Review Article Current and Future Lymphatic Imaging...

Review ArticleCurrent and Future Lymphatic Imaging Modalities forTumor Staging

Ghulam Murtaza1 Kuo Gao2 Tiegang Liu2 Imran Tariq3 Ashif Sajjad4

Muhammad Rouf Akram5 Meiying Niu2 Guokai Liu6 Zahid Mehmood4 and Guihua Tian6

1 Department of Pharmacy COMSATS Institute of Information Technology Abbottabad 22060 Pakistan2 Beijing University of Chinese Medicine 11 Bei San Huan Dong Lu Chao Yang District Beijing 100029 China3University College of Pharmacy University of the Punjab Lahore 54000 Pakistan4 Institute of Biochemistry University of Balochistan Quetta 87300 Pakistan5 Department of Pharmacy University of Sargodha Sargodha 40100 Pakistan6Beijing University of Chinese Medicine Dongzhimen Hospital Dong Cheng District Beijing 100700 China

Correspondence should be addressed to Ghulam Murtaza gmdogar356gmailcom and Guihua Tian rosetghdzm126com

Received 6 January 2014 Accepted 13 February 2014 Published 16 March 2014

Academic Editor Robert J Lee

Copyright copy 2014 Ghulam Murtaza et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Tumor progression is supported by the lymphatic system which should be scanned efficiently for tumor staging as well as theenhanced therapeutic outcomes Poor resolution and low sensitivity is a limitation of traditional lymphatic imaging modalitiesthus new noninvasive approaches like nanocarriers magnetic resonance imaging positron-emission tomography and quantumdots are advantageous Some newer modalities which are under development and their potential uses will also be discussed in thisreview

1 Introduction

The lymphatic system also recognized as body drainagesystem consists of capillaries vessels and nodes Its functionis to collect the lymph (rich in proteins and waste products)from the extracellular spacewithinmajority of the organs andput into the systemic circulation It is also involved in thefiltration of prospective immunogens from the extracellularspace thus the lymphatic system is considered as an impor-tant part of the immune system [1]

The conventional approaches used for the delivery ofchemotherapeutic agents to the lymphatic system are notsufficiently promising and have resulted in the limited drugdelivery to the lymphatic tissues However the conceptof lymphangiogenesis (development of lymphatics and thegrowth of vessels) has enlightened the new role of lymphaticsin cancer progression as well as its targeted therapy [2]Thereis an active role of lymphatic system in the metastasis of

cancer and distribution of infection Once the tumor cellsinvade the regional lymph nodes they rapidly spread to otherparts of the body However the specific complex anatomy oflymphatics limits the localization of drugs in the lymphaticsystem In new studies specific markers carried by the tumorlymphatics have been revealed These markers can be usedto exclusively target the chemotherapeutic agents to thetumor lymphatic system [3] In the literature different drugdelivery systems like microemulsions and nanoparticles aswell as various complimentary routes of administration likeintramuscular subcutaneous oral and intraperitoneal havebeen narrated [1]

2 Literature Search Methodology

An extensive literature review in English was conductedusing electronic databases like EMBASE (1980ndash2012) andMedline (1966ndash2012) At the start a test search was carried

Hindawi Publishing CorporationBioMed Research InternationalVolume 2014 Article ID 714674 10 pageshttpdxdoiorg1011552014714674

2 BioMed Research International

out using terms such as ldquolymphaticsrdquo and ldquoscanningrdquo simul-taneously Subsequently different terms such as ldquopolymersrdquoldquoquantum dotsrdquo ldquotumor metastasisrdquo ldquolymphatic imagingrdquoand ldquosentinel lymph nodesrdquo were combined with ldquolymphat-icsrdquo and ldquoscanningrdquo for an advanced search The literatureevaluation was done by assessing the bibliographies of theselected publications demonstrating original researches forconstructing an authentic review The studies only in theEnglish languagewere included in this study Any duplicationin data was excluded from the literature

3 Results and Discussion

31 Lymphatic Imaging For precise mapping of the drainageof solid tumors via lymph nodes particularly the sentinellymph node (SLN the initial lymph node or cluster of nodesapproached by metastasized cancer cells originated fromsolid tumor) a noteworthy curiosity has been observed inthe development of imaging approaches There is increasedprobability of presence of the metastasized tumor cells in theSLN comparison to other lymph nodes [19]

For cancer staging and therapy the sentinel node has beenfocused in many clinical studies during the last 12 years [20]In 1992 Morton et al used vital dyes for the mapping ofearly stage melanoma In their studies they assumed that thesentinel node was principally responsible for the spreadingof metastatic ailment [21] Just after 2 years Giuliano et alemployed the dyes in mapping the lymphatic metastasis inbreast cancer [22] In order to elaborate the possible role ofthe sentinel node in auxiliary metastasis in breast carcinomaTurner et al clearly showed the potential involvement of theSLN in the metastasis of breast carcinoma [23]

The investigation of the pathology of the lymph sys-tem has ever been problematic due to the specific com-plex anatomy of lymphatics In comparison to bipedallymphography (previous primarily used approach for thelymphatic imaging) the advance of noninvasive approacheslike lymphoscintigraphy ultrasound computed tomographypositron emission tomography magnetic resonance imagingand optical imaging has facilitated the perfect assessment oflymph nodes [1 23]

32 Lymphoscintigraphic Approach It is a nuclear imag-ing approach involving the use of radionuclide In lym-phoscintigraphy the subcutaneous injections are used formapping the lymphatic drainage The principally used radi-olabelled agents are 99mTc-labeled human serum albumin99mTc-labeled dextran or 99mTc-labeled sulfur colloid thatexhibit the gamma ray emission [24ndash27]

The lymphoscintigraphy has twomain limitations that isfirst poor spatial resolution which does not allow assessmentof the accurate anatomic site of sentinel node and second theshort half-life of 99mTc (six hours) that requires the onsitegeneration potentials [1]

33 Ultrasonographic Approach Ultrasonography (US) actsby preparing a map by creating the sound waves which getin touch with a surface or infiltrate the tissues and create

an echo followed by the conversion of this echo into animage by the transducer [28] Medical ultrasonography iscarried out by four different mechanisms that is A-mode(a single transducer scans a line through the subject withthe echoes plotted on the display as a function of intensity)B-mode (a group of transducers all together scan a planethrough the subject that can be seen as a two-dimensionalimage on display) M-mode (a swift series of B-mode scanswhose images go behind each other in series on the screento assess range of motion) and D-mode (it involves theDoppler effect in the measurement and imaging the poignantconstraints like blood flow) The B- and M-mode medicalultrasonographies are most frequently used for lymphaticimaging with respect to cancer [28]

The diagnosis of lymphatic problems in patients sufferingfrom the cancer of head and neck is promisingly done usingB-mode ultrasonography [29]The transducers having high-resolution as well as elevated frequency ranged between5ndash20MHz produce optimal ultrasonographic results (90accuracy rate) of the head and neck The carcinoma ofthe tongue salivary gland and floor of the mouth can bedetected by ultrasonography at both T1 and T2 staging [30]In patients with post-thyroidectomy ultrasonography is themost promising mapping approach to investigate recurrenceof the thyroid cancer The efficiency of the ultrasonographyfor detection of the metastatic lymph nodes can be aug-mented by coupling it with the detectable stimulated serumthyroglobulin [31] The ultrasonography coupled with fineneedle aspiration (FNA) has played an important role inthe revealing of recurrence of thyroid cancer This approachhas exhibited 80ndash90 sensitivity in diagnosis of periodicdisease in post-thyroidectomy patients with high levels ofthyroglobulin [31] For the detection and staging of pancreaticand rectal carcinomas the development of endoscopic ultra-sound (EUS) has become indispensable The EUS-FNA hasplayed an efficient role for the tissue diagnosis of pancreaticcancer [32] A new meta-analysis has elaborated that EUSis an essential and perfect approach in the assessment ofregional nodes in rectal cancer showing a pooled sensitivityand specificity of 73 and 76 respectively [33]

