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Advances and perspectives in nanoprobes for noninvasive lymph node mapping

Sentinel lymph node (SLN) biopsy is now being well accepted as a practical approach to determine axillary lymph node status. For SLN biopsy, the mapping of SLN is an important procedure. However, blue dyes and radioactive colloids used for clinical SLN mapping are associated with a few issues such as adverse side effects and short retention time in SLN. In recent years, nanoscale probes for noninvasive SLN mapping have received attention due to their adaptable synthesis methods, adjustable optical properties and good biocompatibility. This review thoroughly summarizes the design of the nanoprobes and their properties in SLN mapping. The aim is to understand the status of nanomaterials for SLN mapping, challenging work and potential clinical translation in the future. Keywords:  imaging • nanoparticles • nanotechnology • sentinel lymph node • theranostics

Global cancer statistics data show that breast cancer instead of cervical cancer has been a leading cause of cancer death among women in the world since 2011 [1] . Although breast cancer is the most frequently diagnosed cancer in women, it surprisingly accounts for 23% of the total cancer cases in 2008. Particularly, in developing countries (e.g., People’s Republic of China), the breast cancer incidence has doubled during the past three decades [2,3] . From the clinical point of view, an axillary lymph node dissection (ALND) is regularly conducted in clinical treatment of breast cancer. This surgery mainly involves the removal of entire lymphatic axillary chain, in order to prevent cancer metastasis and learn cancer staging by histology analysis. However, ALND is associated with a lot of issues such as pain, lymphocel, limited arm movement and chronic lymphedema. In 1960, Gould et al. coined the term ‘sentinel lymph node’ (SLN), which is referred to as the first regional lymph node-draining cancer cells migrating from a primary tumor [4,5] . In 1977, Cabanas first proposed SLN biopsy for the treatment of penile carcinoma [6] . Subsequently, technique details of SLN mapping

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for early stage melanoma were described by Morton et al. [7] , which further confirms that SLN biopsy may help physicians evaluate lymphatic node status and choose an effective therapy protocol. To date, SLN biopsy has been utilized widely for clinical diagnosis of metastatic primary cancer cells migrating to regional lymph nodes. This approach gains advantages over conventional ALND in terms of reduced morbidity and short hospital time. Further, SLN biopsy can aid in not only breast cancer surgery [8] , but other cancer-related surgery such as colorectal neoplasia, vulvar cancer, cervical cancer, endometrial cancer and melanomas [9] . Accordingly, SLN biopsy plays a pivotal role in clinical cancer diagnosis. An accurate SLN mapping is a critical prerequisite to accomplish SLN biopsy [10] . Thus far, different imaging methods have been developed for SLN mapping in animal models and patients. MRI is an effective approach due to its advantages including high spatial and temporal resolution, deep detection range as well as acquisition of 3D images. In addition to this approach, in recent years, much effort has been made in

Nanomedicine (Lond.) (2015) 10(6), 1019–1036

Jiejing Li1,2,†, Zhigang Zhuang2,†, Beiqi Jiang2, Peng Zhao1 & Chao Lin*,1 1 Shanghai East Hospital, The Institute for Biomedical Engineering & Nanoscience, Tongji University School of Medicine, Tongji University, Shanghai, 200092, PR China 2 Department of Breast Surgery, Shanghai First Maternity & Infant Hospital, Tongji University School of Medicine, Shanghai, 200040, PR China *Author for correspondence: Tel.: +86 21 65988029 Fax: +86 21 65983706 0 [email protected] † Authors contributed equally

