Imaging methods to evaluate tumor microenvironment factors affecting nanoparticle drug delivery and antitumor response

Abstract

Standard small molecule and nanoparticulate chemotherapies are used for cancer treatment; however, their effectiveness remains highly variable. One reason for this variable response is hypothesized to be due to nonspecific drug distribution and heterogeneity of the tumor microenvironment, which affect tumor delivery of the agents. Nanoparticle drugs have many theoretical advantages, but due to variability in tumor microenvironment (TME) factors, the overall drug delivery to tumors and associated antitumor response are low. The nanotechnology field would greatly benefit from a thorough analysis of the TME factors that create these physiological barriers to tumor delivery and treatment in preclinical models and in patients. Thus, there is a need to develop methods that can be used to reveal the content of the TME, determine how these TME factors affect drug delivery, and modulate TME factors to increase the tumor delivery and efficacy of nanoparticles. In this review, we will discuss TME factors involved in drug delivery, and how biomedical imaging tools can be used to evaluate tumor barriers and predict drug delivery to tumors and antitumor response.

Keywords

Tumor microenvironment / imaging / drug delivery / nanoparticles

References

[1] Baghban R,Jahanban-Esfahlan R.Tumor microenvironment complexity and therapeutic implications at a glance..Cell Commun Signal2020;18:59 PMCID:PMC7140346

[2] Król M,Majchrzak K,Motyl T.Why chemotherapy can fail?.Pol J Vet Sci2010;13:399-406

[3] Boyce MW,Hummon AB.Assessing chemotherapeutic effectiveness using a paper-based tumor model..Analyst2017;142:2819-27 PMCID:PMC5557652

[4] Jain RK,Fukumura D.Measuring vascular permeability in mice..Cold Spring Harb Protoc2013;2013:444-6

[5] Madden AJ,Sandison K.Evaluation of the efficiency of tumor and tissue delivery of carrier-mediated agents (CMA) and small molecule (SM) agents in mice using a novel pharmacokinetic (PK) metric: relative distribution index over time (RDI-OT)..J Nanoparticle Res2014;16:2662 PMCID:PMC4574509

[6] Truong AS.Oxygen as a chemoattractant: Confirming cellular hypoxia in paper-based invasion assays..Analyst2016;141:3874-82

[7] Diop-Frimpong B,Krane S,Jain RK.Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors..Proc Natl Acad Sci U S A2011;108:2909-14 PMCID:PMC3041115

[8] Geevarghese A.Pericyte-endothelial crosstalk: Implications and opportunities for advanced cellular therapies..Transl Res2014;163:296-306 PMCID:PMC3976718

[9] Stylianopoulos T.Combining two strategies to improve perfusion and drug delivery in solid tumors..Proc Natl Acad Sci U S A2013;110:18632-7 PMCID:PMC3832007

[10] Zhang B,Pang Z.Modulating the tumor microenvironment to enhance tumor nanomedicine delivery..Front Pharmacol2017;8:952 PMCID:PMC5744178

[11] Cairns R,Denko N.Overcoming physiologic barriers to cancer treatment by molecularly targeting the tumor microenvironment..Mol Cancer Res2006;4:61-70

[12] Jing X,Shao C.Role of hypoxia in cancer therapy by regulating the tumor microenvironment..Mol Cancer2019;18:157 PMCID:PMC6844052

[13] Lucas AT,Deal AM.Profiling the relationship between tumor-associated macrophages and pharmacokinetics of liposomal agents in preclinical murine models..Nanomedicine2017;13:471-82

[14] Zamboni WC,Strychor S.Tumor disposition of pegylated liposomal CKD-602 and the reticuloendothelial system in preclinical tumor models..J Liposome Res2011;21:70-80

[15] Zhao CY,Yang Z.Nanotechnology for cancer therapy based on chemotherapy..Molecules2018;23:826 PMCID:PMC6017446

[16] Jain RK.Normalizing tumor microenvironment to treat cancer: Bench to bedside to biomarkers..J Clin Oncol2013;31:2205-18 PMCID:PMC3731977

[17] Henke E,Ergün S.Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy..Front Mol Biosci2020;6:160 PMCID:PMC7025524

[18] Gonzalez-Avila G,Mendoza-Posada DA,Garcia-Hernandez AA.Matrix metalloproteinases participation in the metastatic process and their diagnostic and therapeutic applications in cancer..Crit Rev Oncol Hematol2019;137:57-83

[19] Nwabo KAH,Simo RT.Mesenchymal stromal cells’ role in tumor microenvironment: involvement of signaling pathways..Cancer Biol Med2017;14:129-41 PMCID:PMC5444925

[20] Liu T,Li D,Zhang Y.Cancer-associated fibroblasts build and secure the tumor microenvironment..Front Cell Dev Biol2019;7:60 PMCID:PMC6492564

[21] Yoshida GJ.Regulation of heterogeneous cancer-associated fibroblasts: The molecular pathology of activated signaling pathways..J Exp Clin Cancer Res2020;39:112 PMCID:PMC7296768

[22] Yin Y,Hu Y.The immune-microenvironment confers chemoresistance of colorectal cancer through macrophage-derived IL6..Clin Cancer Res2017;23:7375-87

[23] Castells M,Delord JP.Implication of tumor microenvironment in chemoresistance: Tumor-associated stromal cells protect tumor cells from cell death..Int J Mol Sci2012;13:9545-71 PMCID:PMC3431813

[24] Senthebane DA,Thomford NE.The role of tumor microenvironment in chemoresistance: To survive, keep your enemies closer..Int J Mol Sci2017;18:1586 PMCID:PMC5536073

[25] Bagnoli M,Nicoletti R.Choline metabolism alteration: A focus on ovarian cancer..Front Oncol2016;6:153 PMCID:PMC4916225

[26] Saggar JK,Tan Q.The tumor microenvironment and strategies to improve drug distribution..Front Oncol2013;3:154 PMCID:PMC3677151

[27] Zhong S,Chen Z,Luo JL.Targeting tumor microenvironment by small-molecule inhibitors..Transl Oncol2020;13:57-69 PMCID:PMC6909103

[28] Correia AL.The tumor microenvironment is a dominant force in multidrug resistance..Drug Resist Updat2012;15:39-49 PMCID:PMC3658318

[29] Graham K.Overcoming tumor hypoxia as a barrier to radiotherapy, chemotherapy and immunotherapy in cancer treatment..Int J Nanomedicine2018;13:6049-58 PMCID:PMC6177375

[30] Tian Y,Teng Z.pH-dependent transmembrane activity of peptide-functionalized gold nanostars for computed tomography/photoacoustic imaging and photothermal therapy..ACS Appl Mater Interfaces2017;9:2114-22

[31] Liu H,Xu Y.Lactobionic acid-modified dendrimer-entrapped gold nanoparticles for targeted computed tomography imaging of human hepatocellular carcinoma..ACS Appl Mater Interfaces2014;6:6944-53

[32] Kim Y,Oh E.Chip-based protease assay using fluorescence resonance energy transfer between quantum dots and fluorophores..Biochip J2007;1:228-33

[33] Ramanathan RK,Raghunand N.Correlation between ferumoxytol uptake in tumor lesions by MRI and response to nanoliposomal irinotecan in patients with advanced solid tumors: A pilot study..Clin Cancer Res2017;23:363848

[34] Cuccarese MF,Pfirschke C.Heterogeneity of macrophage infiltration and therapeutic response in lung carcinoma revealed by 3D organ imaging..Nat Commun2017;8:14293 PMCID:PMC5309815

[35] Banerjee SR,Horhota A.¹¹¹In- and IRDye800CW-Labeled PLA-PEG Nanoparticle for Imaging Prostate-Specific Membrane Antigen-Expressing Tissues..Biomacromolecules2017;18:201-9 PMCID:PMC5516902

[36] Lee H,Siegel BA.64Cu-MM-302 positron emission tomography quantifies variability of enhanced permeability and retention of nanoparticles in relation to treatment response in patients with metastatic breast cancer..Clin Cancer Res2017;23:4190-202 PMCID:PMC6790129

[37] Rojas JD,Czernuszewicz TJ.Ultrasound Measurement of Vascular Density to Evaluate Response to Anti-Angiogenic Therapy in Renal Cell Carcinoma..IEEE Trans Biomed Eng2019;66:873-80 PMCID:PMC6691901

[38] Du J,Nie S.Stimuli-responsive nanoparticles for targeting the tumor microenvironment..J Control Release2015;219:205-14 PMCID:PMC4656063

[39] Yin C,Liu C.Organic Semiconducting Polymer Nanoparticles for Photoacoustic Labeling and Tracking of Stem Cells in the Second Near-Infrared Window..ACS Nano2018;12:12201-11

[40] Wu X,Zhou L.In vivo tracking of superparamagnetic iron oxide nanoparticle-labeled mesenchymal stem cell tropism to malignant gliomas using magnetic resonance imaging: Laboratory investigation..J Neurosurg2008;108:320-9

[41] Karageorgis A,Sancey L.An MRI-based classification scheme to predict passive access of 5 to 50-nm large nanoparticles to tumors..Sci Rep2016;6:21417 PMCID:PMC4759815

[42] Miller MA,Pfirschke C.Predicting therapeutic nanomedicine efficacy using a companion magnetic resonance imaging nanoparticle..Sci Transl Med2015;7:314ra183 PMCID:PMC5462466

[43] Hauge A,Gaustad JV,Andersen LMK.Diffusion-weighted MRI-derived ADC values reflect collagen I content in PDX models of uterine cervical cancer..Oncotarget2017;8:105682-91 PMCID:PMC5739670