In the future there is possibility of the utilization ofcontrast enhanced ultrasound which augments the capabilityof ultrasound to assess the SLN as well as occult metastasesthrough the use of a gray-scale sonographic contrast sub-stance [18] In addition sonophoresis is another promisingarea of research where ultrasonography is used to augmentthe drug permeability through skin [4] Another emergingultrasound technology is the photoacoustic imaging whichcouples the ultrasound technology with laser [28]

34 Computer Tomographic Approach X-ray computer tom-ographic (X-ray CT) modality is economical and thus ausually used diagnostic imaging tool The mode of workingof X-ray CT involves the visualization of difference in tissuedensity that gives image distinction by X-ray attenuationbetween electron-dense bone and soft tissues To enhancethe distinction between the cancerous and normal tissue itis advantageous to use the X-ray contrast agents to increase

BioMed Research International 3

the contrast of diseased tissue [34] To know the tumorstaging and lymphatic system CT lymphography coupledwith superb temporal and spatial resolution is generallyemployed Some representative examples of CT distinctionenhancers for the imaging of sentinel node include smallhydrophilic iodinated organic moieties like iopamidol Thecharacteristic features of sentinel lymph node play an impor-tant role in its imaging Suga et al used iopamidol in CT-lymphography (CT-LG) to visualize the breast lymphaticsystem considering that breast tumors disseminate via thelymphatic pathways [35 36] They noticeably envisaged thedirect linkage between the sentinel node and maximum CTattenuation of 269 plusmn 137HU after subcutaneous injection of05 and 1mL of iopamidol to 10 female dogs [36] In thisstudy no considerable side effects were observed In nextstudy in 17 human patients they obtained correct imagingof the sentinel nodes after subcutaneous injection of 2mLiopamidol into peritumoral and periareolar regions [37] In2008 Takahashi et al administered subcutaneous injectionsto the breast cancer patients and accurately detected thesentinel nodes with CT-LG with an identification rate of 96and 92 with dye guided procedures [38] These results werealso supported by Wu et al [39]

Two main limitations of this approach are inadequatecapability to get factual time images and strike of the ionizingradiation on the patientrsquos body However the advancementin CT technology has significantly reduced the ionizingradiation employing some new CT technologies such asautomatic exposure control and sinogram affirmed iterativereconstructionThese developments have helped to diminishthe harmful outcomes and enhance the patient protectionfrom CT radiation by using the adequately ample quantityof radiation to perform a CT examination In this wayradiation contact is reserved as low as reasonably achievable(ALARA) [40] since CT is a digital technology that showsno apparent image quality-related benefit for amplified dosesof CT radiation above a specific intensity Rather it merelydeposits additional radiation into the body of patient [14 4142] The radiation contact to the patient can be considerablyreduced by using the automatic exposure control (AEC)systems in current CT scanners The usage of the AEC savesthe radiation dose to a substantial degree and produces moreuniform image noise in a scan [43] In clinical settings itera-tive reconstruction (IR)modality is another recently exploreddiagnostic approach that produces uniform low noise andhigh contrast images with good accuracy at significantlylesser radiation dose [44 45] Sinogram affirmed iterativereconstruction (SAFIRE) is the earliest raw-data-dependentIR that involves the use of algorithms for the improvement ofimage quality especially on exposure to low radiation doseThe SAFIRE-enabled reconstruction produced abdominalCT images devoid of decrease in diagnostic significanceat 50 decreased radiation dose [46] Later on Kalra etal reported good quality image of chest at reduced doseobtained by the SAFIRE [47] In another study Schabelet al proposed potential radiation dose diminution of thenovel SAFIREmodality in abdominal computed tomographyangiography [48]There are few studies that describe the roleof IRmodality for dose-saving in cardiacCT imaging [49 50]

35 Positron-Emission Tomographic Approach Positron-emission tomographic (PET) approach is a partially invasivescanning approach which is useful for detecting thelymphatic cancer through producing a three-dimensionalimage of metabolic processes in the body MechanisticallyPET involves the detection of gamma ray pairs emittedfrom positron-emitting radionuclide as a tracer Thesegamma rays are introduced into the body coupled with abioactive substance such as F18-fluorodeoxyglucose (FDG)which is a glucose analogue Through glucose transportersbody cells specifically the inflammatory and cancer cellswhich exhibit higher rate of metabolism as compared tothe normal cells take up the FDG Some newer agents like((18)F)-21015840-fluoro-21015840-deoxy-1-beta-D-beta-arabinofuranosyl-5-ethyluracil ((18)F) (11C)-acetoacetate and (11C)-cholineare also being used for advanced detection of metastaticmalignancies of breast and prostate [10 51] PET scanningis also used for the detection of lymphatics malignancies ofgastrointestinal and lung [28] Since local and metastaticdiseases are efficiently detected by PET PET coupled with CT(PET-CT) is promisingly used to detect gastrointestinal suchas esophageal and gastric cancers [52] There is increasinguse of PET-CT scanning in lung and thorax cancers [53]

36 Magnetic Resonance Imaging Magnetic resonance imag-ing (MRI) is one of the most useful noninvasive medicalscanning modality thus it is frequently used in clinical setupfor mapping the tissue structure In comparison to X-rayCT MRI usually gives enhanced distinction between varioussoft tissues MRI works through the mutual interaction ofprotons magnetic field (for the perturbance of protons)and contrast agent (for altering longitudinal or transverserelaxation times) [1]

For improving contrast in MRI scanning of lymphaticpathways various researchers have presented different con-trast agents like iron oxide nanoparticles gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) and den-drimers and liposomes loaded with Gd(III) or iron oxides[54ndash56] Nanoparticles loaded with iron oxide (superparam-agnetic iron oxide nanoparticles SPIONs) are advantageousbecause they are biocompatible less toxic than optical scan-ning substances like quantum dots and readily detectableat low quantities [57 58] For active targeting antibodiespeptides and proteins have been coupled with SPIONs In anexperimental murine model Wunderbaldinger et al devel-oped dextran-SPION and used with contrast enhanced MRIfor the detection of lymph node metastases [59] Helbiechfound ultrasmall superparamagnetic iron oxide (USPIO) par-ticles (lt50 nm diameter) as contrast substance for improvingthe capability of MRI to visualize the lymph nodes Forsystemic lymph node scanning USPIO nanoparticles possesslong serum half-life [60 61]

To detect lymph-node metastasis in 33 patients withprostate cancer through noninvasive elevated resolutionMRI Harisinghani et al employed extremely lymphotropicsuperparamagnetic nanoparticles (26mg of ironkg of bodyweight) as contrast enhancers The obtained MRI scans


showed that the used MRI approach was superior in sensi-tivity (gt90) and diagnostic specificity (gt97) than conven-tional MRI [62] In other studies [63ndash65] the authors usedintravenous infusions of ferumoxtran-10 (26mg of ironkgof body weight) as contrast media and effectively detectedthe lymph node metastases in patients with prostate cancerTo detect the malignant lymph node in thirty patients withpelvic and urological cancers Bellin et al described highsensitivity (100) and selectivity (80) of USPIO showing nosevere side effects [66] In 9 patients with renal cell cancerGuimaraes et al also presented high sensitivity (100) andspecificity (957) of method in lymph node scanning usingferumoxtran-10 [67]

Catzeddu et al proved the axillary lymph node statusas a potential aspect for staging and survivorship in breastcancer [68] In some other studies [63ndash66] the authorsemployed immune and microscopic histological assessmentapproach after surgical dissection of the nodes however thistechnique can be distressing and destructive resulting insevere problems To know noninvasive staging of the axillarylymph nodes in 47 women suffering from new primarybreast cancer Murray et al employed dynamic gadopentetatedimeglumine (Gd) enhanced MRI and found that sensitivityand specificity method were 100 and 56 respectively [69]Michel et al usedMRI coupledwithUSPIO and administered100mL infusion (26mg of ironkg of body weight) in salineto 20 patients for studying the preoperative evaluation ofbreast axillary lymph nodes and observed no severe sideeffects [70] Kimura et al utilized USPIO lymphography forthe differentiation of normal and diseased nodes throughenhancement patterns [71]