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Review  Li, Zhuang, Jiang, Zhao & Lin optical imaging for SLN mapping because of its fast, inexpensive and noninvasive profiles [11] . Quantitative spectral imaging devices can also offer valuable data related to histological landscape [12] . Nguyen et al. indicated that breast tumor margins could be detected by optical tomography imaging in 20 patients [13] . In addition, optical imaging technology was adopted for lymphatic imaging in patients [14] . Particularly, near-infrared (NIR) fluorescence imaging holds great promise for intraoperative SLN mapping, because NIR fluorescence displays relatively high deep-tissue penetration ability (up to 1 cm) and low living tissue autofluorescence background in NIR region [15] . For accurate SLN mapping, an efficient probe is indispensable. Traditional blue dyes (isosulfan blue [16] and methylene blue [17]) and radioactive colloids (99mTc-colloids  [18]) are two types of imaging probes used in clinical SLN mapping. However, these probes have a few drawbacks: after injection of blue dyes, blue stain will be left at injection point for a long time. Besides, surgical operation has to be run to expose SLN for visualization detection by physicians with clinical experience; SLN radiolocalization procedure is always associated with a low level of radiation exposure; lymphatic drainage might be changed after breast or its regional lymph node basin undergoes radiation exposure; for SLN radiolocalization, a special facility and safe spacious room are required which are however not always available; a long waiting time (e.g., 24 h) is often needed for nodal uptake of large-sized radioactive colloids (100–200 nm); blue dye (e.g., patent blue vital dye [19]) may unfavorably influence intraoperative pulse oximetric recordings during breast cancer surgery. For these reasons, noninvasive probes are highly preferred for high-resolution SLN mapping in clinic. An ideal NLS mapping probe should possess following properties: a long retention time in the SLN to supply an adequate operation time; high signal emitting for high signal intensity; nontoxicity and biocompatibility to patients; a high spatial/temporal resolution to accurately visualize SLN; high photostability for repeated imaging; handy modification; appropriate sizes in the range of 10–50 nm in diameter. As shown in Figure 1, there normally exists a relationship between the size and migration time of nanoparticles [20] . The nanoparticles with 5–10 nm in diameter can move along lymphatic capillaries from SLN to adjacent nodes in the chain. Although the nanoparticles smaller than 5 nm can also move in lymphatic capillaries, they will quickly diffuse from lymphatic nodes, causing an enhanced background and poor identification of SLN. Those with larger size (>300 nm) rarely move from injection site. Although those nanoparticles with the diameter of 20–200 nm are useful for SLN mapping,

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those with the diameter of 10–50 nm are optimal for efficient uptake in SLN. Obviously, it is hard to generate a small molecular probe with all these properties by conventional organic synthesis protocols. Nanotechnology offers new opportunities to design nanoscale and nanostructured probes. A variety of nanoparticles such as quantum dots (QDs), gold nanocages and nanorods, silica-based nanoparticles, polymeric nanogels and superparamagnetic nanoparticles have been exploited as nanoprobes for SLN mapping  [21,22] . Moreover, novel nanoprobes can be well designed with different functionalities for multimodality SLN mapping. However, current progress in these nanoprobes for SLN mapping is not thoroughly reviewed. In this paper, we thus outline these nanoprobes and their physiochemical/optical properties, and discuss their effectiveness in SLN imaging. We point out current research status of the nanoprobes in SLN mapping and their potentials for clinical translation as well as challenging work which should be addressed in the near future. It is anticipated that further development of the nanoprobes will generate great impact on clinical SLN mapping in the future. Clinical background on SLN mapping The lymphatic system belongs to the part of circulatory system and comprises a network of lymphatic vessels. The lymphatic system is a unidirectional and open network which can transport lymph-to-lymph nodes and eventually back into circulatory system. It is well known that lymphatic system has multiple physiological functions, including absorption and delivery of fat and fatty acids, transportation of antigens in lymph to the dendritic cells in lymph nodes for immune activation and draining interstitial fluid from tissues. Lymphatic capillary can also serve as the channels to help cancer cells migrate and reach the first draining lymph node, which is referred to as SLN. If cancer cells are detected in the SLN, this gives a hint that the cells could have already spread to distant lymph nodes and other organs. However, if the SLN is metastatic negative, there is no need for lymph node dissection surgery, minimizing risk on disfigurement and complications such as lymphedema. Thus, SLN biopsy has received much attention in metastatic cancer diagnosis. SLN biopsy has been part of the standard of care for breast cancer and also applicable for the diagnosis of other cancers such as melanoma [23] and gastric cancer metastasis [24] . Traditional imaging approaches such as computed tomography (CT) and MRI have been clinically utilized to detect metastases status in lymph nodes. Normally, these approaches mainly depend on imaging of lymphadenopathy (lymph node enlargement) and

