Targeted drug delivery using nano-sized carrier systems with targeting functions to malignant and inflammatory tissue and tailored controlled drug release inside targeted tissues or cells has been and is still intensively studied. A detailed understanding of the correlation between the pharmacokinetic properties and structure of the nano-sized carrier is crucial for the successful transition of targeted drug delivery nanomedicines into clinical practice. In preclinical research in particular, fluorescence imaging has become one of the most commonly used powerful imaging tools. Increasing numbers of suitable fluorescent dyes that are excitable in the visible to near-infrared (NIR) wavelengths of the spectrum and the non-invasive nature of the method have significantly expanded the applicability of fluorescence imaging. This chapter summarizes non-invasive fluorescence-based imaging methods and discusses their potential advantages and limitations in the field of drug delivery, especially in anticancer therapy. This chapter focuses on fluorescent imaging from the cellular level up to the highly sophisticated three-dimensional imaging modality at a systemic level. Moreover, we describe the possibility for simultaneous treatment and imaging using fluorescence theranostics and the combination of different imaging techniques, e.g., fluorescence imaging with computed tomography.

Institute of Macromolecular Chemistry Czech Academy of Sciences Heyrovského nám 2 162 06 Prague 6 Czech Republic

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Ulbrich K., Holá K., Šubr V., Bakandritsos A., Tuček J., Zbořil R. Targeted Drug Delivery with Polymers and Magnetic Nanoparticles: Covalent and Noncovalent Approaches, Release Control, and Clinical Studies. Chem. Rev. 2016;116:5338–5431. doi: 10.1021/acs.chemrev.5b00589. PubMed DOI

Boas D.A., Brooks D.H., Miller E.L., DiMarzio C.A., Kilmer M., Gaudette R.J., Zhang Q. Imaging the body with diffuse optical tomography. IEEE Signal. Proc. Mag. 2001;18:57–75. doi: 10.1109/79.962278. DOI

Gibson A.P., Hebden J.C., Arridge S.R. Recent advances in diffuse optical imaging. Phys. Med. Biol. 2005;50:R1–R43. doi: 10.1088/0031-9155/50/4/R01. PubMed DOI

Leblond F., Davis S.C., Valdes P.A., Pogue B.W. Pre-clinical whole-body fluorescence imaging: Review of instruments, methods and applications. J. Photochem. Photobiol. B. 2010;98:77–94. doi: 10.1016/j.jphotobiol.2009.11.007. PubMed DOI PMC

Etrych T., Lucas H., Janoušková O., Chytil P., Mueller T., Mäder K. Fluorescence optical imaging in anticancer drug delivery. J. Control. Release. 2016;226:168–181. doi: 10.1016/j.jconrel.2016.02.022. PubMed DOI

Patra J.K., Das G., Fraceto L.F., Campos E.V.R., Rodriguez-Torres M.d.P., Acosta-Torres L.S., Diaz-Torres L.A., Grillo R., Swamy M.K., Sharma S., et al. Nano based drug delivery systems: Recent developments and future prospects. J. Nanobiotechnol. 2018;16:71. doi: 10.1186/s12951-018-0392-8. PubMed DOI PMC

Ganta S., Devalapally H., Shahiwala A., Amiji M. A review of stimuli-responsive nanocarriers for drug and gene delivery. J. Control. Release. 2008;126:187–204. doi: 10.1016/j.jconrel.2007.12.017. PubMed DOI

Dozono H., Yanazume S., Nakamura H., Etrych T., Chytil P., Ulbrich K., Fang J., Arimura T., Douchi T., Kobayashi H., et al. HPMA Copolymer-Conjugated Pirarubicin in Multimodal Treatment of a Patient with Stage IV Prostate Cancer and Extensive Lung and Bone Metastases. Target. Oncol. 2016;11:101–106. doi: 10.1007/s11523-015-0379-4. PubMed DOI

Duncan R., Gaspar R. Nanomedicine(s) under the Microscope. Mol. Pharm. 2011;8:2101–2141. doi: 10.1021/mp200394t. PubMed DOI

Jain R.K., Stylianopoulos T. Delivering nanomedicine to solid tumors. Nat. Rev. Clin. Oncol. 2010;7:653–664. doi: 10.1038/nrclinonc.2010.139. PubMed DOI PMC