[44] Wahyudi H,Li Y,Yu SM.Targeting collagen for diagnostic imaging and therapeutic delivery..J Control Release2016;240:323-31 PMCID:PMC4936964

[45] Shiftan L,Cohen M.Magnetic resonance imaging visualization of hyaluronidase in ovarian carcinoma..Cancer Res2005;65:10316-23

[46] Guo C,Cai H.Gadolinium-Labeled Biodegradable Dendron-Hyaluronic Acid Hybrid and Its Subsequent Application as a Safe and Efficient Magnetic Resonance Imaging Contrast Agent..ACS Appl Mater Interfaces2017;9:23508-19

[47] Granot D,Kalchenko V,Kunz-Schughart LA.In vivo imaging of the systemic recruitment of fibroblasts to the angiogenic rim of ovarian carcinoma tumors..Cancer Res2007;67:9180-9 PMCID:PMC4087196

[48] Granot D,Neeman M.Labeling fibroblasts with biotin-BSA-GdDTPA-FAM for tracking of tumor-associated stroma by fluorescence and MR imaging..Magn Reson Med2005;54:789-97 PMCID:PMC1382177

[49] Reagan MR.Concise review: Mesenchymal stem cell tumor-homing: Detection methods in disease model systems..Stem Cells2011;29:920-7 PMCID:PMC4581846

[50] Loebinger MR,Turmaine M.Magnetic resonance imaging of mesenchymal stem cells homing to pulmonary metastases using biocompatible magnetic nanoparticles..Cancer Res2009;69:8862-7 PMCID:PMC2833408

[51] Belmar-Lopez C,Oberg D.Tissue-derived mesenchymal stromal cells used as vehicles for anti-tumor therapy exert different in vivo effects on migration capacity and tumor growth..BMC Med2013;11:139 PMCID:PMC3670996

[52] Lewis CE.Distinct role of macrophages in different tumor microenvironments..Cancer Res2006;66:605-12

[53] Zolnik BS,Sadrieh N.Minireview: Nanoparticles and the immune system..Endocrinology2010;2:458-65 PMCID:PMC2817614

[54] Song G,Yoshino K.Factors affecting the pharmacokinetics and pharmacodynamics of liposomal drugs..J Liposome Res2012;Sep22:177-92

[55] Daldrup-Link HE,Ruffell B.MRI of tumor-associated macrophages with clinically applicable iron oxide nanoparticles..Clin Cancer Res2011;17:5695-704 PMCID:PMC3166957

[56] Reichel D,Perez JM.Biological effects of nanoparticles on macrophage polarization in the tumor microenvironment..Nanotheranostics2019;3:66-88 PMCID:PMC6328304

[57] Harisinghani MG,Hahn PF.Noninvasive detection of clinically occult lymph-node metastases in prostate cancer..N Engl J Med2003;348:2491-9

[58] Harisinghani MG.Sensitive, noninvasive detection of lymph node metastases..PLoS Med2004;1:e66 PMCID:PMC539052

[59] Heesakkers RAM,Hövels AM.Prostate cancer: Detection of lymph node metastases outside the routine surgical area with ferumoxtran-10-enhanced MR imaging..Radiology2009;251:408-14

[60] Lepage M,Melchior M.Noninvasive detection of matrix metalloproteinase activity in vivo using a novel magnetic resonance imaging contrast agent with a solubility switch..Mol Imaging2007;6:393-403

[61] Lebel R,Therriault H.Novel solubility-switchable MRI agent allows the noninvasive detection of matrix metalloproteinase-2 activity in vivo in a mouse model..Magn Reson Med2008;60:1056-65

[62] Lebel R.A comprehensive review on controls in molecular imaging: Lessons from MMP-2 imaging..Contrast Media Mol Imaging2014;9:187-210

[63] Ansari C,Hong SH.Development of novel tumor-targeted theranostic nanoparticles activated by membrane-type matrix metalloproteinases for combined cancer magnetic resonance imaging and therapy..Small2014;10:566-75417 PMCID:PMC3946335

[64] Matsuo K,Mizusawa K.Specific detection and imaging of enzyme activity by signal-amplifiable self-assembling 19Fa MRI probes..Chemistry2013;19:12875-83

[65] Crisp JL,Glasgow HL,Whitney MA.Dual targeting of integrin αvβ3 and matrix metalloproteinase-2 for optical imaging of tumors and chemotherapeutic delivery..Mol Cancer Ther2014;13:1514-25 PMCID:PMC4051287

[66] Kawamura W,Kokuryo D.Density-tunable conjugation of cyclic RGD ligands with polyion complex vesicles for the neovascular imaging of orthotopic glioblastomas..Sci Technol Adv Mater2015;16:035004 PMCID:PMC5099842

[67] Yan C,Feng J.Anti-αvβ3 antibody guided three-step pretargeting approach using magnetoliposomes for molecular magnetic resonance imaging of breast cancer angiogenesis..Int J Nanomedicine2013;8:245-55 PMCID:PMC3548418

[68] Barrett T,Bernardo M.MRI of tumor angiogenesis..J Magn Reson Imaging2007;26:235-49

[69] Willats L.The 39 steps: Evading error and deciphering the secrets for accurate dynamic susceptibility contrast MRI..NMR Biomed2013;26:913-31

[70] Morita N,Chawla S,Melhem ER.Dynamic susceptibility contrast perfusion weighted imaging in grading of nonenhancing astrocytomas..J Magn Reson Imaging2010;32:803-8

[71] Chakhoyan A,Chen J.Probabilistic independent component analysis of dynamic susceptibility contrast perfusion MRI in metastatic brain tumors..Cancer Imaging2019;19:14 PMCID:PMC6423873

[72] Barnes SL,Loveless ME.Practical Dynamic Contrast Enhanced MRI in Small Animal Models of Cancer: Data Acquisition, Data Analysis, and Interpretation..Pharmaceutics2012;4:442-78 PMCID:PMC3480221

[73] Brix G,Kiessling F.Tracer kinetic modelling of tumour angiogenesis based on dynamic contrast-enhanced CT and MRI measurements..Eur J Nucl Med Mol Imaging.2010;37 Suppl 1:S30-51

[74] Koh TS,Koh DM.Fundamentals of tracer kinetics for dynamic contrast-enhanced MRI..J Magn Reson Imaging2011;34:1262-76

[75] O’Connor JPB,Waterton JC,Parker GJM.Imaging intratumor heterogeneity: Role in therapy response, resistance, and clinical outcome..Clin Cancer Res2015;21:249-57 PMCID:PMC4688961

[76] Koh DM,Orton MR.Intravoxel incoherent motion in body diffusion-weighted MRI: Reality and challenges..AJR Am J Roentgenol2011;Jun196:1351-61

[77] Pathak AP,Bhujwalla ZM.MR Molecular Imaging of Tumor Vasculature and Vascular Targets..Adv Genet2010;69:1-30 PMCID:PMC4921063

[78] Abramovitch R,Smouha E,Neeman M.In vivo prediction of vascular susceptibility to vascular endothelial growth factor withdrawal: Magnetic resonance imaging of C6 rat glioma in nude mice..Cancer Res1999;59:5012-6

[79] Carmeliet P,Herber JM.Role of HIF-1α in hypoxiamediated apoptosis, cell proliferation and tumour angiogenesis..Nature1998;394:485-90

[80] O’Connor JPB,Jamin Y.Oxygen-enhanced MRI accurately identifies, quantifies, and maps tumor hypoxia in preclinical cancer models..Cancer Res2016;76:787-95 PMCID:PMC4757751

[81] O’Connor JPB,Waterton JC.Imaging tumour hypoxia with oxygen-enhanced MRI and BOLD MRI..Br J Radiol2019;92:20180642 PMCID:PMC6540855

[82] White DA,Li L.Developing oxygen-enhanced magnetic resonance imaging as a prognostic biomarker of radiation response..Cancer Lett2016;380:69-77 PMCID:PMC4967391

[83] Zhao D,Hahn EW.Comparison of1H blood oxygen level-dependent (BOLD) and 19F MRI to investigate tumor oxygenation..Magn Reson Med2009;62:357-64 PMCID:PMC4426862

[84] Lin YC,Hong JH.Noninvasive monitoring of microvascular changes with partial irradiation using dynamic contrast-enhanced and blood oxygen level-dependent magnetic resonance imaging..Int J Radiat Oncol Biol Phys2013;85:1367-74

[85] Stoyanova R,Sandler K.Mapping tumor hypoxia in vivo using pattern recognition of dynamic contrast-enhanced MRI data..Transl Oncol2012;5:437-47 PMCID:PMC3546126

[86] Egeland TAM,Gaustad JV,Rofstad EK.Dynamic contrast-enhanced-MRI of tumor hypoxia..Magn Reson Med2012;67:519-30

[87] Gulliksrud K,Mathiesen B.Differentiation between hypoxic and non-hypoxic experimental tumors by dynamic contrast-enhanced magnetic resonance imaging..Radiother Oncol2011;98:360-4

[88] Wojtkowiak JW,Schramm KJ.Drug resistance and cellular adaptation to tumor acidic pH microenvironment..Mol Pharm2011;8:2032-8 PMCID:PMC3230683

[89] Yamamoto K,Seki T.Molecular Imaging of the Tumor Microenvironment Reveals the Relationship between Tumor Oxygenation, Glucose Uptake, and Glycolysis in Pancreatic Ductal Adenocarcinoma..Cancer Res2020;80:2087-93 PMCID:PMC7272278

[90] Rodrigues TB,Kennedy BWC,Kettunen MI.Magnetic resonance imaging of tumor glycolysis using hyperpolarized 13 C-labeled glucose..Nat Med2014;20:93-7 PMCID:PMC3886895