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Advances in nanoprobes for noninvasive lymph node mapping 

subsequently deduce cancer metastasis. However, this diagnosis method often leads to a false-positive result since a few other factors can also cause the enlargement. Moreover, early-stage metastasis in lymph nodes is often not strongly related with the enlargement, thus causing missing undetection [25] . Figure 2A shows typical clinical MRI picture of axillary lymph node in the body with gadolinium (Gd)-based contrast agents, which are however not sensitive enough to identify all the SLN location by MRI. Now, two methods are being clinically used for SLN recognition, in other words, SLN visualization with blue dyes and SLN lymphoscintigraphy with 99mTc-colloids. The major drawback of blue-dye method is the lack of preoperative localization of the SLN. Isosulfan blue dye (LymphazurinTM, Covidien, Inc., MN, USA) was observed to induce allergic reactions in lot of patients. Instead, methylene blue has an equal effectiveness with isosulfan blue but negligible side reactions in SLN detection [26] , thus being clinically used in The People’s Republic of China (Figure 2B & C) . Although lymphoscintigraphy is applicable for preoperative SLN localization, this method only offers a low imaging resolution. In recent years, different NIR dyes have been employed for SLN fluorescence mapping (Figure 2D) . For example, indocyanine green (ICG), approved by the US FDA, has received attention by clinicians due to its application of lymphatic flow and SLN imaging [27] . However, lack of reactive group in ICG makes it difficult for further chemical conjugation with other agents such as homing devices and contrast agents. Current context indicates that new SLN imaging probes are urgently needed to assist pre- and intra-operative SLN localization. Nanoprobes in SLN mapping Superparamagnetic iron oxide nanoparticles

MRI technology is one of the most widely employed clinical diagnosis tools. The development of superparamagnetic iron oxide (SPIO) nanoparticles as contrast agents further accelerates implementation of MRI in clinical lymph node imaging. For example, dextranated SPIO nanopartilces have been employed for clinical intravenous lymphangiography [28,29] . The nanoparticles were also examined for MRI of lymph node in animal models [30] and volunteers [31] . The early studies focus on the utilization of SPIO to determine whether nodes are metastatic. For example, interstitial injection of ferumoxtran-10 (AMI-227; 35 nm; Combidex®; AMAG Pharmaceuticals, MA, USA) was used for node mapping and staging in urinary bladder patients by MR lymphangiography  [32] . However, subsequent studies indicate that SPIO nanoparticles (AMI-227, 20 nm) by subcutaneous administration can migrate from SLN to

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2nd LNs Injection site

Lymphatic vessels 800 nm) and enhanced quantum yield, enabling SLN imaging in a rat model at a dose of 150 pmol. Recently, an appealing self-illuminating bio-QD, CdTe/CdS-QD coated with bioluminescent protein, Renilla reniformis luciferase, were reported [53] . In the presence of coelenterazine, this bio-QD was capable of emitting bioluminescence for SLN imaging in a mouse model without the utility of additional optical sources. Water-soluble QDs can also be prepared by physical encapsulation in either liposomes or micelles. This strategy promotes rapid advancement of QD-based nanocarriers. For example, Chu et al. prepared fluorescent nanolipsomes by incorporating CdTe-QDs into the liposomes of soybeanlecithin [54] . They indicated that the nanoliposome with the diameter of approximately 55 nm was most efficient for SLN imaging lasting 24 h in a mouse model. Recently, Cd-free QDs of group I–III–VI elements were exploited by Bezdetnaya  et al., who constructed CuInS2 /ZnS core/shell QDs (5.5 nm) with emitting wavelength of 650–800 nm  [55] . After encapsulated in phospholipid-PEG

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Therma-Max 55 Figure 3. Illustration of thermosensitive Therma-Max nanoparticles for MRI of sentinel lymph node.

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ZnSe InP InAsxP1-x Core Shell Coatings Figure 4. Quantum dots developed as lymph node mapping probes. Illustration of (A) bi-layer core/shell quantum dots and (B) triple-layer InAsxP1-x /InP/ZnSe quantum dots.