37 Optical Imaging Optical imaging modality is advanta-geous over other techniques for lymphatic imaging becauseit is cost effective noninvasive and of greater speed andneeds no exposure of any radiation and improved sensitivityand shows high resolution at shallow depths In literaturedifferent studies are reported for the optical imaging ofthe sentinel lymph node However this review describesthe application of quantum dots (QDs) that are fluorescentsemiconductor nanocrystals having distinctive electrical andoptical features [72] Their size ranges between 1ndash100 nmQDs possess many excellent characteristics for example 10ndash100 times more brightness than many dyes quantum yieldequal to approximately unity in comparison to the organicdyes and fluorescent proteins extensive absorption proper-ties a comparatively lengthy fluorescence life time a thin linewidth in emission spectra continuous emissionmaxima andinsignificant photolightning The absorption and emissionproperties of QDs depend upon its size and compositionwhich is controlled by various synthetic approaches Inaddition the polymeric surface functionalization of QDsassists in targeting and avoiding from macrophage clearance[73 74]whichmakeQDs suitable for biosensing cell labelingnucleic acid assessment and in vivo fluorescence scanning[75 76]

An important application of QDs is to identify the lymphnode pathways The small size of QDs is responsible for its

endocytosis by cells especially by the macrophages in lymphnode localizing the QDs in sentinel lymph node facilitatingfor fluorescence scanning If QDs do not localize in lymphat-ics away from sentinel node and thus may not be promisingfor scanning the distal lymphatic drainage Ballou et al in2004 coated four QDs with various surface coating agentsfor their localization According to results the QDs remainedfluorescent for at least 4months in vivo [77] Formapping theSLN Ballou et al reported the movement of quantum dotswith different charged surface groups injected into murinetumor models [9] The investigators prepared dual coat QDsfirst coating consisted of an amphiphilic polymer containinga large number of surface carboxy groups while polyethyleneglycols containing terminal carboxy methoxy or aminofunctional groups constituted the second layer resulting inthe formation of QDs with no negative and positive chargesThus the produced dual coat QDs contained cores as 800 nmemitting ZnS-CdSe-CdTe and 655 nm emitting ZnS-CdSeThese QDs having different sizes (neutral (226) negative(304) and positive (412)) were then injected to mice withM21 melanoma andMH-15 teratocarcinoma for fluorescencescanning The results exhibited that size and charge did notaffect the migration of QDs in the lymph nodes [9]

Based on the emission spectra Kobayashi injected same-sized five different types of multiple QDs (Cd-Se with emis-sion peaks at 565 605 and 655 nm and CD-Te with emissionpeaks at 705 and 800 nm) to get multispectrum scanning oflymphatic pathways (Table 1) and concurrently observed fivedifferent lymphatic pathways which elaborated this modalitybetter than other approaches like X-ray lymphangiographyand MR-LG or radionuclide scintigraphy by which multiplelymphatic pathways cannot be tested all together [78 79]Bhang et al used hyaluronic acid-QD conjugates (size rangeof 50ndash120 nm) to scan lymphatic drainage using an easyelectrostatic coupling approach [16] Robe et al administered20120583L subcutaneous injection of QDs solution with a core ofCdSeZnS emitting about 655 nm leading to the localizationof QDs in the axillary lymph nodes in healthy nudemiceTheproduced scans showed a maximum concentration (242 ofthe administered dose) assessed after 60min [80]

The QD fluorescence combined with radiotracer scintig-raphy or MRI can be used to better map the deep nodesas compared to single techniques alone Besides manyadvantages of QDs in vivo imaging over other traditionalapproaches the use of QDs also presents some disadvantagessuch as the use of heavymetals in the synthesis of QDs raisingquestions about their safety [1 6 58]

Sharma et al has successfully applied a near-infrared(NIR) fluorophore through intradermal injections for quan-tifying the lymphatic drainage [81] In addition the distinctscanning of the cancer cells and lymphatic pathways is alsopossible through the use of specific fluorescent antibodiesLicha et al used fluorophore-conjugated antibody throughintravenous injection to the marginal lymph nodes [82] Theauthors confirmed the specificity of this antibody throughthe analysis of organ distribution and microautoradiographyand then developed MECA-79 antibody-near-IR cyaninefluorescent dye (with fluorescence and absorption peaks at


Table 1 Various research modalities

Modality Product Type of cancer Application ReferenceUltrasound Sonophoresis Breast cancer Therapeutic Husseini and Pitt 2009 [4]Nanotechnology Nanoconjugate drug Breast cancer Therapeutic Cai et al 2011 [5]Nanotechnology Stealth liposome Breast cancer Therapeutic Qiang et al 2009 [6]MRI Combine with ultrasound Prostate cancer Therapeutic Nune et al 2011 [1]Nanotechnology Nanoconjugate drug Breast cancer Therapeutic Cai et al 2010 [7]Nanotechnology Iron oxide Melanoma Therapeutic Balivada et al 2010 [8]Nanotechnology Quantum dot Melanoma Diagnostic Ballou et al 2007 [9]PET New tracer Breast cancer Diagnostic Authier et al 2008 [10]PET New tracer Prostate cancer Diagnostic Mease 2010 [11]Nanotechnology Quantum dot Melanoma Diagnostic Kobayashi et al 2009 [12]Ultrasound Contrast enhanced Breast cancer Diagnostic Wang andThanou 2010 [13]PET New tracer Melanoma Diagnostic Cody et al 2004 [14]Ultrasound Photoacoustic imaging Melanoma Diagnostic Staley et al 2010 [15]Ultrasound Photoacoustic imaging Breast cancer Diagnostic Bhang et al 2009 [16]Ultrasound Photoacoustic imaging Breast cancer Diagnostic Song et al 2008 [17]Ultrasound Contrast enhanced Breast cancer Diagnostic Weskott 2008 [18]

771 nm and 750 nm resp) conjugate (product 1) Using a con-trol antibody another conjugate having similar features wasdeveloped (product 2) Both conjugates were then admin-istered through intravenous injection into the tail vein atidentical doses in nudemice followed by fluorescent imagingAfter 10min of injection it was observed that product 1attached particularly with the lymph nodes while product 2failed to accumulate in the lymph nodes Then the animalswere sacrificed after 10min of injections lymph nodes werecrushed and the product was analyzed for fluorescence signalintensity The nodes with product 1 exhibited higher fluores-cence intensities those that of product 2 identifying MECA-79 antibody as a suitable scanning investigation of lymphnodes However the MECA-79 antibody did not home incancer cells specifically To tackle this problem Sampath et alformulated dual-labeled monoclonal antibody (trastuzumabwhich is a therapeutic agent against HER2-positive breastcancer) specific for the HER2 (human epidermal growthfactor receptor) homing at the surface of up to 30 of breastcancer and injected intravenously to the nude rabbits [83]It was observed that cancer-specific antibodies can targetcancer cells after delivering through the intravenous route