[91] Gallagher FA,Day SE.Magnetic resonance imaging of pH in vivo using hyperpolarized 13C-labelled bicarbonate..Nature2008;453:940-3

[92] Scholz DJ,Köllisch U.Quantified pH imaging with hyperpolarized 13C-bicarbonate..Magn Reson Med2015;73:2274-82

[93] Ward KM.Determination of pH using water protons and Chemical Exchange Dependent Saturation Transfer (CEST)..Magn Reson Med2000;Nov44:799-802

[94] Huang Y,Ali MM.Lanthanide ion (III) complexes of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraaminophosphonate for dual biosensing of pH with chemical exchange saturation transfer (CEST) and biosensor imaging of redundant deviation in shifts (BIRDS)..Contrast Media Mol Imaging2015;10:51-8 PMCID:PMC4222994

[95] Chen LQ,Jones KM,Howison CM.Evaluations of tumor acidosis within in vivo tumor models using parametric maps generated with AcidoCEST MRI..Mol Imaging Biol2015;17:488-96 PMCID:PMC4880367

[96] Longo DL,Consolino L,Uggeri F.A general MRI-CEST ratiometric approach for pH imaging: Demonstration of in vivo pH mapping with iobitridol..J Am Chem Soc2014;136:14333-6 PMCID:PMC4210149

[97] Aime S,Terreno E.Novel pH-reporter MRI contrast agents..Angew Chem Int Ed Engl2002;41:4334-6

[98] Sheth VR,Chen LQ,Flask CA.Measuring in vivo tumor pHe with CEST-FISP MRI..Magn Reson Med2012;67:760-8 PMCID:PMC3572795

[99] Chen Y,Ji X.Manganese oxide-based multifunctionalized mesoporous silica nanoparticles for pH-responsive MRI, ultrasonography and circumvention of MDR in cancer cells..Biomaterials2012;33:7126-37

[100] Dixon WT,Lubag AJM.A concentration-independent method to measure exchange rates in PARACEST agents..Magn Reson Med2010;63:625-32 PMCID:PMC2925112

[101] Marathe K,Li A,Meakin S.Topiramate induces acute intracellular acidification in glioblastoma..J Neurooncol2016;130:465-72

[102] Albatany M,Meakin S.Dichloroacetate induced intracellular acidification in glioblastoma: in vivo detection using AACID-CEST MRI at 9.4 Tesla..J Neurooncol2018;136:255-62

[103] Albatany M,Meakin S.In vivo detection of acute intracellular acidification in glioblastoma multiforme following a single dose of cariporide..Int J Clin Oncol2018;23:812-9

[104] Albatany M,Meakin S.Brain tumor acidification using drugs simultaneously targeting multiple pH regulatory mechanisms..J Neurooncol2019;144:453-62

[105] Harris RJ,Liau LM.PH-weighted molecular imaging of gliomas using amine chemical exchange saturation transfer MRI..Neuro Oncol2015;17:1514-24 PMCID:PMC4648305

[106] Yao J,Schlossman J.pH-weighted amine chemical exchange saturation transfer echoplanar imaging (CEST-EPI) as a potential early biomarker for bevacizumab failure in recurrent glioblastoma..J Neurooncol2019;142:587-95 PMCID:PMC6482078

[107] Longo DL,Consolino L.In vitro and in vivo assessment of nonionic iodinated radiographic molecules as chemical exchange saturation transfer magnetic resonance imaging tumor perfusion agents..Invest Radiol2016;51:155-62

[108] Longo DL,Consolino L.In vivo imaging of tumor metabolism and acidosis by combining PET and MRI-CEST pH imaging..Cancer Res2016;76:6463-70

[109] Anemone A,Conti L.In vivo evaluation of tumour acidosis for assessing the early metabolic response and onset of resistance to dichloroacetate by using magnetic resonance pH imaging..Int J Oncol2017;51:498-506

[110] Aime S,Biondi L.Iopamidol: Exploring the potential use of a well-established x-ray contrast agent for MRI..Magn Reson Med2005;53:830-4

[111] Anemone A,Longo DL.MRI-CEST assessment of tumour perfusion using X-ray iodinated agents: comparison with a conventional Gd-based agent..Eur Radiol2017;27:2170-9

[112] Jones KM,Yoshimaru ES.Clinical Translation of Tumor Acidosis Measurements with AcidoCEST MRI..Mol Imaging Biol2017;19:617-25 PMCID:PMC6010170

[113] Sun PZ,Hu W,Wu R.Quantification of iopamidol multi-site chemical exchange properties for ratiometric chemical exchange saturation transfer (CEST) imaging of pH..Phys Med Biol2014;59:4493-504 PMCID:PMC4139413

[114] Jones KM,Howison CM.Respiration gating and Bloch fitting improve pH measurements with acidoCEST MRI in an ovarian orthotopic tumor model..Proc SPIE Int Soc Opt Eng2016;9788:978815 PMCID:PMC4871271

[115] Randtke EA,Howison CM,Cárdenas-Rodríguez J.Multislice CEST MRI improves the spatial assessment of tumor pH..Magn Reson Med2017;78:97-106 PMCID:PMC5274589

[116] Wu R,Aime S.Quantitative description of radiofrequency (RF) power-based ratiometric chemical exchange saturation transfer (CEST) pH imaging..NMR Biomed2015;28:555-65 PMCID:PMC4423622

[117] Arena F,Consolino L,Zaiss M.Flip-angle based ratiometric approach for pulsed CEST-MRI pH imaging..J Magn Reson2018;287:1-9

[118] Khalil MM,Bayomy TB.Molecular SPECT Imaging: An Overview..Int J Mol Imaging2011;2011:796025 PMCID:PMC3094893

[119] Phelps ME.PET: The merging of biology and imaging into molecular imaging..J Nucl Med2000;41:661-81

[120] Chen K.Design and Development of Molecular Imaging Probes..Curr Top Med Chem2010;10:1227-36 PMCID:PMC3632640

[121] Niu G.PET Imaging of Angiogenesis..PET Clinics2009;4:17-38 PMCID:PMC2753532

[122] Scherer RL,Matrisian LM.Imaging matrix metalloproteinases in cancer..Cancer Metastasis Rev2008;27:679-90

[123] Dwyer RM,Havelin RJ.Mesenchymal stem cell-mediated delivery of the sodium iodide symporter supports radionuclide imaging and treatment of breast cancer..Stem Cells2011;29:1149-57 PMCID:PMC3998644

[124] Sakr TM,El-Essawy FA.Synthesis and biodistribution of 99m Tc-PyDA as a potential marker for tumor hypoxia imaging..Radiochemistry2014;56:76-80

[125] Juergens RA,Singnurkar A,Valliant JF.Imaging Biomarkers in Immunotherapy..Biomark Cancer2016;8:1-13 PMCID:PMC4768940

[126] Man F,T. M. de Rosales R.Imaging Nanomedicine-Based Drug Delivery: a Review of Clinical Studies..Mol Imaging Biol2018;Oct20:683-95 PMCID:PMC6139024

[127] Koukourakis MI,Giatromanolaki A.Liposomal doxorubicin and conventionally fractionated radiotherapy in the treatment of locally advanced non-small-cell lung cancer and head and neck cancer..J Clin Oncol1999;17:3512-21

[128] Koukourakis MI,Giatromanolaki A.High intratumoral accumulation of stealth liposomal doxorubicin in sarcomas - Rationale for combination with radiotherapy..Acta Oncol2000;39:207-11

[129] Pérez-Medina C,Tang J.Nanoreporter PET predicts the efficacy of anti-cancer nanotherapy..Nat Commun2016;7:11838 PMCID:PMC4915130

[130] Matusiak N,Tuin AW.A dual inhibitor of matrix metalloproteinases and a disintegrin and metalloproteinases, [¹⁸F]FB-ML5, as a molecular probe for non-invasive MMP/ADAM-targeted imaging..Bioorganic Med Chem2015;23:192-202

[131] Altiparmak B,Citak A.Design of radiolabeled gelatinase inhibitor peptide (99mTc-CLP) and evaluation in rats..Appl Radiat Isot2014;89:130-3

[132] Da Rocha Gomes S,Azéma L.99mTc-MAG3-aptamer for imaging human tumors associated with high level of matrix metalloprotease-9..Bioconjug Chem2012;23:2192-200

[133] Kondo N,Shimizu Y,Higano K.Miniaturized antibodies for imaging membrane type-1 matrix metalloproteinase in cancers..Cancer Sci2013;104:495-501 PMCID:PMC7657219

[134] van Duijnhoven SMJ,Nicolay K.In vivo biodistribution of radiolabeled MMP-2/9 activatable cell-penetrating peptide probes in tumor-bearing mice..Contrast Media Mol Imaging2015;10:59-66

[135] Huang T,Zheng H.(18)F-misonidazole PET imaging of hypoxia in micrometastases and macroscopic xenografts of human non-small cell lung cancer: a correlation with autoradiography and histological findings..Am J Nucl Med Mol Imaging2013;3:142-53 PMCID:PMC3601474

[136] Knoop K,Klutz K.Image-guided, tumor stroma-targeted 131 i therapy of hepatocellular cancer after systemic mesenchymal stem cell-mediated nis gene delivery..Mol Ther2011;19:1704-13 PMCID:PMC3182369

[137] Wolfs E,Notelaers T.18F-FDG labeling of mesenchymal stem cells and multipotent adult progenitor cells for PET imaging: Effects on ultrastructure and differentiation capacity..J Nucl Med2013;54:447-54

[138] Patrick PS,Zaw Thin M.Lung delivery of MSCs expressing anti-cancer protein TRAIL visualised with 89Zr-oxine PET-CT..Stem Cell Res Ther2020;11:256 PMCID:PMC7318529

