled tissues labeled can be confused with other dark areas including calcification, bleeding, or metal deposition.35 In addition, the high magnetic moment of SPIONs can cause perturbed magnetic field in local area, resulting in ‘blooming effect’ which overestimates the size of labeled tissues and makes the image cloudy.36-38 Therefore, T1 contrast agents are advantageous than T2 agent for accurate MR imaging with high-resolution. For these reasons, Kim et al developed ultrasmall particles of iron oxide (USPIO) which can be used as T1 contrast agents.38 They reported that the uniform USPIO with diameter below 4 nm can generate T1 MR signals (Figure 2). High-resolution blood pool T1 MR imaging with USPIOs could clearly showed various vessels including veins, arteries, and vena cava in mouse model. These USPIOs also can generate heat under magnetic field and result in hyperthermia for tumor therapy (explained later).


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Figure 2. Iron oxide nanoparticles for imaging and therapy of tumor. (a) T1 weighted MR images of 3 nm-sized iron oxide nanoparticles. (b) Relaxivities of various size of iron oxide nanoparticles. T1 weight MR images of MCF cells after incubation with (c) 3 nm, (d) 12 nm iron oxide nanoparticles. High-resolution blood pool T1 weighted MR image using (e) extremely small-sized iron oxide nanoparticles and (f) DOTAREM. Reproduced with permission from Ref 38. Monitoring the localization of stem cells in vivo has gathered increasing amounts of interests in recent years because the vast potential of stem cell therapy is also increasing in treatments of various diseases. MRI is the most popular form of high spatial resolution imaging to track and analyze stem cells during therapy.39, 40 It is because that MRI is noninvasive, non-ionizing, and can provide fine images at three-dimension. To enhance the accuracy of imaging in analysis, people use MRI contrast agents including gadolinium or SPION. When the stem cells are labeled with SPION, their migration in disease site can be monitored by MRI non-invasively. Several studies have shown stem cell imaging in cancer model using SPION and MRI. Kalber et al. showed an MR



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imaging of SPION-labeled mesenchymal stem cells (MSCs) in vivo using OVCAR-3 tumor-bearing mice.41 When the tumor site was heated by alternating magnetic field (AMF), they can observe the increased migration of the labeled MSCs in tumor site in MR images (Figure 3). The results were also confirmed histologically using DiI fluorescence dye and Prussian Blue staining for SPIONs.

Figure 3. Iron oxide nanoparticles labeled mesenchymal stem cells (MSCs) for hyperthermia treatment of tumors. (a) Treatment plan of MRI and AMF heating. (b) T2 weighted MR images of OVCAR-3 tumor post injected with Ferucarbotran-labeled MSCs, at days 14, 18, and 22 (white arrow indicates signal recovery). (c) Heat image of tumor on the flank of a nude mouse. (d) Tissue analysis images from representative tumor stained with cell labeling dye (DiI), Perl’s prussian blue stain, and H&E on day 22. (e) Percentage stained areas of tumors for both Perl’s prussian blue and DiI staining. Reproduced with CC-BY permission from Ref 41. For therapy, Gorden et al. first demonstrated the concept of alternating magnetic field (AMF)-induced hyperthermia using magnetic nanoparticles in vivo at 1979. In an AMF, SPION induce the local high temperature through Neel and Rrownian relaxation with


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the hysteresis.42 Some researchers modified SPIONs with temperature-responsive materials to make drug carriers, which can control the release of drugs in response to the external AMF.43-45 When heat is generated by SPIONs, the structure of the surrounding temperature-responsive materials is changed and becomes relatively loose than original form, resulting in the controlled release of loaded drugs. Recently, photothermal therapy guided by MRI and using SPIONs has gathered great attention due to its convenience and high efficacy. Li et al. developed magnetoplasmonic

nanoassembly

(MPNA)