Maeda H., Wu J., Sawa T., Matsumura Y., Hori K. Tumor vascular permeability and the EPR effect in macromolecular therapeutics: A review. J. Control. Release. 2000;65:271–284. doi: 10.1016/S0168-3659(99)00248-5. PubMed DOI

Matsumura Y., Maeda H. A New Concept for Macromolecular Therapeutics in Cancer-Chemotherapy - Mechanism of Tumoritropic Accumulation of Proteins and the Antitumor Agent Smancs. Cancer Res. 1986;46:6387–6392. PubMed

Hoffman A.S. The origins and evolution of “controlled” drug delivery systems. J. Control. Release. 2008;132:153–163. doi: 10.1016/j.jconrel.2008.08.012. PubMed DOI

Mulder W.J.M., Strijkers G.J., Van Tilborg G.A.F., Cormode D.P., Fayad Z.A., Nicolay K. Nanoparticulate Assemblies of Amphiphiles and Diagnostically Active Materials for Multimodality Imaging. Acc. Chem. Res. 2009;42:904–914. doi: 10.1021/ar800223c. PubMed DOI PMC

Ulbrich K., Šubr V. Structural and chemical aspects of HPMA copolymers as drug carriers. Adv. Drug Deliv. Rev. 2010;62:150–166. doi: 10.1016/j.addr.2009.10.007. PubMed DOI

Venditto V.J., Szoka F.C. Cancer nanomedicines: So many papers and so few drugs! Adv. Drug Deliv. Rev. 2013;65:80–88. doi: 10.1016/j.addr.2012.09.038. PubMed DOI PMC

Kunjachan S., Jayapaul J., Mertens M.E., Storm G., Kiessling F., Lammers T. Theranostic Systems and Strategies for Monitoring Nanomedicine-Mediated Drug Targeting. Curr. Pharm. Biotechnol. 2012;13:609–622. doi: 10.2174/138920112799436302. PubMed DOI

Lammers T., Aime S., Hennink W.E., Storm G., Kiessling F. Theranostic Nanomedicine. Acc. Chem. Res. 2011;44:1029–1038. doi: 10.1021/ar200019c. PubMed DOI

Phillips M.A., Gran M.L., Peppas N.A. Targeted nanodelivery of drugs and diagnostics. Nano. Today. 2010;5:143–159. doi: 10.1016/j.nantod.2010.03.003. PubMed DOI PMC

Allmeroth M., Moderegger D., Biesalski B., Koynov K., Rosch F., Thews O., Zentel R. Modifying the Body Distribution of HPMA-Based Copolymers by Molecular Weight and Aggregate Formation. Biomacromolecules. 2011;12:2841–2849. doi: 10.1021/bm2005774. PubMed DOI

Lammers T., Kuhnlein R., Kissel M., Šubr V., Etrych T., Pola R., Pechar M., Ulbrich K., Storm G., Huber P., et al. Effect of physicochemical modification on the biodistribution and tumor accumulation of HPMA copolymers. J. Control. Release. 2005;110:103–118. doi: 10.1016/j.jconrel.2005.09.010. PubMed DOI

Lu Z.R. Molecular imaging of HPMA copolymers: Visualizing drug delivery in cell, mouse and man. Adv. Drug Deliv. Rev. 2010;62:246–257. doi: 10.1016/j.addr.2009.12.007. PubMed DOI

Licha K., Olbrich C. Optical imaging in drug discovery and diagnostic applications. Adv. Drug Deliv. Rev. 2005;57:1087–1108. doi: 10.1016/j.addr.2005.01.021. PubMed DOI

Ntziachristos V. Fluorescence molecular imaging. Annu. Rev. Biomed. Eng. 2006;8:1–33. doi: 10.1146/annurev.bioeng.8.061505.095831. PubMed DOI

Ke S., Wen X.X., Gurfinkel M., Charnsangavej C., Wallace S., Sevick-Muraca E.M., Li C. Near-infrared optical imaging of epidermal growth factor receptor in breast cancer xenografts. Cancer Res. 2003;63:7870–7875. PubMed

Wunder A., Tung C.H., Muller-Ladner U., Weissleder R., Mahmood U. In vivo imaging of protease activity in arthritis—A novel approach for monitoring treatment response. Arthritis Rheum. 2004;50:2459–2465. doi: 10.1002/art.20379. PubMed DOI