micelles, CuInS2 /ZnS-QDs (∼20 nm) were effective for fluorescence SLN mapping within 8 h in a 4T1-metastatic mouse model after subcutaneous injection at a low dose of 20 pmol [56] . CuInS2 /ZnS-QDs also showed five-times lower cytotoxicity at 100 nM against MRC-5 cells and minor hemolytic activity as compared with CdTeSe/ZnS-QDs, which conversely induced severe hemolysis. However, CuInS2 /ZnS-QDs were eliminated slowly from mouse (3 months) and thus further surface modification was suggested by the authors. Taken together, current researches indicate that versatile double- or multilayer QDs with adjustable NIR emission are useful for SLN imaging. An appropriate coating material in outer layer is crucial to improve the solubility and stability in physiological conditions. However, controversial biosafety of QDs likely impedes their clinical translation in NLS mapping. It is normally accepted that the coating matrixes of QDs can affect systemic toxicity. For example, by intravenous injection into a mouse, PEG-silica-PbS-QDs caused low toxicity in each organs [57] . By contrast, CdSe-QDs without PEG coating induced calcium homeostasis dysregulation in primary rat hippocampal neuron  [58] . Other work also revealed that QDs could stay in mouse body for a long period of time [59] and migrate from pregnant mouse to its fetuses [60] . Obviously, appropriate coating with biocompatible materials such as PEG is favorable to minimize inherent toxicity of QDs. However, it is difficult to make sure no leakage of heavy metals (Cd, Se and Te) from QDs in a long period of time and these metals could lead to a chronic systemic toxicity [61] . Therefore, clinical translation of QDs will be undoubtedly hampered unless biosafety profiles in animals and humans are completely elucidated. Gold nanocages & nanorods

Gold nanocages (AuNCs) are a class of hollow gold nanocubes [62] . They are prepared by qalvanic replace-

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ment reaction of Ag nanocubes and chloroauric acid in water [63] . AuNCs are dispersed well in water by coating with polyvinylpyrrolidone. In the past decade, AuNCs have been studied for a broad range of biomedical applications including biosensing, bioimaging and therapy due to their unique physicochemical properties  [64] : chemically inert under physiological conditions; localized surface plasmon resonance peak of AuNCs can be adjusted from 600 to 1200 nm; their size (20–500 nm) and wall thickness (2–10 nm) can be modified to meet different biomedical applications; hollow interior can be utilized for drug loading and ultrathin porous wall for drug release. Photoacoustic imaging (PAI) modality is an emerging hybrid imaging method which is highly sensitive to endogenous and exogenous optical contrast. The spatial resolution of the imaging is influenced by lightgenerated photoacoustic signals rather than regular light diffusion. As such, compared with conventional optical imaging, PAI is capable of providing a high spatial resolution [65] . Song et al. used AuNCs as a lymph node tracer for PAI in a rat model and captured SLN with enhanced contrast and good spatial resolution [66] . They also found that PAI allowed AuCNs for mapping of the SLN at approximately 33 mm depth. Xia et al. evaluated the transportation of AuNCs of different sizes in the lymphatic system in a rat model [67] . Their research results manifested that, due to its larger optical absorption cross section, 50 nm AuNCs was more efficient as a contrast agent for PAI as compared with 30 nm counterparts. Moreover, surface charge of AuNCs may affect their transportation rate in SLN with the order of neutral > negative > positive [68] . In parallel with AuCNs, gold nanorods (GNRs) are rod-shaped gold nanoparticles. In the past decade, GNRs have been exploited as contrast agents for optical imaging. Particularly, surface-enhanced Raman scattering on GNRs is of interest for bioimaging due to their stability and high imaging contrast [69] . He et al. prepared a nanorod-based probe which is trapped with 3, 3’-diethylthiatricarbocyanine iodide inside and coated with PEG outside [70] . This functionalized GNR probe allows for fast SLN mapping in mice by NIR imaging and distinguishing nanorod-containing tissues from their surrounding tissues through unique surface-enhanced Raman scattering spectrum. Gold-based nanomaterials are inherently inert to biological system, thus displaying good biocompatibility. However, no adequate data on biodistribution of AuCNs is presented owing to analysis technical limitation. It was shown that no clearance of AuCNs in a rat model was detected within 5 h [66] . A prolonged accumulation of AuCNs might augment the potential of systemic toxicity. Further, it is shown that the coating

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Advances in nanoprobes for noninvasive lymph node mapping 

polymers of GNRs will influence their cytocompatibility  [71] . For example, GNRs coated by biocompatible materials such as PEG and poly(acrylic acid) exerted relatively low cytotoxicity in cell lines and stem cells. Overall, thorough biosafety evaluation of AuCNs and GNRs is needed for their clinical translation in the future. The high price of gold nanoparticles as contrast agents is also a huge obstacle to their clinical utilization Silicon-QDs & mesoporous silicon-based nanoparticles