which

can

sensor

surrounding

microenvironment as an alternative theranostic agent for multimodal imaging-guided photothermal cancer therapy.46 MPNA is composed of Fe3O4 nanocluster (NC) as the core and gold nanoshell. After intravenous injection, MPNAs could stably move in blood circulation and accumulate in tumor tissues by the EPR effect. Under NIR light irradiation, MPNA can act as an efficient light-to-heat conversion agent for photothermal cancer therapy. Furthermore, it can be used as multifunctional contrast agent for trimodal imaging of magnetic resonance imaging (MRI), computed tomography (CT), and photoacoustic tomography (PAT) imaging, simultaneously, which provides precise imaging of the tumor tissue and guidance for the following therapy. High intensity focused ultrasound (HIFU) is also considered to be another promising methodology for hyperthermia, and it can be used in SPION-based drug delivery. This approach delivers focused mechanical sound waves with high frequency through an ultrasound transducer to generate heat in the target tissue locally.47, 48 During the process, the temperature-sensitive liposomes loaded with drug and SPIONs are disrupted to release the loaded molecules in target tissue and generate MR signal. Acoustic energy-



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induced changes in tissue pressure and potential tissue displacement in local area may also increase the diffusion and permeation of the released drugs into deep tissue and deliver them to the target cells efficiently.

1.3 Tungsten oxide nanoparticles Tungsten has high atomic number (Z=74) and higher X-ray absorption property (30.49 cm2 at 125 keV) than that of iodine (3.45 cm2 at 125 keV).49 Tungsten oxide nanoparticles have been used for electrochromic devices and photo-catalyst due to the high surface energy property and surface-to-volume ratio of them.50-52 Recently, tungsten oxide-based nanoparticles, nanosheets, and nanorods have been applied for IGT using X-ray CT imaging and photothermal therapy.53 For the X-ray CT imaging contrast agents based on the tungsten oxide, Jakhmola et. al., developed biodegradable poly-ε-carprolactone (PCL)-coated tungsten oxide nanocrystals (WO3) which can surmount the limitations of the iodinated X-ray CT contrast agents.54 They synthesized WO3 using benzyl alcohol and tungsten hexachlorides (WCl6) by nano-aqueous and low-temperature synthesis method.55 Then, WO3 was coated with various weight ratio of PCL (50/50, 80/20 wt %) in the presence of PEGylated surfactants (Vortex®). These PCL-WO3 showed that various particle sizes in the range from 120 nm to 200 nm and the X-ray attenuation increased linearly by the concentration of WO3 in vitro. In addition, the attenuation property of PCL-WO3, at the concentration of 0.1 M of WO3, was similar to Fenestra VC® which is commercially available iodinated CT contrast agent. Finally, they showed in vivo CT contrast enhancement and prolonged circulation time of PCL-WO3 without toxicities after intravenous injection.


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Figure 4. Tungsten nanoparticles for in vivo CT imaging and PTT. (a) CT images of mice before and after I.T or I.V injection of WS2-PEG. (T : Tumor, L : Liver). (b) Infrared thermal images of 4T1-tumor bearing mice with I.T injection of saline, I.T injection of WS2-PEG (2 mg/kg, irradiated at 0.5h post injection) or I.V injection of WS2-PEG (20 mg/kg, irradiated at 24 h post injection). (c) Tumor growth of 4T1 tumors after treatment with I.T or I.V injection of WS2-PEG. (d) Survival rate of (c). Reproduced with permission from Ref 56. As photothermal theranostic agents, Cheng et. al. developed the tungsten sulfide (WS2) nanosheets (Figure 4).56 After PEGylation of WS2 nanosheets, they showed excellent biocompatibility in vivo and in vitro. These WS2 nanosheets showed broad photo absorption from 700 nm to 1000 nm and concentration-dependent temperature