Zaheer A., Lenkinski R.E., Mahmood A., Jones A.G., Cantley L.C., Frangioni J.V. In vivo near-infrared fluorescence imaging of osteoblastic activity. Nat. Biotechnol. 2001;19:1148–1154. doi: 10.1038/nbt1201-1148. PubMed DOI

Ntziachristos V., Ripoll J., Wang L.H.V., Weissleder R. Looking and listening to light: The evolution of whole-body photonic imaging. Nat. Biotechnol. 2005;23:313–320. doi: 10.1038/nbt1074. PubMed DOI

Hebden J.C., Arridge S.R., Delpy D.T. Optical imaging in medicine.1. Experimental techniques. Phys. Med. Biol. 1997;42:825–840. doi: 10.1088/0031-9155/42/5/007. PubMed DOI

Mahmood U., Weissleder R. Near-infrared optical imaging of proteases in cancer. Mol. Cancer Ther. 2003;2:489–496. PubMed

Hoffmann S., Vystrčilová L., Ulbrich K., Etrych T., Caysa H., Mueller T., Mäder K. Dual Fluorescent HPMA Copolymers for Passive Tumor Targeting with pH-Sensitive Drug Release: Synthesis and Characterization of Distribution and Tumor Accumulation in Mice by Noninvasive Multispectral Optical Imaging. Biomacromolecules. 2012;13:652–663. doi: 10.1021/bm2015027. PubMed DOI

Chytil P., Hoffmann S., Schindler L., Kostka L., Ulbrich K., Caysa H., Mueller T., Mäder K., Etrych T. Dual fluorescent HPMA copolymers for passive tumor targeting with pH- sensitive drug release II: Impact of release rate on biodistribution. J. Control. Release. 2013;172:504–512. doi: 10.1016/j.jconrel.2013.05.008. PubMed DOI

Pu Y., Tang R., Xue J., Wang W.B., Xu B., Achilefu S. Synthesis of dye conjugates to visualize the cancer cells using fluorescence microscopy. Appl. Opt. 2014;53:2345–2351. doi: 10.1364/AO.53.002345. PubMed DOI PMC

Rodríguez-Rodríguez H., Acebrón M., Iborra F.J., Arias-Gonzalez J.R., Juárez B.H. Photoluminescence Activation of Organic Dyes via Optically Trapped Quantum Dots. ACS Nano. 2019;13:7223–7230. doi: 10.1021/acsnano.9b02835. PubMed DOI

Xiong J., Cao X., Yang S., Mo Z., Wang W., Zeng W. Fluorescent Probes for Detection of Protein: From Bench to Bed. Protein Pept. Lett. 2018;25:548–559. doi: 10.2174/0929866525666180531080624. PubMed DOI

Kumar S., Richards-Kortum R. Optical molecular imaging agents for cancer diagnostics and therapeutics. Nanomedicine-Uk. 2006;1:23–30. doi: 10.2217/17435889.1.1.23. PubMed DOI

Freidus L.G., Pradeep P., Kumar P., Choonara Y.E., Pillay V. Alternative fluorophores designed for advanced molecular imaging. Drug Discov. Today. 2018;23:115–133. doi: 10.1016/j.drudis.2017.09.008. PubMed DOI

Gao X.H., Nie S.M. Molecular profiling of single cells and tissue specimens with quantum dots. Trends Biotechnol. 2003;21:371–373. doi: 10.1016/S0167-7799(03)00209-9. PubMed DOI

Xue J.P., Shan L.L., Chen H.Y., Li Y., Zhu H.Y., Deng D.W., Qian Z.Y., Achilefu S., Gu Y.Q. Visual detection of STAT5B gene expression in living cell using the hairpin DNA modified gold nanoparticle beacon. Biosens. Bioelectron. 2013;41:71–77. doi: 10.1016/j.bios.2012.06.062. PubMed DOI

Hoffman R.M. Application of GFP imaging in cancer. Lab. Investig. 2015;95:432–452. doi: 10.1038/labinvest.2014.154. PubMed DOI PMC

McCann T., Kosaka N., Choyke P., Kobayashi H. The Use of Fluorescent Proteins for Developing Cancer-Specific Target Imaging Probes. In: Hoffman R.M., editor. In Vivo Cellular Imaging Using Fluorescent Proteins. Volume 872. Humana Press; Totowa, NJ, USA: 2012. pp. 191–204. PubMed PMC