Silicon (Si) is a relatively inert semi-conductive element. Compared with mental elements in group II– VI, Si is considered to be more biocompatible. Thus, silica quantum dots (Si-QDs) have been developed for biomedical imaging and theranostic applications [72] . There are different synthesis routes in the preparation of Si-QDs, including porous Si etching, low-pressure plasma synthesis, thermal processing of silesquioxanes and laser pyrolysis of silica [73] . Normally, Si-QDs have low quantum yield as compared with Cd-based QDs. Erogbogbo  et al. reported that, by laser pyrolysis of silica and acid etching, Si-QDs with high quantum yield (70%) and NIR emitting wavelength could be produced [74] . The authors also prepared water-soluble Si-QDs using phospholipid-based micelles and found that 20 nm of the dots were practical for SLN imaging in a mouse model. Furthermore, the decoration of the dots with homing device, transferrin, allows for tumor-targeted imaging. Biosafety data indicated that Si-QDs had good biocompatibility in mice than Cdbased QDs at a dose of 380 mg/kg and that they were totally eliminated by liver and spleen 2 months after injection without adverse effects on liver and kidney functions. In addition to Si-QDs, Si-based nanoparticles are another type of valuable nanoprobes for single- or multi-modality imaging. Cong et al. prepared Sicoated fluorescent polystyrene nanoparticles (40 nm in diameter) for SLN mapping in a rat model and they found that the nanoparticles were uptaken in macrophages and dendritic cells of SLN [75] . Another work by Qian et al. showed SLN imaging in a mouse model using IR-820 NIR fluorophore-doped Si-nanoparticles (42 nm; Figure 5A) [76] . Winsner et al. developed Cy5encapsulated Si nanoparticles with enhanced quantum yield and photostability as compared with Cy5 [77] . They revealed that PEGylated-Si nanoparticles (30 nm) were applicable for SLN mapping and cell labeling [78,79] . By intravenous injection into a mouse, these nanoparticles were nontoxic at 0.33 μmol per mouse with complete elimination by live after 21 days. The authors also developed 125I-cRGD-PEG-coated Si nanoparticles for dual-modality SLN mapping using

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Review

positron emission tomography (PET) and NIR imaging in spontaneous melanoma miniswine model [80] . Huang et al. prepared a mesoporous silica-nanoprobe having ZW800 dye, contrast agent Gd3+ and 64Cu for triple-modality SLN imaging (NIR/MRI/PET, Figure 5B) in 4T1-tumor rats [81] . In addition to fluorophore-doping approach, Si-nanopartilces can be modified with different dyes for SLN imaging [82] . For example, Chuang et al. generated fluorescent Sinanoparticles (75 nm) by their surface modification of Rhodamine B isothiocyanate (RITC) and examined their possibility for lymph node imaging in living mice [83] . A few studies have demonstrated relatively low cytotoxicity of Si-based nanoparticles in vitro  [84–86] . Although Si-based nanoparticles are metal-free, their potential toxicity might be a big concern. Particularly, long-term toxicity of Si-QDs and mesoporous Si-nanoprobes is not well elucidated, which may be an obstacle to clinical translation. Further studies should focus on systematic biosafety evaluation of Si-nanoparticles, potential toxicity mechanisms as well as preclinical trials. Nanoscale polymeric particles, complexes, liposomes & micelles

Over the past decade, π-π conjugated polymers have been exploited for bioimaging due to their high chromophore density. However, most of the conjugated polymers have relatively low fluorescence quantum yield in NIR region. An exceptional example is cyanosubstituted poly(p-phenylenevinylene) (CN-PPV) derivatives which have relatively high quantum yield. Kim  et al. produced CN-PPV polymer dots (cvPDs) through in situ colloidal Knoevenagel polymerization in Tween 80 (Figure 6A) . A few advantages such as bright emission, colloidal stability and below 50 nm make cvPDs favorable for SLN mapping in a Doped-MSi

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Figure 5. Silicon-based nanoparticles. (A) fluorescence dye-doped silicon-based nanoparticles and (B) three-modality MSi nanoparticles with Cd3+, 64Cu and ZW800 dye. MSi: Mesoporous Si.