It has been studied that there is an association betweenthe VEGF (vascular endothelial growth factor)-C expressionlymphatic metastasis and lymphangiogenesis through theinteraction of VEGF-C with two receptors VEGFR-2 andVEGFR-3 [75 76] He et al combined the fluorescencelymphangiography with VEGFR-2 and VEGFR-3 specificantibodies to study the influences of VEGF-C on the devel-opment function and morphology of lymphatic system[84] In this project melanoma cells and fibrosarcoma werefirmly engineered for the overexpression of VEGF-C andtransduced for the expression of green fluorescent protein(GFP) Fluorescence lymphangiography and blue dye wereused to study the lymphatic pathways present in the earof nude mice followed by the implantation of VEGF-C

overexpressing melanoma cells and fibrosarcoma at ear-tipAs compared to mock-transduced control cancer cells thesecells exhibited increased lymphatic metastasis due to theVEGF-C-induced increase of peritumor lymphatic channelsAfter 10 days of tumor implantation the authors showed a200-time increase in tumor cell buildup in the lymphnodes intumors overexpressing VEGF-C in comparison to the controltumors using the fluorescence scanning approach After theblockage of VEGFR-3 there was a reduction in the lymphatichyperplasia as well as the tumor cell delivery to the lymphaticsystem but no effect was observed on the growth of tumorcells implanted in the lymph node while there was successfulinhibition of growth of primary tumors and lymph nodemetastases after the blockade of VEGFR-2 [85 86]

In a previous study the fluorophore-conjugatedlymphatic-specific antibody LYVE-1 has been combined withthe fluorescent-protein-labeled cancer cells for achieving invivo color-coded scanning of cancer cell moving in lymphnodes and lymphatic ducts [87] LYVE-1 a hyaluronicacid receptor is specific for lymphatic endothelial cellsThe lymphatic pathways are likely immunohistochemicallystained using anti-LYVE-1-antibodies In this contextanti-LYVE-1-antibodies-AlexaFluor 488 conjugates weredeveloped for imaging the lymphatic system and theninjected into the inguinal lymph node In contrast theinjection of control FITC-dextran or conjugated IgG tothe inguinal lymph node exhibited greatly reduced durablesignals The fluorescence microscopy was used ex vivo toverify the specificity of anti-LYVE-1-antibody [1 87]

38 New Modalities In addition to the traditional standardand currently used scanning approaches like CT MRI PETand ultrasound methods for mapping of the lymphaticcancer the emerging and newly evolved modalities likephotoacoustic imaging and nanotechnology are replacingthese traditional techniques [28]


39 Photoacoustic Imaging Photoacoustic imaging (PAI) isa hybrid biomedical mapping approach which couples thesonography and laser pulses for the delivery of energy asshort pulses of a nonionizing laser into the biological tissuesA part of this delivered energy converts into heat throughthermoelastic expansion It creates an ultrasonic emission(ie photoacoustic signal) detectible by the ultrasound trans-ducer translating these signals into an image The degree ofthe photoacoustic signal is proportional to the local energyaccumulation and exhibits the optical absorption contrastspecific to physiological system permitting the formation of2D and 3D images [88] Kimura et al injected the indocya-nine green and detected its accumulation in the SLN of ratsusing noninvasive PAI Song et al injected the methyleneblue and detected its accumulation in the SLN of rats usingnoninvasive PAI demonstrating that the SLN with 20mmdepth in 3D mapping and 31mm depth in 2D mapping werepotentially recognized [17] Staley et al successfully used invivo noninvasive PAI to detect the metastasis of melanoma inrat brain to detect the implantation spot and any metastaticphenomenon [15]

310 Nanotechnology Nanotechnology has been used todevelop the engineered multifunctional tools having nano-scale dimensions identical to those of bulky biologicalmolecules in the body for the diagnostic and therapeuticobjectives Nanoparticles have been used as passive as wellas active targeted drug delivery tool to accumulate the drugin tumor cells or at its surface possibly due to the damagedlymphatic pathways and permeable angiogenic ducts in theregion of tumors In recent studies tumor cell recognizingmolecules like fluorophores or peptides are being conjugatedwith the nanoparticles to augment the cell-specific attach-ment aswell as uptakeMany studies on cancer involve the useof quantum dot dendrimers inorganic nanoparticles andstealth liposomes [13]

The biorecognition conjugates like hyaluronan (HA anonsulfated polysaccharide) have played very important rolein the mapping of cancer lymphatics to enhance therapeuticoutcomes Many studies on HA have elaborated HA asa perfect target in biomedical research due to its widedistribution in body especially in connective epithelial andneural tissues aswell as in lymphatics In addition an increasein metastasis and cancer progression has been observed withincrease in HA formation and uptake [89 90] Cai et alcarried out the imaging of lymphatics to study the localizationof hyaluronan nanoconjugates coupled with fluorescent tag(like Texas Red) in sentinel nodes in mouse [7] In can-cer lymphatic scanning quantum dots (QDs also termedas nanocrystals) are also used On receiving energy (likeultraviolet light) from some external sources the flushingof QDs is observed depending upon the number of atomsin QDs Kobayashi et al carried out the lymphatic imagingof melanoma cells labeled with QDs and dendrimers asa macromolecular contrast media after injecting into miceusing in vivo multichannel fluorescence microscopy Due touse of combination of QDs and dendrimer an enhancedrecognition of metastatic cancer cells within the lymphatic

system was observed [12] Ballou et al successfully detectedthe SLN in teratocarcinoma and melanoma using fluorescentmicroscopy after injecting fluorescent-labeled QDs to miceIn addition nanotechnology based QDs are being combinedwith standard scanning approaches like PET of MRI fornoninvasive sentinel lymph node mapping for melanomasand breast cancer [91] To treat some malignancy inorganicnanoparticles have been coupled with magnetic resonancemodality to developmagnetic nanoparticle for targeted deliv-ery to cancer with the help of a magnetic field Balivada et alinjectedmagnetic nanoparticles to mice withmelanoma sub-jecting to an irregular magnetic field employing a magneticresonance scanner showing an excellent antitumor activity aswell as an edge over the existing state of the art modalities[8 28]

Scintigraphy is an excellent modality used to develop andassess the liposome labeled with gamma-emitting radionu-clide through two-dimensional imaging after intravenousinjection of this swiftly excreted radioactive substance tothe patient Lymphoscintigraphy a quite new technologyin nuclear medicine mapping is used to generate the two-dimensional scintigrams of lymphatics after administer-ing a radioactive substance through oral intravenous orpulmonary route [5] After travelling through lymph chan-nels the radioactive substance is taken up by the lymphaticsystem During this course gamma rays generated from theradioactive substance are identified by a PET scanner orgamma camera This tool is generally employed for identi-fying the SLN and diagnosing the disease like lymphedemaand lymphoma [92ndash95] Using scintigraphic mapping Pillipset al successfully employed technetium-99m (99mTc) labeledliposomes for the assessment of viral infection fracturedbones and delivery of liposomal product [96] For syn-chronized distribution and excretion of isosulfan (pyrogen-free blue dye having low molecular weight) Plut et al suc-cessfully prepared a formulation kit containing radioactiveblue liposomal formulation a combination of isosulfan and99mTc labeled liposomes [97] Fujimoto et al employed long-circulating palmityl-D-glucuronide liposomes to formulategadolinium-diethylenetriamine pentaacetic acid labeled lipo-somes which were successfully used to detect lymph nodes(popliteal as well as retroperitoneal) after injecting it subcu-taneously into the hind feet of rabbits The potential accu-mulation of liposomes in the lymphatic system was probablyattributable to the macrophagal entrapment of liposomes[98ndash100]

The main problem of liposomes is their rapid clearanceafter injection In order to develop long-circulating liposomesand their accumulation in diseased tissues and the SLNZavaleta et al employed avidinbiotin-liposome systems ina rodent grafted with ovarian cancer demonstrating signif-icantly enhanced uptake of liposomes by lymphatics aftertwo hours of injection [101] For the determination of tissuebiodistribution of 99mTc-labeled liposomal formulations andthemost useful injection site in rats Medina et al employed amodified avdin99mTc-bluebiotin-liposomal formulation fortargeting the mediastinal node demonstrating that the lymph


node targeting effect did not depend upon the cavity in whichthe formulation was injected [102 103]