[139] Locke LW,Yoo AD,Berr SS.PET imaging of tumor associated macrophages using mannose coated 64Cu liposomes..Biomaterials2012;33:7785-93 PMCID:PMC6547362

[140] Rashidian M,Bilate AM.Noninvasive imaging of immune responses..Proc Natl Acad Sci U S A2015;112:6146-51 PMCID:PMC4434737

[141] Tavaré R,Zettlitz KA,Salazar FB.Engineered antibody fragments for immuno-PET imaging of endogenous CD8 + T cells in vivo..Proc Natl Acad Sci U S A2014;111:1108-13 PMCID:PMC3903195

[142] Chotipanich C,Kunawudhi A.(11)C-Choline and FDG PET/CT Imaging of Primary Cholangiocarcinoma: A Comparative Analysis..Asia Ocean J Nucl Med Biol2015;3:18-25 PMCID:PMC4937685

[143] Jadvar H.Prostate cancer: PET with 18F-FDG, 18F- or 11C-acetate, and 18F- or 11C-choline..J Nucl Med2011;52:81-9 PMCID:PMC3012154

[144] Kryza D,Filannino MA,Lemoucheux L.Fully automated [18F]fluorocholine synthesis in the TracerLab MXFDG Coincidence synthesizer..Nucl Med Biol2008;35:255-60

[145] Kumar R,Alavi A.PET in the management of urologic malignancies..Radiol Clin North Am2004;42:1141-53ix

[146] Laking GR,Buckley DL,Price PM.Imaging vascular physiology to monitor cancer treatment..Crit Rev Oncol Hematol2006;58:95-113

[147] Wilson RA,de Landsheere CM.Validation of quantitation of regional myocardial blood flow in vivo with 11C-labeled human albumin microspheres and positron emission tomography..Circulation1984;70:717-23

[148] Mullani NA,Abbruzzese JL,Lamki L.First pass FDG measured blood flow in tumors: A comparison with O-15 labeled water measured blood flow..Clin Positron Imaging2000;3:153

[149] Laking GR.Positron emission tomographic imaging of angiogenesis and vascular function..Br J Radiol.2003;76 Spec No 1:S50-9

[150] Hoffend J,Schuhmacher J.Gallium-68-DOTA-albumin as a PET blood-pool marker: Experimental evaluation in vivo..Nucl Med Biol2005;32:287-92

[151] Kimura RH,Shen B.Evaluation of integrin αvβ6 cystine knot PET tracers to detect cancer and idiopathic pulmonary fibrosis..Nat Commun2019;10:4673 PMCID:PMC6791878

[152] Flechsig P,Loktev A.PET/CT Imaging of NSCLC with a αvβ6 Integrin-Targeting Peptide..Mol Imaging Biol2019;21:973-83

[153] Notni J,Maltsev OV.In Vivo PET imaging of the cancer integrin αvβ6 using 68Ga-labeled cyclic RGD nonapeptides..J Nucl Med2017;58:671-7

[154] Beer AJ,Carlsen J.[18F]Galacto-RGD positron emission tomography for imaging of αvβ3 expression on the neovasculature in patients with squamous cell carcinoma of the head and neck..Clin Cancer Res2007;13:6610-6

[155] Beer AJ,Sarbia M.Positron emission tomography using [18F]Galacto-RGD identifies the level of integrin αvβ3 expression in man..Clin Cancer Res2006;

[156] Haubner R,Burkhart F.Glycosylated RGD-containing peptides: Tracer for tumor targeting and angiogenesis imaging with improved biokinetics..J Nucl Med2001;42:326-36

[157] Chen K,Li ZB,Chen X.Quantitative PET imaging of VEGF receptor expression..Mol Imaging Biol2009;11:15-22

[158] Zhang Y,Cai W.PET tracers based on Zirconium-89..Curr Radiopharm2011;4:131-9 PMCID:PMC3246366

[159] Levashova Z,Horng G,Backer JM.SPECT and PET imaging of EGF receptors with site-specifically labeled EGF and dimeric EGF..Bioconjug Chem2009;20:742-9

[160] Nagengast WB,Hospers GA.In vivo VEGF imaging with radiolabeled bevacizumab in a human ovarian tumor xenograft..J Nucl Med2007;48:1313-9

[161] Collingridge DR,Glaser M.The development of [124I]iodinated-VG76e: A novel tracer for imaging vascular endothelial growth factor in vivo using positron emission tomography..Cancer Res2002;62:5912-9

[162] Scheer MGW,Boerman OC.Imaging liver metastases of colorectal cancer patients with radiolabelled bevacizumab: Lack of correlation with VEGF-A expression..Eur J Cancer2008;44:1835-40

[163] Strauss LG,Klippel S.Impact of angiogenesis-related gene expression on the tracer kinetics of 18F-FDG in colorectal tumors..J Nucl Med2008;49:1238-44

[164] Cai W,Mohamedali KA.PET of vascular endothelial growth factor receptor expression..J Nucl Med2006;47:2048-56

[165] Backer M V.,Patel V.Molecular imaging of VEGF receptors in angiogenic vasculature with single-chain VEGF-based probes..Nat Med2007;13:504-9

[166] Carlin S,Reese M,Chen Q.A comparison of the imaging characteristics and microregional distribution of 4 hypoxia PET tracers..J Nucl Med2014;55:515-21 PMCID:PMC4232233

[167] Kelada OJ.Molecular imaging of tumor hypoxia with positron emission tomography..Radiat Res2014;181:335-49 PMCID:PMC5555673

[168] Kobayashi K,Yamaguchi S.FMISO PET at 4 hours showed a better lesion-to-background ratio uptake than 2 hours in brain tumors..J Nucl Med2015;

[169] Kawai N,Cao WD.Correlation between 18F-fluoromisonidazole PET and expression of HIF-1α and VEGF in newly diagnosed and recurrent malignant gliomas..Eur J Nucl Med Mol Imaging2014;41:1870-8

[170] Gérard M,Lesueur P.Hypoxia Imaging and Adaptive Radiotherapy: A State-of-the-Art Approach in the Management of Glioma..Front Med2019;6:117 PMCID:PMC6582242

[171] Peeters SGJA,Lieuwes NG.A comparative study of the hypoxia PET tracers [18F]HX4, [18F]FAZA, and [18F]FMISO in a preclinical tumor model..Int J Radiat Oncol Biol Phys2015;91:351-9

[172] Segard T,Yusoff IF.Detection of hypoxia with 18F-fluoromisonidazole (18F-FMISO) PET/CT in suspected or proven pancreatic cancer..Clin Nucl Med2013;38:1-6

[173] Servagi-Vernat S,Hanin FX.A prospective clinical study of 18 F-FAZA PET-CT hypoxia imaging in head and neck squamous cell carcinoma before and during radiation therapy..Eur J Nucl Med Mol Imaging2014;41:1544-52

[174] Tachibana I,Shibata T.A prospective clinical trial of tumor hypoxia imaging with 18f-fluoromisonidazole positron emission tomography and computed tomography (f-miso pet/ct) before and during radiation therapy..J Radiat Res2013;54:1078-84 PMCID:PMC3823770

[175] Yu W,Su X.18F-HX4/18F-FMISO-based micro PET for imaging of tumor hypoxia and radiotherapy-associated changes in mice..Biomed Pharmacother2019;119:109454

[176] Bourgeois M,Guerard F.Contribution of [64Cu]-ATSM PET in molecular imaging of tumour hypoxia compared to classical [18F] -MISO - a selected review..Nucl Med Rev Cent East Eur2011;14:90-5

[177] Wu Y,Ramezani S.[(68)Ga]-HP-DO3A-nitroimidazole: A promising agent for PET detection of tumor hypoxia..Contrast Media Mol Imaging2015;10:465-72 PMCID:PMC4695329

[178] Flavell RR,Regan MK.Caged [(18)F]FDG Glycosylamines for Imaging Acidic Tumor Microenvironments Using Positron Emission Tomography..Bioconjug Chem2016;27:170-8 PMCID:PMC4854293

[179] Wyatt LC,Andreev OA,Engelman DM.Applications of pHLIP Technology for Cancer Imaging and Therapy..Trends Biotechnol2017;35:653-64 PMCID:PMC5492987

[180] Vavere AL,Spees WM.A novel technology for the imaging of acidic prostate tumors by positron emission tomography..Cancer Res2009;69:4510-6 PMCID:PMC2690701

[181] Demoin DW,Edwards KJ.PET Imaging of Extracellular pH in Tumors with 64Cu- and 18F-Labeled pHLIP Peptides: A Structure-Activity Optimization Study..Bioconjug Chem2016;27:2014-23 PMCID:PMC5034329

[182] Hanafy NA,Citti C,Leporatti S.Inihibition of glycolysis by using a micro/nano-lipid bromopyruvic chitosan carrier as a promising tool to improve treatment of hepatocellular carcinoma..Nanomaterials2018;8:34 PMCID:PMC5791121

[183] Miao Y,Guo R.(18)F-FDG PET/CT for Monitoring the Response of Breast Cancer to miR-143-Based Therapeutics by Targeting Tumor Glycolysis..Mol Ther Nucleic Acids2016;Aug 305:e357 PMCID:PMC5023410

[184] Witney TH,Shen B.PET imaging of tumor glycolysis downstream of hexokinase through noninvasive measurement of pyruvate kinase M2..Sci Transl Med2015;7:310ra169

[185] Kwee SA.Metabolic positron emission tomography imaging of cancer: Pairing lipid metabolism with glycolysis..World J Radiol2016;8:851-6 PMCID:PMC5120244