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Figure 6. Polymeric nanoparticles, nanogels and nanocomplexes. (A) Cyanovinylene-based polymer dots (cvPDs); (B & C) fluorescent polymeric nanogel based on IRDye 800-conjugated pullulan-cholesterol; (D & E) γ-PGA/ICG nanocomplexes. γ-PGA: poly (γ-glutamic acid); cvPD: Cyano-substituted poly(p-phenylenevinylene) polymer dots; ICG: Indocyanine green; NHS: N-hydroxysuccinimide.

mouse model [87] . However, further studies on the size optimization and toxicity evaluation are needed. NIR-emitting polymer nanogels (NIR-PNGs) and nanoparticles for SLN imaging have received attention in recent years. Noh et al. designed a pullulan-cholesterol polymer nanogels (PNG) formed by spontaneous assembly of hydrophobic cholesterol and hydrophilic pullulan [88] . They also conjugated a NIR dye, IRDye800, on

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the surface of the PNG (Figure 6B & C) and showed that the NIR-PNGs (30 nm in diameter) were more photostable than IRDye800 and applicable for fast fluorescent SLN mapping in small animal (mouse, 2 min) and large animal (pig, 1 min). Because pullulan is nontoxic, the NIR-PNGs displayed no cytotoxicity effects in mouse DC 2.4 dendritic cells and CT-26 adenocarcinoma cells at a tested high concentration of 100 μg/ml. Det-

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Advances in nanoprobes for noninvasive lymph node mapping 

mar et al. designed an IRDye800-labeled PEG as a NIR tracer for SLN mapping in a metastatic mouse model to evaluate lymph node metastases [89] . It was manifested that IRDye800-PEG conjugates with PEG molecular weight of 20 and 40 kDa (8.4 and 11.6 nm, respectively) were applied for SLN mapping in mice. They found that lymphatic dysfunction, induced by metastatic 4T1-tumor, could cause a rerouting of lymphatic flow from metastatic lymph node to other lymph nodes through collateral lymphatic vessels. Recently, Kim et al. prepared squaraine-doped nanoparticles by the coprecipitation of hydrophilic poly(maleic anhydride-alt-octadec1-ene) and hydrophobic fluorescent squaraine [90] . The nanoparticles (26 nm in diameter) emitted fluorescence at 640 nm and performed an efficient SLN mapping 60 min after intradermal injection in a mouse model. Apart from polymeric nanoparticles, fluorescent nanocomplexes can also be designed for SLN mapping. Lim et al. prepared nanocomplexes based on ICG/poly(γ-glutamic acid) (γ-PGA) for SLN imaging (Figure 6D & E)  [91] . The γ-PGA may serve to enhance photostability and retention time of ICG in the SLN. Importantly, the complexes had low cytotoxicity in DC 2.4 cells at a tested 0.1 w/v% concentration. A similar work was also reported on ICG/human serum albumin complexes to improve photostability of ICG A)

Review

for SLN mapping [92] . It can be deduced that different NIR fluorescent probes such as MHI 148 and heptamethine dye (Figure 7A & B) can be integrated to afford polymeric nanosystems suited for SLN imaging [93,94] . Besides NIR-based probes for SLN mapping, Gdlabeled polyamidoamine (PAMAM) dendrimers as magnetic resonance contrast agents were studied for preoperative mapping of lymphatic drainage and lymph node. Kobayashi et al. investigated Gd-labeled PAMAM dendrimers for SLN mapping and they found that sixgeneration PAMAM dendrimer (12 nm) was efficient for MRI of SLN occurred at 24–36 min postinjection  [95] . The authors also labeled Gd and NIR fluorescent probe (Cy5.5) in six-generation PAMAM and showed their potential usage for MRI/NIR dual-modality SLN imaging [96] . Another work on polymeric probes for dual-modality SLN imaging was shown by Li et al., who conjugated poly(L-glutamic acid) with pentetic acid (DTPA)-Gd and NIR813 NIR dye (Figure 7C & D) [97] . This probe had the size of 46 nm and was useful for MRI/NIR imaging of SLN in a mouse model. Polymeric nanomicelles are class of versatile nanocarriers which can encapsulate varying hydrophobic fluorophores and drugs. He et al. fabricated a phospholipid-PEG nanomicelle containing Z-2,3-bis[4(N-4-(diphenylamino)styryl)phenyl]-acrylonitrile B)

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Figure 7. Near-infrared fluorescence dyes used for lymph node imaging probes. (A & B) chemical structure of near-infrared (NIR) fluorescence dyes and (C & D) poly( l-glutamic acid) based bi-modality probe with NIR 813 and DTPA-Gd for NIR and MRI. DTPA: Diethylenetriamine pentaacetic acid; NIR: Near-infrared.