4 Conclusion

An important role of lymphatic system has been observedin tumor progression For cancer staging new noninvasivelymphatic imaging modalities are being investigated elim-inating the patient risks Although all lymphatic imagingapproaches involve the application of general tissue imagingmethods imaging agents developed exclusively for the lym-phatic system will increase the efficiency of existing toolsDuring the last twenty years there is an extensive researchin lymphatic imaging particularly cancer lymphatic imagingIn this context new approaches include ultrasonographyPET imagingMRI nanoparticle detection fluorescence andphotoacoustic imaging The novel modalities in combina-tion with comparatively traditional approaches have guidedtowards new developments in diagnostic as well as therapeu-tic scanning of lymphatic involvement in tumor progressionThese scanning modalities can be useful in the targeted drugdelivery and thus improved therapeutic outcomes

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Authorsrsquo Contribution

Ghulam Murtaza Kuo Gao and Tiegang Liu contributedequally to this paper

References

[1] S K Nune P Gunda B K Majeti P K Thallapally and ML Forrest ldquoAdvances in lymphatic imaging and drug deliveryrdquoAdvanced Drug Delivery Reviews vol 63 no 10-11 pp 876ndash8852011

[2] GOliver andMDetmar ldquoThe rediscovery of the lymphatic sys-tem old and new insights into the development and biologicalfunction of the lymphatic vasculaturerdquoGenes and Developmentvol 16 no 7 pp 773ndash783 2002

[3] P Laakkonen K Porkka J A Hoffman and E Ruoslahti ldquoAtumor-homing peptide with a targeting specificity related tolymphatic vesselsrdquo Nature Medicine vol 8 no 7 pp 751ndash7552002

[4] G A Husseini and W G Pitt ldquoUltrasonic-activated micellardrug delivery for cancer treatmentrdquo Journal of PharmaceuticalSciences vol 98 no 3 pp 795ndash811 2009

[5] S Cai Q Yang T R Bagby and M L Forrest ldquoLymphaticdrug delivery using engineered liposomes and solid lipidnanoparticlesrdquoAdvanced Drug Delivery Reviews vol 63 no 10-11 pp 901ndash908 2011

[6] T Qiang S H U Xiao-gang L U Xiao-ming et al ldquoEffects ofmagnetic gemcitabine stealth nano-liposomes on the character-istics of Breast Cancer cell line MCF-7rdquo Yaoxue Xuebao vol 44no 2 pp 181ndash187 2009

[7] S Cai S Thati T R Bagby et al ldquoLocalized doxorubicinchemotherapy with a biopolymeric nanocarrier improves sur-vival and reduces toxicity in xenografts of human BreastCancerrdquo Journal of Controlled Release vol 146 no 2 pp 212ndash218 2010

[8] S Balivada R S Rachakatla H Wang et al ldquoAC magnetichyperthermia of melanoma mediated by iron(0)iron oxidecoreshellmagnetic nanoparticles amouse studyrdquoBMCCancervol 10 article 119 2010

[9] B Ballou L A Ernst S Andreko et al ldquoSentinel lymphnode imaging using quantum dots in mouse tumor modelsrdquoBioconjugate Chemistry vol 18 no 2 pp 389ndash396 2007

[10] S Authier S Tremblay V Dumulon et al ldquo[11C] acetoacetateutilization by breast and prostate tumors a PET and biodistri-bution study in micerdquo Molecular Imaging and Biology vol 10no 4 pp 217ndash223 2008

[11] R C Mease ldquoRadionuclide based imaging of prostate cancerrdquoCurrent Topics in Medicinal Chemistry vol 10 no 16 pp 1600ndash1616 2010

[12] HKobayashiMOgawaNKosaka P L Choyke andYUranoldquoMulticolor imaging of lymphatic function with two nanoma-terials quantum dot-labeled cancer cells and dendrimer-basedoptical agentsrdquo Nanomedicine vol 4 no 4 pp 411ndash419 2009

[13] M Wang and M Thanou ldquoTargeting nanoparticles to cancerrdquoPharmacological Research vol 62 no 2 pp 90ndash99 2010

[14] D D Cody D M Moxley K T Krugh J C OrsquoDaniel L KWagner and F Eftekhari ldquoStrategies for formulating appropri-ate MDCT techniques when imaging the chest abdomen andpelvis in pediatric patientsrdquoAmerican Journal of Roentgenologyvol 182 no 4 pp 849ndash859 2004

[15] J Staley P Grogan A K Samadi H Cui M S Cohen andX Yanga ldquoGrowth of melanoma brain tumors monitored byphotoacousticmicroscopyrdquo Journal of Biomedical Optics vol 15no 4 Article ID 040510 2010

[16] S H Bhang NWon T-J Lee et al ldquoHyaluronic acid-quantumdot conjugates for in vivo lymphatic vessel imagingrdquoACSNanovol 3 no 6 pp 1389ndash1398 2009

[17] K H Song E W Stein J A Margenthaler and L V WangldquoNoninvasive photoacoustic identification of sentinel lymphnodes containingmethylene blue in vivo in a ratmodelrdquo Journalof Biomedical Optics vol 13 no 5 Article ID 054033 2008

[18] H P Weskott ldquoEmerging roles for contrast-enhanced ultra-soundrdquoClinical Hemorheology andMicrocirculation vol 40 no1 pp 51ndash71 2008

[19] S H Choi W K Moon J H Hong et al ldquoLymph nodemetastasis ultrasmall superparamagnetic iron oxide-enhancedMR imaging versus PETCT in a rabbit modelrdquo Radiology vol242 no 1 pp 137ndash143 2007

[20] R M Cabanas ldquoAn approach for the treatment of penilecarcinomardquo Cancer vol 39 no 2 pp 456ndash466 1977

[21] D L Morton D-R Wen J H Wong et al ldquoTechnical detailsof intraoperative lymphatic mapping for early stagemelanomardquoArchives of Surgery vol 127 no 4 pp 392ndash399 1992

[22] A E Giuliano D M Kirgan J M Guenther and D L MortonldquoLymphatic mapping and sentinel lymphadenectomy for BreastCancerrdquo Annals of Surgery vol 220 no 3 pp 391ndash401 1994

[23] R R Turner D W Ollila D L Krasne and A E GiulianoldquoHistopathologic validation of the sentinel lymph node hypoth-esis for breast carcinomardquo Annals of Surgery vol 226 no 3 pp271ndash278 1997


[24] E Henze H R Schelbert and J D Collins ldquoLymphoscintigra-phy with Tc-99m-labeled dextranrdquo Journal of Nuclear Medicinevol 23 no 10 pp 923ndash929 1982

[25] E Ohtake K Matsui Y Kobayashi et al ldquoClinical-evaluationof dynamic lymphoscintigraphy with Tc-99m human-serumalbuminrdquo Journal ofNuclearMedicine vol 24 pp P41ndashP41 1983

[26] S D Nathanson P Anaya M Avery F W Hetzel T Sarantouand S Havstad ldquoSentinel lymph node metastasis in experi-mental melanoma relationships among primary tumor sizelymphatic vessel diameter and 99mTc-labeled human serumalbumin clearancerdquo Annals of Surgical Oncology vol 4 no 2pp 161ndash168 1997

[27] I M C Van Der Ploeg R A Valdes Olmos B B R Kroonand O E Nieweg ldquoThe hybrid SPECTCT as an additionallymphatic mapping tool in patients with Breast CancerrdquoWorldJournal of Surgery vol 32 no 9 pp 1930ndash1934 2008

[28] S M Cohen B G Fishinghawk and M S Cohen ldquoTransla-tional imaging of lymphatics in cancerrdquoAdvancedDrugDeliveryReviews vol 63 no 10-11 pp 956ndash962 2011

[29] S Kotecha P Bhatia and P G J Rout ldquoDiagnostic ultrasoundin the head and neck regionrdquo Dental update vol 35 no 8 pp529ndash534 2008

[30] D Koischwitz and N Gritzmann ldquoUltrasound of the neckrdquoRadiologic Clinics of NorthAmerica vol 38 no 5 pp 1029ndash10452000