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increment under 808 nm laser irradiation. Due to their high NIRF absorption property, WS2 nanosheets provided photoacoustic imaging tomography (PAT) of tumor tissue using 4T1 tumor-bearing mice after intratumoral and intravenous injection. Strong photoacoustic contrast in tumor tissue was observed in the CT image after both cases of WS2 nanosheets injections. The hounsfield units (HU) value of tumor tissues dramatically increased about 5.71 and 2.53 fold after intratumoral and intravenous injections, respectively. Moreover, the tumor surface temperature rapidly increased up to 65 oC within 5 min after injection of WS2 nanosheets and irradiation with 808 nm laser. The local heat generation of WS2 nanosheets allows tumor ablation resulting in extending survival rate of mice over 45 days. Liu et. al., also developed PEGylated WO3-x nanoparticles as theranostic probe for NIRF photothermal therapy (PTT) and CT imaging of cancer.57 7 nm of oleic acid (OA)-stabilized WO3-x nanoparticles were used as PTT and CT imaging contrast agent based on the photothermal conversion efficiency and X-ray attenuation property of WO3-x nanoparticles, respectively. PEGylated WO3-x nanoparticles have photo absorption property in the range from 800 to 1100 nm. Based on the photo absorption and photothermal conversion property of WO3-x nanoparticles, they can increase temperature up to 42.5 oC in 500 second after 980 nm laser irradiation. In addition, in vitro cytotoxicity test of WO3-x nanoparticles using 4T1 murine breast cancer cells showed that dosed-dependent enhanced phototoxicity combined with laser irradiation. However, the 4T1 cells showed negligible cell death when they were treated with WO3-x nanoparticles alone. Intratumorally injected WO3-x nanoparticles induced shrunken malignant cells and cytoplasmic acidophilia in the tumor tissues after 980 nm laser irradiation. With laser irradiation, WO3-x nanoparticles-treated tumor tissues were


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ablated during the ten days of observation. The X-ray attenuation property of WO3-x nanoparticles was similar to commercial iodinated CT contrast agent (iobitridol). Finally, in vivo CT value of tumor tissue was significantly enhanced when the WO3-x nanoparticles were directly injected into the tumor tissue. Zhou et. al., reported methoxypoly(ethylene glycol) modified tungsten oxide nanorods (PEGylated WO2.9NRs) with a length of 13.1 ± 3.6 nm and a diameter of 4.4 ± 1.5 nm for simultaneous CT imaging and PTT of tumors in vivo.58 PEGylated WO2.9NRs have strong NIR absorption from 750 nm to 1050 nm based on the surface plasmon resonances.59 In addition, they showed concentration-dependent temperature increase up to 41.7 oC under 980 nm laser irradiation (0.25 W/cm3). PEGylated WO2.9NRs lead to photothermal ablation based on the apoptosis (~71 %) of HeLa cells under 980 nm laser irradiation (0.35 W/cm3). PEGylated WO2.9NRs also showed concentration-dependent increase of CT value (HU), linearly. Intratumorally injected PEGylated WO2.9NRs to HeLa tumor bearing mouse model enhanced X-ray CT signal about 29.77 fold higher than that of before injection. Finally, Intratumorally injected PEGylated WO2.9NRs induced apoptosis in the tumor tissues after 980 nm laser irradiation. With laser irradiation, PEGylated WO2.9NRs-treated tumor tissues were ablated during the 14 days of observation.

2. Image-guided photodynamic therapy Photodynamic therapy (PDT) is one of the strategies for cancer treatment, which uses photosensitizer (PS) and light to generate cytotoxic reactive oxygen species (ROS).60 PDT provides minimal invasiveness and side effect under the light excitation of specific wavelength. The photosensitizers at the excited triplet state react with oxygen molecules



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and generate ROS such as singlet oxygen. These cytotoxic ROS can destroy tumor cells by oxidative stress breaking cellular compartment and blood vessels.60, 61 The major advantage of PDT is high specificity for the treatment of particular lesion using specific wavelengths.62,

63

Many PSs are excited under visible or UV light, which limits

penetration depth due to the absorption and scattering of the lights by biological tissues, resulting in depleting therapeutic effects for the treatment of internal or large tumors.64 The NIR lights in the range of 700 – 1000 nm are ideal for optical imaging and phototherapy based on the minimal light absorption by biological tissues.65 Therefore, PSs with excitation in NIR range are more useful in clinic, particularly for tumor therapy. Recently, people found that several inorganic nanoparticles can act as PSs under laser irradiation for PDT and demonstrated fine results with them in animal studies.