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Review  Li, Zhuang, Jiang, Zhao & Lin (StCN) for SLN and tumor imaging in a mouse model (Figure 8) [98] . The StCN fluorophores encapsulated in the nanomicelle (∼20 nm) have aggregationenhanced fluorescence nature, thus being capable of fluorescence emission at 650 nm for SLN imaging. However, the retention time of the StCN nanomicelle in the SLN was relatively short (60 min) and the cytotoxicity was not reported. Thus, further studies on size optimization and cyto-biocompatibility are needed. Liposomes are another type of nanocarriers for loading of hydrophobic molecules. Chu et al. prepared a chlorophyll-incorporated liposome to improve the solubility of chlorophyll in water and they found that the liposome (∼22 nm) was capable of fluorescence emission at approximately 680 nm for SLN mapping in a mouse model [99] . Moreover, they found the liposome with low cytotoxicity in normal liver and macrophage cell lines, suggesting a high potential for further clinical use. The current studies demonstrate that polymeric systems are flexible to generate versatile probes, which can offer adjustable temporal and spatial resolutions to facilitate imaging of the SLN in experimental animals. Although a large number of polymeric nanoparticles, micelles and liposomes have been developed for biomedical applications, most of these nanosystems reported to date are not ideal for SLN mapping. This is likely attributed to their sizes larger than 50 nm. Although polymer-based nanosystems are regularly biocompatible or low-toxic, incorporation of additional imaging agents into them could significantly alert their biosafety. For example, gradual leaching of free Gd-ion from polymeric carriers caused chronic toxicity [100,101] . Besides, lipid-based

materials could cause acute inflammatory response in vivo  [102] . Therefore, systematic biosafety evaluation is indispensable in future work. Overall, there is a huge space to develop new polymeric nanosystems with controlled size and functionality for SLN mapping. Because of versatile chemical structures and varying compositions, polymeric nanosystems hold an enormous potential to eventually endow an ideal nanoprobe for clinical SLN mapping in the near future. Bioinert inorganic nanoparticles

Bioinert inorganic oxide nanoparticles have been exploited as tracers or contrast agents for SLN mapping over the past few years. Cu2-xSe nanocrystals are alternative contrast agents for use in PAI. Swihart et al. recently reported on Cu 2-xSe nanocrystals for SLN mapping by PAI [103] . These new nanocrystals (7.6 nm) were well dispersed in water by encapsulating into PEG-phospholipid-based nanomicelles. After subcutaneous injection of the nanomicelles (3.2 fmol/g) in a rat model, the SLN at 3.5 mm depth could be detected by PAI within 180 min postinjection. However, the detection limit of Cu2-xSe nanocrystals is 400-folded higher than that of AuNCs (1.7 nM vs 5 pM), suggesting that AuNCs are more efficient for PAI. Besides, Cu 2-xSebased nanomicelles caused cytotoxicity in macrophage cells (IC50 = 22.5 nM). The authors suggested that biocompatibility of Cu2-xSe nanocrystals should be improved by further optimizing their coating matrixes. Another bioinert inorganic material is tantalum oxide (TaOx) that may server as a contrast agent instead of expensive gold [104] . Choi et al. developed bioinert TaOx nanoparticles as a new platform for bioimaging O

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Figure 8. StCN fluorophore-encapsulated nanomicelles for near-infrared imaging of sentinel lymph node. DSPE: Distearoylphosphatidylethanolamine; StCN: Z-2,3-bis[4-(N-4-(diphenylamino)styryl)phenyl]-acrylonitrile.

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Review

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PEG

Figure 9. Bioinert nanoprobes for sentinel lymph node mapping. (A) tantalum oxide and (B) SWNTs. RITC: Rhodamine-B isothiocyanate; SWNT: Single-walled carbon nanotube. (Figure 9A)  [105] .