Karasev M.M., Stepanenko O.V., Rumyantsev K.A., Turoverov K.K., Verkhusha V.V. Near-Infrared Fluorescent Proteins and Their Applications. Biochem-Moscow. 2019;84:32–50. doi: 10.1134/S0006297919140037. PubMed DOI

Heinrich A.K., Lucas H., Schindler L., Chytil P., Etrych T., Mäder K., Mueller T. Improved Tumor-Specific Drug Accumulation by Polymer Therapeutics with pH-Sensitive Drug Release Overcomes Chemotherapy Resistance. Mol. Cancer Ther. 2016;15:998–1007. doi: 10.1158/1535-7163.MCT-15-0824. PubMed DOI

Dolloff N.G., Ma X.H., Dicker D.T., Humphreys R.C., Li L.Z., El-Deiry W.S. Spectral imaging-based methods for quantifying autophagy and apoptosis. Cancer Biol. Ther. 2011;12:349–356. doi: 10.4161/cbt.12.4.17175. PubMed DOI PMC

Galateanu B., Hudita A., Negrei C., Ion R.M., Costache M., Stan M., Nikitovic D., Hayes A.W., Spandidos D.A., Tsatsakis A.M., et al. Impact of multicellular tumor spheroids as an in vivo-like tumor model on anticancer drug response. Int. J. Oncol. 2016;48:2295–2302. doi: 10.3892/ijo.2016.3467. PubMed DOI PMC

Ballou B., Fisher G.W., Hakala T.R., Farkas D.L. Tumor detection and visualization using cyanine fluorochrome-labeled antibodies. Biotechnol. Progr. 1997;13:649–658. doi: 10.1021/bp970088t. PubMed DOI

Lidický O., Janoušková O., Strohalm J., Alam M., Klener P., Etrych T. Anti-Lymphoma Efficacy Comparison of Anti-Cd20 Monoclonal Antibody-Targeted and Non-Targeted Star-Shaped Polymer-Prodrug Conjugates. Molecules. 2015;20:19849–19864. doi: 10.3390/molecules201119664. PubMed DOI PMC

Folli S., Westermann P., Braichotte D., Pelegrin A., Wagnieres G., van den Bergh H., Mach J.P. Antibody-indocyanin conjugates for immunophotodetection of human squamous cell carcinoma in nude mice. Cancer Res. 1994;54:2643–2649. PubMed

Pechar M., Pola R., Janoušková O., Sieglová I., Král V., Fábry M., Tomalová B., Kovář M. Polymer Cancerostatics Targeted with an Antibody Fragment Bound via a Coiled Coil Motif: In Vivo Therapeutic Efficacy against Murine BCL1 Leukemia. Macromol. Biosci. 2018;18:1700173. doi: 10.1002/mabi.201700173. PubMed DOI

Pola R., Studenovsky M., Pechar M., Ulbrich K., Hovorka O., Vetvicka D., Rihova B. HPMA-copolymer conjugates targeted to tumor endothelium using synthetic oligopeptides. J. Drug Target. 2009;17:763–776. doi: 10.3109/10611860903115282. PubMed DOI

Studenovsky M., Pola R., Pechar M., Etrych T., Ulbrich K., Kovar L., Kabesova M., Rihova B. Polymer carriers for anticancer drugs targeted to EGF receptor. Macromol. Biosci. 2012;12:1714–1720. doi: 10.1002/mabi.201200270. PubMed DOI

Song Y., Zhu Z., An Y., Zhang W., Zhang H., Liu D., Yu C., Duan W., Yang C.J. Selection of DNA aptamers against epithelial cell adhesion molecule for cancer cell imaging and circulating tumor cell capture. Anal. Chem. 2013;85:4141–4149. doi: 10.1021/ac400366b. PubMed DOI

Tung C.H. Fluorescent peptide probes for in vivo diagnostic imaging. Biopolymers. 2004;76:391–403. doi: 10.1002/bip.20139. PubMed DOI

Weissleder R. Molecular imaging: Exploring the next frontier. Radiology. 1999;212:609–614. doi: 10.1148/radiology.212.3.r99se18609. PubMed DOI