2.1 Quantum dots (QDs) Quantum dots (QDs) are semiconductor nanocrystals which have nano-size in range from 2 to 10 nm with high quantum yields, high photostability and tunable-emission wavelength by size. The optical properties of QDs are based on quantum confinement effect of valence electrons at nanoscale.66 Because QDs have a narrow emission peak and absorption spectra ranging from UV to visible wavelength, different QDs can be excited simultaneously under UV excitation and allow to multicolor fluorescence imaging. In addition, QDs can prolong photoactivation and generation of ROS than single molecule dyes due to the high photostability. Samia et. al., demonstrated that CdSe QD can be used as sensitizer and PDT agent via fluorescence resonance energy transfer (FRET) process and triplet energy transfer (TET) process, respectively.67 Tsay


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et. al. also developed water-stable peptide-coated QDs-PS conjugates for singlet oxygen generation without degenerating the photophysical properties of both QDs and PS. The peptide-coated QDs-PS conjugates could effectively generate singlet oxygen for PDT via FRET process and direct excitation of PS.68 In addition, targeted delivery of QDs in tumor tissues and tumor cells was achieved by using antibodies or other biomolecules.69, 70

However, typical QDs are composed with heavy metal elements such as Cd2+, Pb2+,

etc. The cytotoxicity of the released heavy metal ions and potential hazard of them in biological systems limit further theranostic applications of QDs.71 Frangioni group and Nie group were the representative leading groups in biomedical researches using quantum dots, previously. However, they recently announced that quantum dots are not promising for human usage any more due to the intrinsic toxicity issue so that they would focus on other materials such as gold nanoparticles or small molecules fluorophores.72 In this point of view, biocompatible QDs with non-toxic atoms like InGaN have attracted for in vivo imaging agents.2, 71, 73 Carbon dots (C-dots) is carbon nanomaterials, which have optical properties similar with QDs, such as high photostability, tunable emission, and large two-photon excitation cross-sections. Huang et. al., reported chlorin e6 (Ce6) conjuaged PEG-coated C-dots (C-dots-Ce6) for simultaneous enhanced photo-fluorescence detection (PFD) and PDT (Figure 5).74 Cdots-Ce6 showed excellent fluorescence intensity and tumor-targeting ability for NIR fluorescence imaging guided PDT of tumor. The C-dots-Ce6 has high stability, good water solubility, biocompatibility, and enhanced PFD/PDT efficacy under 671 nm laser irradiation (100 mW/cm2) for 10 min. The in vivo NIRF imaging and tumor growth results indicated that the C-dots-Ce6 is effective for simultaneous enhanced-PFD and PDT of gastric tumor in vivo.



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Figure 5. Quantum dots (QDs) for in vivo imaging and PDT. (a) Schematic illustration of fluorescence resonance energy transfer (FRET) between carbon dot (C-dots) and chlorin e6 (Ce6) under 430 nm irradiation. (b) Real-time in vivo NIRF images after I.V injection of C-dots-Ce6. (c) Ex-vivo NIRF images (from top to bottom; heart, liver, spleen, lung, kidneys, tumor). (d) the average NIRF intensities from tumor area. (e) Tumor growth from MGC803 tumor-bearing mice with various treatments. Reproduced with permission from Ref 74.


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2.2 Upconversion nanoparticles (UCNPs) Lanthanide-doped upconversion nanoparticles (UCNPs) are typically composed with three components including host lattice, sensitizer, and activator. Based on the photon upconversion process of UCNPs, they can absorb multiple NIR photons sequentially and emit a single high energy photon at the shorter wavelength than absorption.75 UCNPs have attractive photochemical properties such as minimal auto-fluorescence, narrow emission bandwidths, highly stable to photo-bleaching, deep tissue penetration, large anti-Stokes shifts, long-time emission and non-blinking.76 Based on these unique photochemical properties, UCNPs are expected to surmount drawbacks related with conventional fluorophores for imaging and have been utilized as promising nanomaterials for biomedical applications.77 UCNPs can be used as good energy donor and delivery carrier for PS. Zhang et. al. fabricated NaYF4:Yb3+,Er3+ nanoparticles coated with a merocyanine-540 (M-540) and doped porous silica, and functionalized them with tumor-targeting antibody for PDT.78 When these UCNPs were excited using an IR (974 nm) source, strong emission was appeared around 537 and 635 nm, resulting in generating 1O2 and other ROS by the resonance energy transfer from UCNPs to M540 photosensitizer. For tumor-targeted PDT, M-540-doped UCNPs were modified with anti-MUC1/episialin antibody to specifically bind MCF-7/AZ cells. After 974 nm irradiation, MCF-7/AZ cells showed shrinkage and could be stained with trypan blue or propidium iodide (PI), indicating induced cell death. In 2011, the first in vivo PDT based on UCNPs was reported by Wang et. al.79 They physically incorporated a chlorine 6 (Ce6), a photosensitizer, into PEGylated amphiphilic polymer (C18PMH-PEG)-coated NaYF4:Yb,Er nanoparticles (UCNP-Ce6). After direct injection of UCNP-Ce6 into the tumor tissue and 980 nm-continuous-wave (CW) laser excitation, outstanding tumor