[31] J E Langer and S J Mandel ldquoSonographic imaging of cervicallymph nodes in patients with thyroid Cancerrdquo NeuroimagingClinics of North America vol 18 no 3 pp 479ndash489 2008

[32] L V Hernandez and M S Bhutani ldquoEmerging applications ofendoscopic ultrasound in gastrointestinal cancersrdquo Gastroin-testinal Cancer Research vol 2 pp 198ndash202 2008

[33] S R Puli J B K Reddy M L Bechtold A Choudhary M RAntillon andWR Brugge ldquoAccuracy of endoscopic ultrasoundto diagnose nodal invasion by rectal cancers a meta-analysisand systematic reviewrdquo Annals of Surgical Oncology vol 16 no5 pp 1255ndash1265 2009

[34] S-B Yu and A DWatson ldquoMetal-based X-ray contrast mediardquoChemical Reviews vol 99 no 9 pp 2353ndash2377 1999

[35] K Suga N Ogasawara M Okada and N Matsunaga ldquoInter-stitial CT lymphography-guided localization of breast sentinellymph node preliminary resultsrdquo Surgery vol 133 no 2 pp170ndash179 2003

[36] K Suga N Ogasawara Y Yuan M Okada N Matsunagaand A Tangoku ldquoVisualization of breast lymphatic pathwayswith an indirect computed tomography lymphography using anonionicmonometric contrastmedium iopamidol preliminaryresultsrdquo Investigative Radiology vol 38 no 2 pp 73ndash84 2003

[37] K Suga Y Yuan M Okada et al ldquoBreast sentinel lymph nodemapping at CT lymphography with iopamidol preliminaryexperiencerdquo Radiology vol 230 no 2 pp 543ndash552 2004

[38] M Takahashi M Sasa C Hirose et al ldquoClinical efficacy andproblems with CT lymphography in identifying the sentinelnode in Breast CancerrdquoWorld Journal of Surgical Oncology vol6 article 57 2008

[39] H Wu X Xu H Ying et al ldquoPreliminary study of indirectCT lymphography-guided sentinel lymph node biopsy in atongue VX2 carcinoma modelrdquo International Journal of Oraland Maxillofacial Surgery vol 38 no 12 pp 1268ndash1272 2009

[40] J R Haaga ldquoRadiation dose management weighing risk versusbenefitrdquo American Journal of Roentgenology vol 177 no 2 pp289ndash291 2001

[41] E L Nickoloff and P O Alderson ldquoRadiation exposuresto patients from CT reality public perception and policyrdquoAmerican Journal of Roentgenology vol 177 no 2 pp 285ndash2872001

[42] O W Linton and F A Mettler Jr ldquoNational conference ondose reduction in CT with an emphasis on pediatric patientsrdquoAmerican Journal of Roentgenology vol 181 no 2 pp 321ndash3292003

[43] M Sderberg and M Gunnarsson ldquoAutomatic exposure controlin computed tomographymdashan evaluation of systems fromdifferent manufacturersrdquo Acta Radiologica vol 51 no 6 pp625ndash634 2010

[44] C H McCollough ldquoScience to practice automatic exposurecontrol in CT are we done yetrdquo Radiology vol 237 no 3 pp755ndash756 2005

[45] H J Brisse L Madec G Gaboriaud et al ldquoAutomatic exposurecontrol in multichannel CT with tube current modulation toachieve a constant level of image noise experimental assess-ment on pediatric phantomsrdquoMedical Physics vol 34 no 7 pp3018ndash3033 2007

[46] M K Kalra MWoisetschlager N Dahlstrom et al ldquoRadiationdose reduction with Sinogram Affirmed Iterative Reconstruc-tion technique for abdominal computed tomographyrdquo Journalof Computer Assisted Tomography vol 36 no 3 pp 339ndash3462012

[47] MK KalraMWoisetschlager NDahlstrom et al ldquoSinogram-affirmed iterative reconstruction of low-dose chest CT effecton image quality and radiation doserdquo American Journal ofRoentgenology vol 201 no 2 pp W235ndashW244 2013

[48] C Schabel M Fenchel B Schmidt et al ldquoClinical evaluationand potential radiation dose reduction of the novel sinogram-affirmed iterative reconstruction technique (SAFIRE) inabdominal computed tomography angiographyrdquo Acad Radiolvol 20 no 2 pp 165ndash172 2013

[49] J Leipsic B G Heilbron and C Hague ldquoIterative reconstruc-tion for coronary CT angiography finding its wayrdquo Interna-tional Journal of Cardiovascular Imaging vol 38 no 3 pp 613ndash620 2012

[50] M Renker L L Geyer A W Krazinski J R Silverman UEbersberger and U J Schoepf ldquoIterative image reconstructiona realistic dose-saving method in cardiac CT imagingrdquo ExpertReview of Cardiovascular Therapy vol 11 no 4 pp 403ndash4092013

[51] P Brader K Kelly S Gang et al ldquoImaging of lymphnode micrometastases using an oncolytic herpes virus and[18F]FEAUPETrdquoPLoSONE vol 4 no 3 Article ID e4789 2009

[52] I Buchmann T M Ganten and U Haberkorn ldquo[18F]-FDG-PET in the diagnostics of gastrointestinal tumorsrdquoZeitschrift furGastroenterologie vol 46 no 4 pp 367ndash375 2008

[53] J J Erasmus H A Macapinlac and S G Swisher ldquoPositronemission tomography imaging in nonsmall-cell lung cancerrdquoCancer vol 110 no 10 pp 2155ndash2168 2007

[54] H B Na I C Song and T Hyeon ldquoInorganic nanoparticlesfor MRI contrast agentsrdquoAdvancedMaterials vol 21 no 21 pp2133ndash2148 2009

[55] K M Hasebroock and N J Serkova ldquoToxicity of MRI andCT contrast agentsrdquo Expert Opinion on Drug Metabolism andToxicology vol 5 no 4 pp 403ndash416 2009

[56] E A Waters and S A Wickline ldquoContrast agents for MRIrdquoBasic Research in Cardiology vol 103 no 2 pp 114ndash121 2008


[57] MMahmoudi A SimchiM Imani A SMilani andP StroeveldquoOptimal design and characterization of superparamagneticiron oxide nanoparticles coated with polyvinyl alcohol fortargeted delivery and imagingrdquo Journal of Physical Chemistry Bvol 112 no 46 pp 14470ndash14481 2008

[58] N Lewinski V Colvin and R Drezek ldquoCytotoxicity ofnanopartidesrdquo Small vol 4 no 1 pp 26ndash49 2008

[59] P Wunderbaldinger L Josephson C Bremer A Moore and RWeissleder ldquoDetection of lymph node metastases by contrast-enhanced MRI in an experimental modelrdquoMagnetic Resonancein Medicine vol 47 no 2 pp 292ndash297 2002

[60] T H Helbiech ldquoUltra-small iron particle-enhanced magneticresonance imaging of axillary lymph nodes in Breast CancerrdquoBreast Cancer Research vol 10 article P3 2008

[61] T R McCauley M D Rifkin and C A Ledet ldquoPelvic lymphnode visualization withMR imaging using local administrationof ultra-small superparamagnetic iron oxide contrastrdquo Journalof Magnetic Resonance Imaging vol 15 no 4 pp 492ndash497 2002

[62] M G Harisinghani J Barentsz P F Hahn et al ldquoNoninvasivedetection of clinically occult lymph-nodemetastases in prostatecancerrdquo The New England Journal of Medicine vol 348 no 25pp 2491ndash2499 2003

[63] R W Ross A L Zietman W Xie et al ldquoLymphotropicnanoparticle-enhanced magnetic resonance imaging (LNMRI)identifies occult lymph node metastases in prostate cancerpatients prior to salvage radiation therapyrdquoClinical Imaging vol33 no 4 pp 301ndash305 2009