After surface modification of TaOx with PEG and RITC, colloidally stable TaOx (PEGRITC-TaOx) nanoparticles were prepared with the size of 5–15 nm and good solubility in saline buffer. The nanoparticles were useful for SLN imaging by x-ray CT at 2 h after intradermal injection in a rat model (21 mg). Preliminary biosafety evaluation showed that PEG-RITC-TaOx nanoparticles were mainly accumulated in the liver and spleen 24 h after intravenous injection and caused no adverse effects on liver and kidney functions at a tested dose of 840 mg/kg. Accordingly, TaOx nanoparticles have a potential for preclinical trials. Single-walled carbon tubes (SWNT) based contrast agents have been recently developed for PAI (Figure 9B)  [106,107] . Wang et al. reported on SWNTenhanced PAI in a rat model. At a dose of 37.5 μg, PAI offered a high contrast-to-noise ratio and good resolution to visualize SLN [108] . Koo et al. also modified SWNT with ICG, in order to improve the photoacoustic sensitivity. They found that ICG-SWNT had fourfolded higher optical absorption as compared with SWNT, thus being capable of SLN visualization at a low dose of 0.3 μM  [109] . The in vivo biocompatibility of SWNTs is however a big concern for clinical translation  [110] . Normally, SWNTs were functionalized with biocompatible materials such as PEG, thus displaying good stability and no pronounced systemic toxicity in vivo  [111] . SWNTs are less expensive than AuNCs and thus hold a potential in clinical translation in the future. Fluorescent nanodiamond (FND) is a new member of nanocarbon family [112] . Due to the presence of nitrogen-vacancy centers as built-in fluorophores, FND

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is capable of emitting photoluminescence at 600–800 nm upon irradiation with green yellow light [113] . Hsiao et al. prepared BSA-coated FND (100 nm) and examined its application in SLN mapping at a dose of 40 μg in a mouse model [114] . The FND was detected in the SLN 8 day after intradermal injection and mainly in macrophages. Biodistribution and biocompatibility studies indicated that the FND caused no adverse toxicity effects at a dose of 75 mg/kg in mice, suggesting that the FND is suited as a contrast agent for SLN mapping in vivo. DNA tetrahedron

Noncytotoxic DNA strand can self-assemble to form 3D nanocages with tetrahedra, bipyrimids, octahedra and dodecahedra structures [115] . DNA tetrahedron has been found to be useful for biomedical applications due to handy preparation and efficient cellular uptake in cells [116] . As such, fluorescence labeling of DNA tetrahedron brings out a novel probe for bioimaging such as SLN mapping (Figure 10) . Kim et al. prepared a Cy5-labeled DNA tetrahedron (∼9 nm) by the self-assembly of four types of linear S1, S2, S3 and Cy5-S4 DNA strands, following 95°C heating and 4°C annealing [117] . This fluorescent DNA tetrahedron displayed a longer retention time in the SLN as compared with linear DNA duplex, most likely because the latter had a smaller size of approximately 4 nm and shorter stability time in serum (duplex vs tetrahedron: 3 vs 7 days). DNA tetrahedron is useful SLN imaging agent due to its good biocompatibility. DNA nanosystem is however in its infancy and the evaluation in large animals and human should be done in further studies.

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S1 S2

S3 S4

Self-assembly

Cy5

Figure 10. Self-assembly formation of Cy5-labeled DNA tetrahedron for sentinel lymph node mapping.

Upconversion nanoparticles

Rare earth upconversion nanoparticles (UCNPs) as new luminescent probes for biological labeling, bioimaging and therapy have received attention in recent years  [118] . Differed from traditional fluorophores and QDs, UCNPs emit high-energy light upon excitation at a low-energy light (e.g., NIR light), known as antiStokes shift. Moreover, UCNPs are resistant to photobleaching and have good photostability. These properties make UCNPs valuable for lymphatic imaging. UCNPs normally consist of three components, in other words, inorganic host, sensitizer and activator. NaYF4 crystals are the most efficient host materials for upconversion luminescence (UCL) and thus most used in the preparation of UCNPs. Yb3+ is often added into the host material as a sensitizer to enhance the UCL efficiency due to its relatively large absorption crosssection at 980 nm. Other lanthanide elements such as Er3+, Tm3+ and Ho3+ are doped in UCNPs as activators at a low content ( 1 mm) with the use of lymphatic mapping and sentinel lymph node biopsy. Ann. Surg. Oncol. 8(10), 766–770 (2001).

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Advances in nanoprobes for noninvasive lymph node mapping 

•

A useful review article on the summary of lymphatic imaging methods.

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An important work on superparamagnetic nanopartilces for sentinel lymph node (SLN) detection in clinical trail.

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An important progress in clinical translation of superparamagnetic nanoparticles for SLN detection.

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An important work on silicon quantum dots for SLN mapping.

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62

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An important work on gold nanocages for photoacoustic SLN mapping.

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An important work on near-infrared emitting polymeric nanogels for SLN mapping in big animal.

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