[186] Lee N,Hyeon T.Nano-sized CT contrast agents..Adv Mater2013;25:2641-60

[187] Wang CL,Ellis JH,Dunnick NR.Frequency, management, and outcome of extravasation of nonionic iodinated contrast medium in 69,657 intravenous injections..Radiology2007;243:80-7

[188] Sahani DV,Hamberg LM.Assessing tumor perfusion and treatment response in rectal cancer with multisection CT: initial observations..Radiology2005;234:785-92

[189] Fushiki H,Katoh M.Quantification of mouse pulmonary cancer models by microcomputed tomography imaging..Cancer Sci2009;100:1544-9

[190] Samei E,Badea CT.Micro-CT imaging of breast tumors in rodents using a liposomal, nanoparticle contrast agent..Int J Nanomedicine2009;4:277-82 PMCID:PMC2789439

[191] Ghaghada KB,Karumbaiah L.Evaluation of tumor microenvironment in an animal model using a nanoparticle contrast agent in computed tomography imaging..Acad Radiol2011;18:20-30 PMCID:PMC3016875

[192] Liu Y,Lu L.Nanoparticulate X-ray computed tomography contrast agents: From design validation to in vivo applications..Acc Chem Res2012;45:1817-27

[193] Meng X,Zhang M.Negative CT Contrast Agents for the Diagnosis of Malignant Osteosarcoma..Adv Sci2019;6:1901214 PMCID:PMC6891899

[194] Meng X,Bu W.Functional CT Contrast Nanoagents for the Tumor Microenvironment..Adv Healthc Mater2020;e2000912

[195] Zou Y,Sun Y.Cyclic RGD-functionalized and disulfide-crosslinked iodine-rich polymersomes as a robust and smart theranostic agent for targeted CT imaging and chemotherapy of tumor..Theranostics2019;9:8061-72 PMCID:PMC6857068

[196] Luo G,Jin C.LyP-1-conjugated nanoparticles for targeting drug delivery to lymphatic metastatic tumors..Int J Pharm2010;385:150-6

[197] Xing H,Ren Q.Computed tomography imaging-guided radiotherapy by targeting upconversion nanocubes with significant imaging and radiosensitization enhancements..Sci Rep2013;3:1751 PMCID:PMC3638198

[198] Shi H,Huang C.A Functional CT Contrast Agent for In Vivo Imaging of Tumor Hypoxia..Small2016;12:3995-4006

[199] Apte S,E. Graves E.Molecular Imaging of Hypoxia: Strategies for Probe Design and Application..Curr Org Synth2011;8:593-603 PMCID:PMC3279754

[200] Huo D,Zhang C.Hypoxia-Targeting, Tumor Microenvironment Responsive Nanocluster Bomb for Radical-Enhanced Radiotherapy..ACS Nano2017;11:10159-74

[201] Facciabene A,Hagemann IS.Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T reg cells..Nature2011;475:226-30

[202] Wang A,He L.An acidic pH/reduction dual-stimuli responsive nanoprobe for enhanced CT imaging of tumours in vivo..Nanoscale2018;10:20126-30

[203] Xiong D,Peng S,Zhang L.Smart pH-sensitive micelles based on redox degradable polymers as DOX/GNPs carriers for controlled drug release and CT imaging..Colloids Surf B Biointerfaces2018;163:29-40

[204] Lusic H.X-ray-computed tomography contrast agents..Chem Rev2013;113:1641-66 PMCID:PMC3878741

[205] Tharkar P,Wong WSF,Chrzanowski W.Nano-Enhanced Drug Delivery and Therapeutic Ultrasound for Cancer Treatment and Beyond..Front Bioeng Biotechnol2019;7:324 PMCID:PMC6883936

[206] Zhou QL,Wang YX,Lin Y.Ultrasound-mediated local drug and gene delivery using nanocarriers..Biomed Res Int2014;2014:963891 PMCID:PMC4150504

[207] Chowdhury SM,Willmann JK.Ultrasound-guided drug delivery in cancer..Ultrasonography2017;36:171-84 PMCID:PMC5494871

[208] Ghoshal G,O’brien WD.Quantitative ultrasound history and successes..In: Quantitative Ultrasound in Soft Tissues2013;

[209] Feleppa EJ,Porter CR.Quantitative ultrasound in cancer imaging..Semin Oncol2011;38:136-50 PMCID:PMC3057450

[210] Destrempes F.Review of envelope statistics models for quantitative ultrasound imaging and tissue characterization..In: Quantitative Ultrasound in Soft Tissues2013;

[211] Mamou J.Quantitative ultrasound in soft tissues..Quantitative Ultrasound in Soft Tissues2013;

[212] Lizzi FL,Feleppa EJ,Yaremko MM.Relationship of Ultrasonic Spectral Parameters to Features of Tissue Microstructure..IEEE Trans Ultrason Ferroelectr Freq Control1987;34:319-29

[213] Chandraratna PA,Chandraratna PM,Kloner RA.Characterization of collagen by high-frequency ultrasound: evidence for different acoustic properties based on collagen fiber morphologic characteristics..Am Heart J1997;133:364-8

[214] Kreitz S,Hasken S,Mela P.Nondestructive method to evaluate the collagen content of fibrin-based tissue engineered structures via ultrasound..Tissue Eng Part C Methods2011;17:1021-6

[215] Mercado KP,Hocking DC.Noninvasive Quantitative Imaging of Collagen Microstructure in Three-Dimensional Hydrogels Using High-Frequency Ultrasound..Tissue Eng Part C Methods2015;21:671-82 PMCID:PMC4499776

[216] Riggin CN,Freedman BR,Soslowsky LJ.Analysis of collagen organization in mouse achilles tendon using high-frequency ultrasound imaging..J Biomech Eng2014;136:021029 PMCID:PMC4023654

[217] Mohanty K,Newsome IG,Dayton PA.Ultrasound multiple scattering with microbubbles can differentiate between tumor and healthy tissue in vivo..Phys Med Biol2019;64:115022 PMCID:PMC6876296

[218] Gessner RC,Foster FS.Acoustic angiography: a new imaging modality for assessing microvasculature architecture..Int J Biomed Imaging2013;2013:936593 PMCID:PMC3730364

[219] Dayton PA.Targeted imaging using ultrasound..J Magn Reson Imaging2002;16:362-77

[220] Lindsey B,Martin K,Dayton P.Acoustic characterization of contrast-to-tissue ratio and axial resolution for dual-frequency contrast-specific acoustic angiography imaging..IEEE Trans Ultrason Ferroelectr Freq Control2014;61:1668-87

[221] Shelton SE,Lee M.Quantification of microvascular tortuosity during tumor evolution using acoustic angiography..Ultrasound Med Biol2015;41:1896-904 PMCID:PMC4778417

[222] Shelton SE,Tsuruta JK,Dayton PA.Molecular acoustic angiography: a new technique for high-resolution superharmonic ultrasound molecular imaging..Ultrasound Med Biol2016;42:769-81 PMCID:PMC5653972

[223] Dunleavey JM,Thompson J.Vascular channels formed by subpopulations of PECAM1+ melanoma cells..Nat Commun2014;5:5200 PMCID:PMC4261234

[224] Kasoji SK,Gessner RC,Dayton PA.Early assessment of tumor response to radiation therapy using high-resolution quantitative microvascular ultrasound imaging..Theranostics2018;8:156-68 PMCID:PMC5743466

[225] Jiang Z zhen,Shen H liang.Clinical applications of superb microvascular imaging in the liver, breast, thyroid, skeletal muscle, and carotid plaques..J Ultrasound Med2019;38:2811-20

[226] Christensen-Jeffries K,Dayton PA.Super-resolution ultrasound imaging..Ultrasound Med Biol2020;46:865-91

[227] Leung K.Microbubbles conjugated with anti-matrix metalloproteinase 2 mouse monoclonal antibody sc-13595. In: Molecular Imaging and Contrast Agent Database (MICAD) [Internet].2004-2013;Bethesda (MD)National Center for Biotechnology Information (US)

[228] Pochon S,Bussat P.BR55: a lipopeptide-based VEGFR2-targeted ultrasound contrast agent for molecular imaging of angiogenesis..Invest Radiol2010;45:89-95

[229] Sugimoto K,Negishi Y.Quantification in molecular ultrasound imaging a comparative study in mice between healthy liver and a human hepatocellular carcinoma xenograft..J Ultrasound Med2012;31:1909-16

[230] Pysz MA,Rosenberg J,Schneider M.Antiangiogenic cancer therapy: Monitoring with molecular US and a clinically translatable contrast agent (BR55)..Radiology2010;256:519-27 PMCID:PMC2909432

[231] Bzyl J,Rix A.The high angiogenic activity in very early breast cancer enables reliable imaging with VEGFR2-targeted microbubbles (BR55)..Eur Radiol2013;23:468-75

[232] Lindsey BD,Foster FS.Assessment of Molecular acoustic angiography for combined microvascular and molecular imaging in preclinical tumor models..Mol Imaging Biol2017;19:194-202 PMCID:PMC5575860

[233] Lakshman M.Screening and quantification of the tumor microenvironment with micro-ultrasound and photoacoustic imaging..Nat Methods2015;12:iii-v

[234] Doyley MM.Elastography: general principles and clinical applications..Ultrasound Clinics2014;9:1-11 PMCID:PMC3896304

[235] Swartz MA.Lymphatic and interstitial flow in the tumour microenvironment: linking mechanobiology with immunity..Nat Rev Cancer2012;12:210-9

[236] Itoh A,Tohno E.Breast disease: Clinical application of US elastography for diagnosis..Radiology2006;239:341-50