[64] R A M Heesakkers G J Jager A M Hovels et al ldquoProstatecancer detection of lymph node metastases outside the routinesurgical area with ferumoxtran-10-enhanced MR imagingrdquoRadiology vol 251 no 2 pp 408ndash414 2009

[65] M G Harisinghani J O Barentsz P F Hahn et al ldquoMRlymphangiography for detection of minimal nodal disease inpatients with prostate cancerrdquo Academic Radiology vol 9 no2 pp S312ndashS313 2002

[66] M-F Bellin C Roy K Kinkel et al ldquoLymph node metastasessafety and effectiveness of MR imaging with ultrasmall super-paramagnetic iron oxide particlesmdashinitial clinical experiencerdquoRadiology vol 207 no 3 pp 799ndash808 1998

[67] A R Guimaraes S Tabatabei D Dahl W S McDougal RWeissleder andM G Harisinghani ldquoPilot study evaluating useof lymphotrophic nanoparticle-enhanced magnetic resonanceimaging for assessing lymph nodes in renal cell CancerrdquoUrology vol 71 no 4 pp 708ndash712 2008

[68] T Catzeddu G Bertelli L Del Mastro and M VenturinildquoSentinel lymph node biopsy in Breast Cancer patients themedical oncology perspectiverdquo Journal of Surgical Oncologyvol 85 no 3 pp 129ndash132 2004

[69] A DMurray R T Staff TW Redpath et al ldquoDynamic contrastenhanced MRI of the axilla in women with Breast Cancercomparison with pathology of excised nodesrdquo British Journal ofRadiology vol 75 no 891 pp 220ndash228 2002

[70] S C A Michel T M Keller J M Frohlich et al ldquoPreoperativeBreast Cancer staging MR imaging of the axilla with ultrasmallsuperparamagnetic iron oxide enhancementrdquo Radiology vol225 no 2 pp 527ndash536 2002

[71] K Kimura N Tanigawa M Matsuki et al ldquoHigh-resolutionMR lymphography using ultrasmall superparamagnetic ironoxide (USPIO) in the evaluation of axillary lymph nodes inpatients with early stage Breast Cancer preliminary resultsrdquoBreast Cancer vol 17 no 4 pp 241ndash246 2010

[72] H Zhang D Yee and C Wang ldquoQuantum dots for cancerdiagnosis and therapy biological and clinical perspectivesrdquoNanomedicine vol 3 no 1 pp 83ndash91 2008

[73] A L Dif F Boulmedais M Pinot et al ldquoSmall and stablepeptidic PEGylated quantum dots to target polyhistidine-tagged proteins with controlled stoichiometryrdquo Journal of theAmerican Chemical Society vol 131 no 41 pp 14738ndash147462009

[74] M L Schipper G Iyer A L Koh et al ldquoParticle size surfacecoating and PEGylation influence the biodistribution of quan-tum dots in living micerdquo Small vol 5 no 1 pp 126ndash134 2009

[75] X Gao Y Cui R M Levenson L W K Chung and S NieldquoIn vivo cancer targeting and imaging with semiconductorquantum dotsrdquo Nature Biotechnology vol 22 no 8 pp 969ndash976 2004

[76] RD KMisra ldquoQuantumdots for tumor-targeted drug deliveryand cell imagingrdquoNanomedicine vol 3 no 3 pp 271ndash274 2008

[77] B Ballou B C Lagerholm L A Ernst M P Bruchez and AS Waggoner ldquoNoninvasive imaging of quantum dots in micerdquoBioconjugate Chemistry vol 15 no 1 pp 79ndash86 2004

[78] H Kobayashi Y Hama Y Koyama et al ldquoSimultaneousmulticolor imaging of five different lymphatic basins usingquantum dotsrdquo Nano Letters vol 7 no 6 pp 1711ndash1716 2007

[79] Y Hama Y Koyama Y Urano P L Choyke and H KobayashildquoSimultaneous two-color spectral fluorescence lymphangiogra-phy with near infrared quantum dots to map two lymphaticflows from the breast and the upper extremityrdquo Breast CancerResearch and Treatment vol 103 no 1 pp 23ndash28 2007

[80] A Robe E Pic H-P Lassalle L Bezdetnaya F Guillemin andF Marchal ldquoQuantum dots in axillary lymph node mappingbiodistribution study in healthy micerdquo BMC Cancer vol 8article 111 2008

[81] R Sharma W Wang J C Rasmussen et al ldquoQuantitativeimaging of lymph functionrdquo American Journal of Physiologyvol 292 no 6 pp H3109ndashH3118 2007

[82] K Licha N Debus S Emig-Vollmer et al ldquoOptical molecularimaging of lymph nodes using a targeted vascular contrastagentrdquo Journal of Biomedical Optics vol 10 no 4 Article ID041205 2005

[83] L SampathWWang and EM Sevick-Muraca ldquoNear infraredfluorescent optical imaging for nodal stagingrdquo Journal ofBiomedical Optics vol 13 no 4 Article ID 041312 2008

[84] Y He I Rajantie M Ilmonen et al ldquoPreexisting lymphaticendothelium but not endothelial progenitor cells are essentialfor tumor lymphangiogenesis and lymphatic metastasisrdquo Can-cer Research vol 64 no 11 pp 3737ndash3740 2004

[85] A Kadambi C M Carreira C-O Yun et al ldquoVascularendothelial growth factor (VEGF)-C differentially affects tumorvascular function and leukocyte recruitment role of VEGF-receptor 2 and host VEGF-Ardquo Cancer Research vol 61 no 6pp 2404ndash2408 2001

[86] T Hoshida N Isaka J Hagendoorn et al ldquoImaging steps oflymphatic metastasis reveals that vascular endothelial growthfactor-C increases metastasis by increasing delivery of can-cer cells to lymph nodes therapeutic implicationsrdquo CancerResearch vol 66 no 16 pp 8065ndash8075 2006

[87] M McElroy K Hayashi B Garmy-Susini et al ldquoFluorescentLYVE-1 antibody to image dynamically lymphatic trafficking ofCancer cells in vivordquo Journal of Surgical Research vol 151 no 1pp 68ndash73 2009


[88] H F Zhang K Maslov G Stoica and L V Wang ldquoFunctionalphotoacoustic microscopy for high-resolution and noninvasivein vivo imagingrdquo Nature Biotechnology vol 24 no 7 pp 848ndash851 2006

[89] T Ahrens V Assmann C Fieber et al ldquoCD44 is the principalmediator of hyaluronic-acid-induced melanoma cell prolifera-tionrdquo Journal of Investigative Dermatology vol 116 no 1 pp 93ndash101 2001

[90] A Dietrich E Tanczos W Vanscheidt E Schopf and J CSimon ldquoHigh CD44 surface expression on primary tumours ofmalignant melanoma correlates with increased metastatic riskand reduced survivalrdquo European Journal of Cancer Part A vol33 no 6 pp 926ndash930 1997


[92] S P Bagaria M B Faries and D L Morton ldquoSentinel nodebiopsy in melanoma technical considerations of the procedureas performed at the John Wayne Cancer Instituterdquo Journal ofSurgical Oncology vol 101 no 8 pp 669ndash676 2010

[93] T YamamotoM Tamura THamauzu et al ldquoIntestinal Behcetrsquosdisease associated with non-Hodgkinrsquos lymphomardquo Journal ofGastroenterology vol 32 pp 241ndash245 1997

[94] J A Luongo L R Scalcione D S Katz and E Y YungldquoProgression of clinically stable lymphedemaon lymphoscintig-raphyrdquo Clinical Nuclear Medicine vol 34 no 9 pp 585ndash5882009

[95] P Bourgeois J-L Dargent D Larsimont et al ldquoLymphoscintig-raphy in angiomyomatous hamartomas and primary lower limblymphedemardquo Clinical Nuclear Medicine vol 34 no 7 pp 405ndash409 2009