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suppression was observed in UCNP-Ce6-treated mice group. In addition, UCNPs were gradually cleared out from mouse organs without major organs toxicity to the animals. Lucky et. al. developed titanium dioxide-coated NaYF4:Yb,Er nanoparticles surface modified with PEG (Mal-PEG-TiO2-UCN) for NIR-triggered PDT (Figure 6).80 Under 980 nm NIR irradiation, NaYF4:Yb,Er emitted ultra-violet (UV) to the TiO2 shell. Then, the electron holes in valence band and photo-excited electrons in the conduction band of the TiO2 shell interaction with surrounding O2 and H2O molecules, resulting in generating ROS. When Mal-PEG-TiO2-UCN was directly injected into the tumor tissue and 980 nm-laser was irradiated, upconversion luminescence was observed in tumor tissues and high tumor suppression was observed in Mal-PEG-TiO2-UCN-treated mice group.

Figure 6. Upconversion nanoparticles (UCNPs) for in vivo imaging and PDT. (a) Schematic illustration of generating ROS from Mal-TiO2-UCN under 980 nm


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irradiation. TEM images of (b) TiO2-UCN and (c) Mal-PEG-TiO2-UCN. (d) In vivo upconversion luminescence images from OSCC tumor bearing mice after I.T injection of Mal-PEG-TiO2-UCN (0.1 mg). (e) Upconversion luminescence images of desected tumor tissues 4 h post I.T injection of 0.1 mg of TiO2-UCN (i), (iii) and Mal-PEG-TiO2UCN (ii), (iv). Evan’s blue vital stain images of tumors from 980 nm irradiation alone and (g) Mal-PEG-TiO2-UCN + 980 nm irradiation. Reproduced with permission from Ref 80.

3. Conclusions and future perspectives Over the several decades, various inorganic nanoparticles have been developed for biomedical applications as imaging probes and targeted drug carriers. They are attractive due to their intrinsic physicochemical properties including heat/ROS generation and energy transfer resulting in imaging and therapeutic effect. This review introduced metal (Au), metal oxide (Fe3O4, WO3, WO2.9), QDs, and UCNPs with their special properties for image-guided therapy. The guidance of diagnostic information from CT, MR, or NIRF imaging can provide more precise spatio-temporal information about the exact location, size and shape of tumors. Inorganic nanoparticles also can lead to successful tumor ablation, because they become toxic in response to foreign stimuli such as light, magnetic field, or ultrasound. Nevertheless, limitations still remain for the clinical translation of inorganic nanoparticles. The most important disadvantage of inorganic nanoparticles is the potential toxicity related to long-term safety. It is intrinsic problem of them and hard to overcome by simple method. To overcome the toxicity issue of inorganic nanoparticles, some researchers focused on the secretion of nanoparticles by size and surface modulation. In 2007, Choi et al. demonstrated that nanoparticles can be completely eliminated from body by urine in case that their hydrodynamic diameter is below 5.5 nm and its surface is non-fouling.81 However, to fabricate nanoparticles below 5.5 nm is not easy and most nanoparticles are much



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bigger than that. It means that the inorganic nanoparticles will stay in body for long time. Therefore, biomedical researchers should keep attention to the toxicity data from their inorganic nanoparticles, and if the safety concerns are perfectly clarified, inorganic nanoparticles definitely will be the most useful materials in clinic.

4. Author information Corresponding authors * E-mail: [email protected] * E-mail: [email protected]. Notes The authors declare no competing financial interest.

5. Acknowledgement This work was supported by the GRL project (NRF-2013K1A1A2A02050115), High Medical Technology Project (HI14C2755) of KHIDI, the Intramural Research Program (CATS) of KIST, Basic Science Research Program by the Ministry of Education (2016R1C1B3013951) through the National Research Foundation of Korea, and the financial support of the Catholic Medical Center Research Foundation made in the program year of 2016.

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