[237] Cho N,Jeong SP,Jang M.Nonpalpable breast masses: evaluation by US elastography..Korean J Radiol2008;9:111-8 PMCID:PMC2627231

[238] Cho N,Lyou CY,Choi HY.Distinguishing benign from malignant masses at breast US: Combined US elastography and color Doppler US-influence on radiologist accuracy..Radiology2012;262:80-90

[239] Yi A,Chang JM,La Yun B.Sonoelastography for 1786 non-palpable breast masses: Diagnostic value in the decision to biopsy..Eur Radiol2012;22:1033-40

[240] Hao Y,Ma B,Liu L.Relationship between ultrasound elastography and myofibroblast distribution in breast cancer and its clinical significance..Sci Rep2016;6:19584 PMCID:PMC4742804

[241] Wang Y,Li H.Assessment of tumor stiffness with shear wave elastography in a human prostate cancer xenograft implantation model..J Ultrasound Med2017;36:955-63

[242] Riegler J,Rosenzweig S.Tumor elastography and its association with collagen and the tumor microenvironment..Clin Cancer Res2018;24:4455-67

[243] Insana MF,Sridhar M.Viscoelastic imaging of breast tumor microenvironment with ultrasound..J Mammary Gland Biol Neoplasia2004;9:393-404 PMCID:PMC2715558

[244] Wang H,Ahmed R.Elastography can map the local inverse relationship between shear modulus and drug delivery within the pancreatic ductal adenocarcinoma microenvironment..Clin Cancer Res2019;25:2136-43 PMCID:PMC6445768

[245] Massoud TF.Molecular imaging in living subjects: Seeing fundamental biological processes in a new light..Genes Dev2003;17:545-80

[246] Weissleder R.Imaging in the era of molecular oncology..Nature2008;452:580-9 PMCID:PMC2708079

[247] Weissleder R.Advancing biomedical imaging..Proc Natl Acad Sci U S A2015;112:14424-8 PMCID:PMC4664297

[248] Imamura T,Kawakami R.In vivo optical imaging of cancer cell function and tumor microenvironment..Cancer Sci2018;109:912-8 PMCID:PMC5891206

[249] Jeevarathinam AS,Chen F,Jokerst J V.Photoacoustic imaging quantifies drug release from nanocarriers via redox chemistry of dye-labeled cargo..Angew Chem Int Ed Engl2020;59:4678-83 PMCID:PMC7101078

[250] Laufer JG,Treeby BE.In vivo preclinical photoacoustic imaging of tumor vasculature development and therapy..J Biomed Opt2012;17:056016

[251] Lao Y,Yang S.Noninvasive photoacoustic imaging of the developing vasculature during early tumor growth..Phys Med Biol2008;53:4203-12

[252] Omar M,Soliman D,Ntziachristos V.Pushing the optical imaging limits of cancer with multi-frequency-band raster-scan optoacoustic mesoscopy (RSOM)..Neoplasia2015;17:208-14 PMCID:PMC4351295

[253] Chekkoury A,Gateau J.High-resolution multispectral optoacoustic tomography of the vascularization and constitutive hypoxemia of cancerous tumors..Neoplasia2016;18:459-67 PMCID:PMC5018092

[254] Li ML,Xie X.Simultaneous molecular and hypoxia imaging of brain tumors in vivo using spectroscopic photoacoustic tomography..Proc IEEE2008;

[255] Raes F,Le Mee M.High resolution ultrasound and photoacoustic imaging of orthotopic lung cancer in mice: New perspectives for onco- pharmacology..PLoS One2016;11:e0153532 PMCID:PMC4829195

[256] Lavaud J,Coll JL.Exploration of melanoma metastases in mice brains using endogenous contrast photoacoustic imaging..Int J Pharm2017;532:704-9

[257] Imai T,Yeh CH.Direct measurement of hypoxia in a xenograft multiple myeloma model by optical-resolution photoacoustic microscopy..Cancer Biol Ther2017;18:101-5 PMCID:PMC5362988

[258] Quiros-Gonzalez I,Aitken SJ.Optoacoustics delineates murine breast cancer models displaying angiogenesis and vascular mimicry..Br J Cancer2018;118:1098-106 PMCID:PMC5931091

[259] Bendinger AL,Peter J.Photoacoustic imaging to assess pixel-based sO2 distributions in experimental prostate tumors..J Biomed Opt2018;23:1-11

[260] Tomaszewski MR,O’Connor JP.Oxygen enhanced Optoacoustic Tomography (OE-OT) reveals vascular dynamics in murine models of prostate cancer..Theranostics2017;7:2900-13 PMCID:PMC5562224

[261] van den Berg PJ,Steenbergen W.Review of photoacoustic flow imaging: its current state and its promises..Photoacoustics2015;3:89-99 PMCID:PMC4595496

[262] Bohndiek SE,Machtaler S,Hori S.Photoacoustic tomography detects early vessel regression and normalization during ovarian tumor response to the antiangiogenic therapy trebananib..J Nucl Med2015;56:1942-7 PMCID:PMC5612481

[263] Rich LJ.Photoacoustic monitoring of tumor and normal tissue response to radiation..Sci Rep2016;6:21237 PMCID:PMC4756329

[264] Martinho Costa M,Rivens I.Photoacoustic imaging for the prediction and assessment of response to radiotherapy in vivo2018;44:329516

[265] Knox HJ,Kim TW,Dobrucki LW.A bioreducible N-oxide-based probe for photoacoustic imaging of hypoxia..Nat Commun2017;8:1794 PMCID:PMC5702603

[266] Chatni MR,Danielli A,Maslov KI.Functional photoacoustic microscopy of pH..J Biomed Opt2011;16:100503 PMCID:PMC3210191

[267] Jo J,Kopelman R.In vivo quantitative imaging of tumor pH by nanosonophore assisted multispectral photoacoustic imaging..Nat Commun2017;8:471 PMCID:PMC5589864

[268] Lei H,Liu S.Characterizing intestinal inflammation and fibrosis in Crohn’s disease by photoacoustic imaging: feasibility study..Biomed Opt Express2016;7:2837-48 PMCID:PMC4948634

[269] Zhu Y,Huang Z.Identifying intestinal fibrosis and inflammation by spectroscopic photoacoustic imaging: an animal study in vivo..Biomed Opt Express2018;9:1590-1600 PMCID:PMC5905908

[270] Cao Y,Hui J.Fast assessment of lipid content in arteries in vivo by intravascular photoacoustic tomography..Sci Rep2018;8:2400 PMCID:PMC5799328

[271] Wu PC,Tsai ZU.In vivo quantification of the structural changes of collagens in a melanoma microenvironment with second and third harmonic generation microscopy..Sci Rep2015;5:8879 PMCID:PMC4352861

[272] Dragulescu-Andrasi A,Tikhomirov GA,Gambhir SS.Activatable oligomerizable imaging agents for photoacoustic imaging of furin-like activity in living subjects..J Am Chem Soc2013;135:11015-22 PMCID:PMC3771329

[273] Levi J,Bohndiek S.Molecular photoacoustic imaging of follicular thyroid carcinoma..Clin Cancer Res2013;19:1494-502 PMCID:PMC3602312

[274] Yin L,Zhang H.Quantitatively visualizing tumor-related protease activity in vivo using a ratiometric photoacoustic probe..J Am Chem Soc2019;141:3265-73

[275] Egeblad M.New functions for the matrix metalloproteinases in cancer progression..Nat Rev Cancer2002;2:161-74

[276] Tzoumas S,Klemm U,Schaefer K.Immune cell imaging using multi-spectral optoacoustic tomography..Opt Lett2014;39:3523-6

[277] Zheng S,Lai K.Noninvasive photoacoustic and fluorescent tracking of optical dye labeled T cellular activities of diseased sites at new depth..J Biophotonics2018;11:e201800073

[278] Filippi M,Pasquino C.Indocyanine green labeling for optical and photoacoustic imaging of mesenchymal stem cells after in vivo transplantation..J Biophotonics2019;12:e201800035

[279] Weber J,Bohndiek SE.Contrast agents for molecular photoacoustic imaging..Nat Methods2016;13:639-50

[280] Burke K.The use of second harmonic generation to image the extracellular matrix during tumor progression..Intravital2014;3:e984509 PMCID:PMC5226008

[281] Masedunskas A,Porat-Shliom N.Intravital microscopy: a practical guide on imaging intracellular structures in live animals..Bioarchitecture2012;2:143-57 PMCID:PMC3696059

[282] Sturm MB,Lu S.Targeted imaging of esophageal neoplasia with a fluorescently labeled peptide: first-in-human results..Sci Transl Med2013;5:184ra61 PMCID:PMC3859345

[283] Pan Y,Mach KE.Endoscopic molecular imaging of human bladder cancer using a CD47 antibody..Sci Transl Med2014;6:260ra148

[284] Ricard C,Rodriguez T,Rougon G.Dynamic quantitative intravital imaging of glioblastoma progression reveals a lack of correlation between tumor growth and blood vessel density..PLoS One2013;8:e72655 PMCID:PMC3771993

[285] Fisher DT,Kim M.Intraoperative intravital microscopy permits the study of human tumour vessels..Nat Commun2016;7:10684 PMCID:PMC4757793

[286] Zomer A,Verweij FJ.In vivo imaging reveals extracellular vesicle-mediated phenocopying of metastatic behavior..Cell2015;161:1046-57 PMCID:PMC4448148

[287] Qi S,Lu L.Long-term intravital imaging of the multicolor-coded tumor microenvironment during combination immunotherapy..Elife2016;5:e14756 PMCID:PMC5173323