[96] EM Plut G H HinkleW Guo and R J Lee ldquoKit formulationfor the preparation of radioactive blue liposomes for sentinelnode lymphoscintigraphyrdquo Journal of Pharmaceutical Sciencesvol 91 no 7 pp 1724ndash1732 2002

[97] Y Fujimoto Y Okuhata S Tyngi Y Namba andNOku ldquoMag-netic resonance lymphography of profundus lymph nodes withliposomal gadolinium-diethylenetriamine pentaacetic acidrdquoBiological and Pharmaceutical Bulletin vol 23 no 1 pp 97ndash1002000

[98] B Misselwitz and A Sachse ldquoInterstitial MR lymphographyusingGd-carrying liposomesrdquoActa Radiologica vol 38 no 412pp 51ndash55 1997

[99] V S Trubetskoy J ACannillo AMilshteinG LWolf andV PTorchilin ldquoControlled delivery of Gd-containing liposomes tolymph nodes Surface modification may enhance MRI contrastpropertiesrdquoMagnetic Resonance Imaging vol 13 no 1 pp 31ndash371995

[100] C L ZavaletaW T Phillips A Soundararajan and B A GoinsldquoUse of avidinbiotin-liposome system for enhanced peritonealdrug delivery in an ovarian cancermodelrdquo International Journalof Pharmaceutics vol 337 no 1-2 pp 316ndash328 2007

[101] L A Medina S M Calixto R Klipper W T Phillips and BGoins ldquoAvidinbiotin-liposome system injected in the pleuralspace for drug delivery to mediastinal lymph nodesrdquo Journal ofPharmaceutical Sciences vol 93 no 10 pp 2595ndash2608 2004

[102] L A Medina S M Calixto R Klipper Y Li W T Phillips andB Goins ldquoMediastinal node and diaphragmatic targeting afterintracavitary injection of avidin99mTc-blue-biotin-liposomesystemrdquo Journal of Pharmaceutical Sciences vol 95 no 1 pp207ndash224 2006

[103] R H Muller K Mader and S Gohla ldquoSolid lipid nanoparticles(SLN) for controlled drug deliverymdasha review of the state of theartrdquo European Journal of Pharmaceutics and Biopharmaceuticsvol 50 no 1 pp 161ndash177 2000

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


out using terms such as ldquolymphaticsrdquo and ldquoscanningrdquo simul-taneously Subsequently different terms such as ldquopolymersrdquoldquoquantum dotsrdquo ldquotumor metastasisrdquo ldquolymphatic imagingrdquoand ldquosentinel lymph nodesrdquo were combined with ldquolymphat-icsrdquo and ldquoscanningrdquo for an advanced search The literatureevaluation was done by assessing the bibliographies of theselected publications demonstrating original researches forconstructing an authentic review The studies only in theEnglish languagewere included in this study Any duplicationin data was excluded from the literature

3 Results and Discussion

31 Lymphatic Imaging For precise mapping of the drainageof solid tumors via lymph nodes particularly the sentinellymph node (SLN the initial lymph node or cluster of nodesapproached by metastasized cancer cells originated fromsolid tumor) a noteworthy curiosity has been observed inthe development of imaging approaches There is increasedprobability of presence of the metastasized tumor cells in theSLN comparison to other lymph nodes [19]

For cancer staging and therapy the sentinel node has beenfocused in many clinical studies during the last 12 years [20]In 1992 Morton et al used vital dyes for the mapping ofearly stage melanoma In their studies they assumed that thesentinel node was principally responsible for the spreadingof metastatic ailment [21] Just after 2 years Giuliano et alemployed the dyes in mapping the lymphatic metastasis inbreast cancer [22] In order to elaborate the possible role ofthe sentinel node in auxiliary metastasis in breast carcinomaTurner et al clearly showed the potential involvement of theSLN in the metastasis of breast carcinoma [23]

The investigation of the pathology of the lymph sys-tem has ever been problematic due to the specific com-plex anatomy of lymphatics In comparison to bipedallymphography (previous primarily used approach for thelymphatic imaging) the advance of noninvasive approacheslike lymphoscintigraphy ultrasound computed tomographypositron emission tomography magnetic resonance imagingand optical imaging has facilitated the perfect assessment oflymph nodes [1 23]

32 Lymphoscintigraphic Approach It is a nuclear imag-ing approach involving the use of radionuclide In lym-phoscintigraphy the subcutaneous injections are used formapping the lymphatic drainage The principally used radi-olabelled agents are 99mTc-labeled human serum albumin99mTc-labeled dextran or 99mTc-labeled sulfur colloid thatexhibit the gamma ray emission [24ndash27]

The lymphoscintigraphy has twomain limitations that isfirst poor spatial resolution which does not allow assessmentof the accurate anatomic site of sentinel node and second theshort half-life of 99mTc (six hours) that requires the onsitegeneration potentials [1]

33 Ultrasonographic Approach Ultrasonography (US) actsby preparing a map by creating the sound waves which getin touch with a surface or infiltrate the tissues and create

an echo followed by the conversion of this echo into animage by the transducer [28] Medical ultrasonography iscarried out by four different mechanisms that is A-mode(a single transducer scans a line through the subject withthe echoes plotted on the display as a function of intensity)B-mode (a group of transducers all together scan a planethrough the subject that can be seen as a two-dimensionalimage on display) M-mode (a swift series of B-mode scanswhose images go behind each other in series on the screento assess range of motion) and D-mode (it involves theDoppler effect in the measurement and imaging the poignantconstraints like blood flow) The B- and M-mode medicalultrasonographies are most frequently used for lymphaticimaging with respect to cancer [28]

The diagnosis of lymphatic problems in patients sufferingfrom the cancer of head and neck is promisingly done usingB-mode ultrasonography [29]The transducers having high-resolution as well as elevated frequency ranged between5ndash20MHz produce optimal ultrasonographic results (90accuracy rate) of the head and neck The carcinoma ofthe tongue salivary gland and floor of the mouth can bedetected by ultrasonography at both T1 and T2 staging [30]In patients with post-thyroidectomy ultrasonography is themost promising mapping approach to investigate recurrenceof the thyroid cancer The efficiency of the ultrasonographyfor detection of the metastatic lymph nodes can be aug-mented by coupling it with the detectable stimulated serumthyroglobulin [31] The ultrasonography coupled with fineneedle aspiration (FNA) has played an important role inthe revealing of recurrence of thyroid cancer This approachhas exhibited 80ndash90 sensitivity in diagnosis of periodicdisease in post-thyroidectomy patients with high levels ofthyroglobulin [31] For the detection and staging of pancreaticand rectal carcinomas the development of endoscopic ultra-sound (EUS) has become indispensable The EUS-FNA hasplayed an efficient role for the tissue diagnosis of pancreaticcancer [32] A new meta-analysis has elaborated that EUSis an essential and perfect approach in the assessment ofregional nodes in rectal cancer showing a pooled sensitivityand specificity of 73 and 76 respectively [33]

In the future there is possibility of the utilization ofcontrast enhanced ultrasound which augments the capabilityof ultrasound to assess the SLN as well as occult metastasesthrough the use of a gray-scale sonographic contrast sub-stance [18] In addition sonophoresis is another promisingarea of research where ultrasonography is used to augmentthe drug permeability through skin [4] Another emergingultrasound technology is the photoacoustic imaging whichcouples the ultrasound technology with laser [28]

34 Computer Tomographic Approach X-ray computer tom-ographic (X-ray CT) modality is economical and thus ausually used diagnostic imaging tool The mode of workingof X-ray CT involves the visualization of difference in tissuedensity that gives image distinction by X-ray attenuationbetween electron-dense bone and soft tissues To enhancethe distinction between the cancerous and normal tissue itis advantageous to use the X-ray contrast agents to increase


































4 Conclusion






References
















































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















































4 Conclusion






References
















































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of








































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Review Article Current and Future Lymphatic Imaging...

Documents

Transcript of Review Article Current and Future Lymphatic Imaging...