[288] Arlauckas SP,Kohler RH.In vivo imaging reveals a tumor-associated macrophage-mediated resistance pathway in anti-PD-1 therapy..Sci Transl Med2017;9:eaal3604 PMCID:PMC5734617

[289] Karagiannis GS,Wang Y.Neoadjuvant chemotherapy induces breast cancer metastasis through a TMEM-mediated mechanism..Sci Transl Med2017;9:eaan0026 PMCID:PMC5592784

[290] Ntziachristos V.Going deeper than microscopy: the optical imaging frontier in biology..Nat Methods2010;7:603-14

[291] Vakoc BJ,Tyrrell JA.Three-dimensional microscopy of the tumor microenvironment in vivo using optical frequency domain imaging..Nat Med2009;15:1219-23 PMCID:PMC2759417

[292] Junankar S,Jurczyluk J.Real-time intravital imaging establishes tumor-associated macrophages as the extraskeletal target of bisphosphonate action in cancer..Cancer Discov2015;5:35-42 PMCID:PMC4293349

[293] Smith BR,Bouley D.Shape matters: intravital microscopy reveals surprising geometrical dependence for nanoparticles in tumor models of extravasation..Nano Lett2012;12:3369-77 PMCID:PMC3495189

[294] Winfree S,Day RN.Intravital microscopy of biosensor activities and intrinsic metabolic states..Methods2017;128:95-104 PMCID:PMC5776661

[295] Niesner R,Neumann J,Gunzer M.The power of single and multibeam two-photon microscopy for high-resolution and high-speed deep tissue and intravital imaging..Biophys J2007;93:2519-29 PMCID:PMC1965440

[296] You S,Chaney EJ.Intravital imaging by simultaneous label-free autofluorescence-multiharmonic microscopy..Nat Commun2018;9:2125 PMCID:PMC5974075

[297] Katsuno Y,Kanda H.Bone morphogenetic protein signaling enhances invasion and bone metastasis of breast cancer cells through Smad pathway..Oncogene2008;27:6322-33

[298] Hara-Miyauchi C,Hanyu A.Bioluminescent system for dynamic imaging of cell and animal behavior..Biochem Biophys Res Commun2012;419:188-93

[299] Rathbun CM.Bioluminescent probes for imaging biology beyond the culture dish..Biochemistry2017;56:5178-84 PMCID:PMC5914164

[300] Kim YP,Xia Z,Mirkin CA.Bioluminescent nanosensors for protease detection based upon gold nanoparticle-luciferase conjugates..Chem Commun2010;46:76-8 PMCID:PMC3930333

[301] Xia Z,So MK,Sinclair R.Multiplex detection of protease activity with quantum dot nanosensors prepared by intein-mediated specific bioconjugation..Anal Chem2008;80:8649-55 PMCID:PMC2677517

[302] Yao H,Xiao F,Rao J.Quantum dot/bioluminescence resonance energy transfer based highly sensitive detection of proteases..Angew Chem Int Ed Engl2007;46:4346-9

[303] Xia Z,Jeon J.Immobilizing reporters for molecular imaging of the extracellular microenvironment in living animals..ACS Chem Biol2011;6:1117-26 PMCID:PMC3199358

[304] Kidd S,Dembinski JL.Direct evidence of mesenchymal stem cell tropism for tumor and wounding microenvironments using in vivo bioluminescent imaging..Stem Cells2009;27:2614-23 PMCID:PMC4160730

[305] Doucette T,Yang Y.Mesenchymal stem cells display tumor-specific tropism in an RCAS/Ntv-a glioma model..Neoplasia2011;13:716-25 PMCID:PMC3156662

[306] Cao J,Ding H.In vivo tracking of systemically administered allogeneic bone marrow mesenchymal stem cells in normal rats through bioluminescence imaging..Stem Cells Int2016;2016:3970942 PMCID:PMC5005574

[307] Allen AB,Su S,Guldberg RE.In vivo bioluminescent tracking of mesenchymal stem cells within large hydrogel constructs..Tissue Eng Part C Methods2014;20:806-16 PMCID:PMC4186662

[308] Conway M,Kirkpatrick A,Sayler G.Real-time tracking of stem cell viability, proliferation, and differentiation with autonomous bioluminescence imaging..BMC Biol2020;18:79 PMCID:PMC7333384

[309] Vilela CAP,Siqueira RC,Covas DT.Ex vivo evaluation of intravitreal mesenchymal stromal cell viability using bioluminescence imaging..Stem Cell Res Ther2018;9:155 PMCID:PMC5998578

[310] Baklaushev VP,Petkov S.Luciferase expression allows bioluminescence imaging but imposes limitations on the orthotopic mouse (4T1) model of breast cancer..Sci Rep2017;7:7715 PMCID:PMC5552689

[311] Moriyama EH,Jarvi MT.The influence of hypoxia on bioluminescence in luciferase-transfected gliosarcoma tumor cells in vitro..Photochem Photobiol Sci2008;7:675-80

[312] Khalil AA,Broaddus WC.The influence of hypoxia and pH on bioluminescence imaging of luciferase-transfected tumor cells and xenografts..Int J Mol Imaging2013;2013:287697 PMCID:PMC3723249

[313] Gao Y,Liu T.Bioluminescent probe for tumor hypoxia detection via CYP450 reductase in living animals..Anal Chem2017;89:12488-93

[314] Saha D,Zhou H.In vivo bioluminescence imaging of tumor hypoxia dynamics of breast cancer brain metastasis in a mouse model..J Vis Exp2011;3175 PMCID:PMC3227172

[315] McMillin DW,Weisberg E.Tumor cell-specific bioluminescence platform to identify stroma-induced changes to anticancer drug activity..Nat Med2010;16:483-9 PMCID:PMC3786785

[316] Correa de Sampaio P,Krubasik D.A heterogeneous in vitro three dimensional model of tumour-stroma interactions regulating sprouting angiogenesis..PLoS One2012;7:e30753 PMCID:PMC3282728

[317] Hoffman RM.The multiple uses of fluorescent proteins to visualize cancer in vivo..Nat Rev Cancer2005;5:796-806

[318] Hoffman RM.Subcellular imaging in the live mouse..Nat Protoc2006;1:775-82

[319] Nakamura M,Hasegawa K.Color-coded imaging distinguishes cancer cells, stromal cells, and recombinant cancer-stromal cells in the tumor microenvironment during metastasis..Anticancer Res2018;38:4417-23

[320] Yang M,Jiang P,Penman S.Dual-color fluorescence imaging distinguishes tumor cells from induced host angiogenic vessels and stromal cells..Proc Natl Acad Sci U S A2003;100:14259-62 PMCID:PMC283579

[321] Yang M,Hoffman RM.Whole-body subcellular multicolor imaging of tumor-host interaction and drug response in real time..Cancer Res2007;67:5195-200

[322] Egeblad M,Askautrud HA.Visualizing stromal cell dynamics in different tumor microenvironments by spinning disk confocal microscopy..Dis Model Mech2008;1:155-67discussion 165 PMCID:PMC2562195

[323] Mochizuki N,Kurokawa K.Spatio-temporal images of growth-factor-induced activation of Ras and Rap1..Nature2001;411:1065-8

[324] Brown LF,Jackman RW.Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in breast cancer..Hum Pathol1995;26:86-91

[325] Hanyu A,Hatake K.Functional in vivo optical imaging of tumor angiogenesis, growth, and metastasis prevented by administration of anti-human VEGF antibody in xenograft model of human fibrosarcoma HT1080 cells..Cancer Sci2009;100:2085-92

[326] Mayes PA,Liu YY.Noninvasive vascular imaging in fluorescent tumors using multispectral unmixing..Biotechniques2008;45:459-60461-4

[327] Li G,Wang J,Chen K.Near-infrared fluorescence imaging of CD13 receptor expression using a novel Cy5.5-labeled dimeric NGR peptide..Amino Acids2014;46:1547-56

[328] Biswal NC,Yuan B,Backer JM.Fluorescence imaging of vascular endothelial growth factor in tumors for mice embedded in a turbid medium..J Biomed Opt2010;15:016012 PMCID:PMC2839800

[329] Choi M,Choi K.Dynamic fluorescence imaging for multiparametric measurement of tumor vasculature..In: Imaging, Manipulation, and Analysis of Biomolecules, Cells, and Tissues VII.2009;

[330] Zhang Y,Rao J.Protease-modulated cellular uptake of quantum dots..Nano Lett2006;6:1988-92 PMCID:PMC2553895

[331] Xie J,Aronova M.Manipulating the power of an additional phase: a flower-like au-Fe 3O4 optical nanosensor for imaging protease expressions in vivo..ACS Nano2011;5:3043-51 PMCID:PMC3082626

[332] Cobos-Correa A,Diemer S,Schultz C.Membrane-bound FRET probe visualizes MMP12 activity in pulmonary inflammation..Nat Chem Biol2009;5:628-30

[333] Park SY,Kim GB.Gold nanoparticle-based fluorescence quenching via metal coordination for assaying protease activity..Gold Bull2012;45:213-9

[334] Lee S,Park K.A near-infrared-fluorescence-quenched gold-nanoparticle imaging probe for in vivo drug screening and protease activity determination..Angew Chem Int Ed Engl2008;47:2804-7

[335] Li X,Cowell JA.Parallel accumulation of tumor hyaluronan, collagen, and other drivers of tumor progression..Clin Cancer Res2018;24:4798-807 PMCID:PMC6743334

[336] Qi B,Wojtynek NE.Tuned near infrared fluorescent hyaluronic acid conjugates for delivery to pancreatic cancer for intraoperative imaging..Theranostics2020;10:3413-29 PMCID:PMC7069077

[337] Lopès A,Billard E.Deciphering the immune microenvironment of a tissue by digital imaging and cognition network..Sci Rep2018;8:16692 PMCID:PMC6232093

[338] Ke CC,Suetsugu A.In vivo fluorescence imaging reveals the promotion of mammary tumorigenesis by mesenchymal stromal cells..PLoS One2013;8:e69658 PMCID:PMC3723858

[339] Germain RN,Dustin ML.Dynamic imaging of the immune system: progress, pitfalls and promise..Nat Rev Immunol2006;Jul6:497-507

[340] Quante M,Tomita H.Bone marrow-derived myofibroblasts contribute to the mesenchymal stem cell niche and promote tumor growth..Cancer Cell2011;19:257-72 PMCID:PMC3060401

[341] Zhao H,Baddour J.Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism..Elife2016;5:e10250 PMCID:PMC4841778

[342] Li YY,Gao S.Cancer-associated fibroblasts contribute to oral cancer cells proliferation and metastasis via exosome-mediated paracrine miR-34a-5p..EBioMedicine2018;36:209-20 PMCID:PMC6197737

[343] Lo PC,Stefflova K.Photodynamic molecular beacon triggered by fibroblast activation protein on cancer-associated fibroblasts for diagnosis and treatment of epithelial cancers..J Med Chem2009;52:358-68 PMCID:PMC2773291

[344] Cai Q,Zhu W,Qian X.A turn-on fluorescent probe for tumor hypoxia imaging in living cells..Chem Commun2015;51:14739-41

[345] Tian X,Sun Y,Ma H.Near-infrared fluorescent probes for hypoxia detection via joint regulated enzymes: design, synthesis, and application in living cells and mice..Anal Chem2018;90:13759-66

[346] Yang D,Zang TN,Zhou Y.Hypoxia imaging in cells and tumor tissues using a highly selective fluorescent nitroreductase probe..Sci Rep2017;7:9174 PMCID:PMC5569069

[347] Mirabello V,Pascu SI.Oxygen sensing, hypoxia tracing and in vivo imaging with functional metalloprobes for the early detection of non-communicable diseases..Front Chem2018;6:27 PMCID:PMC5829448

[348] Wang L.PH responsive fluorescence nanoprobe imaging of tumors by sensing the acidic microenvironment..J Mater Chem2011;21:15862-71

[349] Fang M,Bi J.Fluorescent probes for sensitive and selective detection of pH changes in live cells in visible and near-infrared channels..J Mater Chem B2017;5:9579-90

[350] Liu Q,Zhao H,Tao W.Tumor cell pH detection based on CdSe quantum dots’ fluorescence charateristics..Technol Health Care2019;27:239-47 PMCID:PMC6597994

[351] Anemone A,Arena F,Longo DL.Imaging tumor acidosis: a survey of the available techniques for mapping in vivo tumor pH..Cancer Metastasis Rev2019;38:25-49 PMCID:PMC6647493

[352] Stuker F,Rudin M.Fluorescence molecular tomography: principles and potential for pharmaceutical research..Pharmaceutics2011;3:229-74 PMCID:PMC3864234

[353] Leimgruber A,Cortez-Retamozo V.Behavior of endogenous Tumor-associated macrophages assessed in vivo using a functionalized nanoparticle..Neoplasia2009;11:459-682 p following 468 PMCID:PMC2672160

[354] Li L,Chen X.Fluorescence molecular imaging and tomography of matrix metalloproteinase-activatable near-infrared fluorescence probe and image-guided orthotopic glioma resection..Mol Imaging Biol2018;20:930-9

[355] Zhang Q,Shen J,Hoffman RM.Time-course imaging of therapeutic functional tumor vascular normalization by antiangiogenic agents..Mol Cancer Ther2011;10:1173-84

[356] Montet X,Alencar H,Mahmood U.Tomographic fluorescence imaging of tumor vascular volume in mice..Radiology2007;242:751-8

[357] Theek B,Kunjachan S.Characterizing EPR-mediated passive drug targeting using contrast-enhanced functional ultrasound imaging..J Control Release2014;182:83-9 PMCID:PMC4031451

[358] Ntziachristos V,Bremer C.Fluorescence molecular tomography resolves protease activity in vivo..Nat Med2002;8:757-60

[359] Fujimoto JG,Boppart SA.Optical coherence tomography: an emerging technology for biomedical imaging and optical biopsy..Neoplasia2000;2:9-25 PMCID:PMC1531864

[360] Goswami M,Zhang P.Novel window for cancer nanotheranostics: non-invasive ocular assessments of tumor growth and nanotherapeutic treatment efficacy in vivo..Biomed Opt Express2019;10:151-66 PMCID:PMC6363190

[361] Marvdashti T,Aasi SZ,Ellerbee Bowden AK.Classification of basal cell carcinoma in human skin using machine learning and quantitative features captured by polarization sensitive optical coherence tomography..Biomed Opt Express2016;7:3721-35 PMCID:PMC5030045

[362] Kiseleva E,Feldchtein F.Differential diagnosis of human bladder mucosa pathologies in vivo with cross-polarization optical coherence tomography..Biomed Opt Express2015;6:1464-76 PMCID:PMC4399683

[363] Chhetri RK,Troester MA.Longitudinal study of mammary epithelial and fibroblast co-cultures using optical coherence tomography reveals morphological hallmarks of pre-malignancy..PLoS One 20122012;7:e49148 PMCID:PMC3495770

[364] Winkler AM,Weichsel J.In vivo, dual-modality OCT/LIF imaging using a novel VEGF receptor-targeted NIR fluorescent probe in the AOM-treated mouse model..Mol Imaging Biol2011;13:1173-82 PMCID:PMC3085637

[365] De Carvalho N,Schuh S.The vascular morphology of melanoma is related to Breslow index: an in vivo study with dynamic optical coherence tomography..Exp Dermatol2018;27:1280-6

[366] Smith BR.Nanomaterials for in vivo imaging..Chem Rev2017;117:901-86

[367] Liba O,Sen D.Contrast-enhanced optical coherence tomography with picomolar sensitivity for functional in vivo imaging..Sci Rep2016;6:23337 PMCID:PMC4796912

[368] Si P,Liba O.Gold nanoprisms as optical coherence tomography contrast agents in the second near-infrared window for enhanced angiography in live animals..ACS Nano2018;12:11986-94

[369] Si P,Dutta R.In vivo molecular optical coherence tomography of lymphatic vessel endothelial hyaluronan receptors..Sci Rep2017;7:1086 PMCID:PMC5430649

[370] Sorelle ED,Liba O.Spatiotemporal tracking of brain-tumor-associated myeloid cells in vivo through optical coherence tomography with plasmonic labeling and speckle modulation..ACS Nano2019;13:7985-95

[371] John R,Adie SG.In vivo magnetomotive optical molecular imaging using targeted magnetic nanoprobes..Proc Natl Acad Sci U S A2010;107:8085-90 PMCID:PMC2889582

[372] Fernandes C,Yergeri MC.Tumor Microenvironment Targeted Nanotherapy..Front Pharmacol2018;9:1230 PMCID:PMC6220447

[373] García-Figueiras R,Padhani AR.How clinical imaging can assess cancer biology..Insights Imaging2019;10:28 PMCID:PMC6399375

[374] Wu Y,Li J.Optical imaging of tumor microenvironment..Am J Nucl Med Mol Imaging2013;3:1-15 PMCID:PMC3545362

[375] Youn H.In vivo non invasive molecular imaging for immune cell tracking in small animals..Immune Netw2012;12:223-9 PMCID:PMC3566416

[376] Condeelis J.In vivo imaging in cancer..Cold Spring Harb Perspect Biol2010;2:a003848 PMCID:PMC2982169

[377] Schinkel AFL,Staub D.Contrast-enhanced ultrasound: clinical applications in patients with atherosclerosis..Int J Cardiovasc Imaging2016;32:35-48 PMCID:PMC4706841

[378] Barr RG.Contrast enhanced ultrasound for focal liver lesions: how accurate is it?.Abdom Radiol2018;43:1128-33

[379] Mallidi S,Emelianov S.Photoacoustic imaging in cancer detection, diagnosis, and treatment guidance..Trends Biotechnol2011;29:213-21 PMCID:PMC3080445

[380] Choo YW,Jung K.Recent advances in intravital microscopy for investigation of dynamic cellular behavior in vivo..BMB Rep2020;53:357-66 PMCID:PMC7396917

[381] Ramamonjisoa N.Characterization of the tumor microenvironment and tumor-stroma interaction by non-invasive preclinical imaging..Front Oncol2017;7:3 PMCID:PMC5281579

[382] Ottobrini L,Trabattoni DL,Lucignani G.In vivo imaging of immune cell trafficking in cancer..Eur J Nucl Med Mol Imaging2011;38:949-68

[383] Narunsky L,Bochner F.Imaging aspects of the tumor stroma with therapeutic implications..Pharmacol Ther2014;141:192-208 PMCID:PMC3947248

[384] Krohn KA,Mason RP.Molecular imaging of hypoxia..J Nucl Med.2008;49 Suppl 2:129S-48S

[385] Dogra P,Wang Z.Establishing the effects of mesoporous silica nanoparticle properties on in vivo disposition using imaging-based pharmacokinetics..Nat Commun2018;9:4551 PMCID:PMC6208419

[386] Schmid D,Hartl CA.T cell-targeting nanoparticles focus delivery of immunotherapy to improve antitumor immunity..Nat Commun2017;8:1747 PMCID:PMC5700944

[387] Mattheolabakis G.Nanoparticle delivery and tumor vascular normalization: the chicken or the egg?.Front Oncol2019;9:1227 PMCID:PMC6863425