Shi H., Lei Y., Ge J., He X., Cui W., Ye X., Liu J., Wang K. A Simple, pH-Activatable Fluorescent Aptamer Probe with Ultralow Background for Bispecific Tumor Imaging. Anal. Chem. 2019;91:9154–9160. doi: 10.1021/acs.analchem.9b01828. PubMed DOI

Muller-Taubenberger A., Anderson K.I. Recent advances using green and red fluorescent protein variants. Appl. Microbiol. Biotechnol. 2007;77:1–12. doi: 10.1007/s00253-007-1131-5. PubMed DOI

Hoffman R.M. The multiple uses of fluorescent proteins to visualize cancer in vivo. Nat. Rev. Cancer. 2005;5:796–806. doi: 10.1038/nrc1717. PubMed DOI

Chudakov D.M., Matz M.V., Lukyanov S., Lukyanov K.A. Fluorescent Proteins and Their Applications in Imaging Living Cells and Tissues. Physiol. Rev. 2010;90:1103–1163. doi: 10.1152/physrev.00038.2009. PubMed DOI

Choy G., Choyke P., Libutti S.K. Current Advances in Molecular Imaging: Noninvasive in Vivo Bioluminescent and Fluorescent Optical Imaging in Cancer Research. Mol. Imaging. 2003;2:15353500200303142. doi: 10.1162/15353500200303142. PubMed DOI

Barua S., Yoo J.W., Kolhar P., Wakankar A., Gokarn Y.R., Mitragotri S. Particle shape enhances specificity of antibody-displaying nanoparticles. PNAS. 2013;110:3270–3275. doi: 10.1073/pnas.1216893110. PubMed DOI PMC

Gratton S.E., Ropp P.A., Pohlhaus P.D., Luft J.C., Madden V.J., Napier M.E., DeSimone J.M. The effect of particle design on cellular internalization pathways. PNAS. 2008;105:11613–11618. doi: 10.1073/pnas.0801763105. PubMed DOI PMC

Huang X., Teng X., Chen D., Tang F., He J. The effect of the shape of mesoporous silica nanoparticles on cellular uptake and cell function. Biomaterials. 2010;31:438–448. doi: 10.1016/j.biomaterials.2009.09.060. PubMed DOI

Shi J., Choi J.L., Chou B., Johnson R.N., Schellinger J.G., Pun S.H. Effect of polyplex morphology on cellular uptake, intracellular trafficking, and transgene expression. ACS nano. 2013;7:10612–10620. doi: 10.1021/nn403069n. PubMed DOI PMC

Koziolová E., Goel S., Chytil P., Janoušková O., Barnhart T.E., Cai W., Etrych T. A tumor-targeted polymer theranostics platform for positron emission tomography and fluorescence imaging. Nanoscale. 2017;9:10906–10918. doi: 10.1039/C7NR03306K. PubMed DOI PMC

Pola R., Laga R., Ulbrich K., Sieglová I., Král V., Fábry M., Kabešová M., Kovář M., Pechar M. Polymer Therapeutics with a Coiled Coil Motif Targeted against Murine BCL1 Leukemia. Biomacromolecules. 2013;14:881–889. doi: 10.1021/bm3019592. PubMed DOI

Pola R., Král V., Filippov S.K., Kaberov L., Etrych T., Sieglová I., Sedláček J., Fábry M., Pechar M. Polymer Cancerostatics Targeted by Recombinant Antibody Fragments to GD2-Positive Tumor Cells. Biomacromolecules. 2019;20:412–421. doi: 10.1021/acs.biomac.8b01616. PubMed DOI

Jiang S., Gnanasammandhan M.K., Zhang Y. Optical imaging-guided cancer therapy with fluorescent nanoparticles. J. R. Soc. Interface. 2010;7:3–18. doi: 10.1098/rsif.2009.0243. PubMed DOI PMC

Koziolová E., Machová D., Pola R., Janoušková O., Chytil P., Laga R., Filippov S.K., Šubr V., Etrych T., Pechar M. Micelle-forming HPMA copolymer conjugates of ritonavir bound via a pH-sensitive spacer with improved cellular uptake designed for enhanced tumor accumulation. J. Mater. Chem. B. 2016;4:7620–7629. doi: 10.1039/C6TB02225A. PubMed DOI

Hovorka O., Etrych T., Šubr V., Strohalm J., Ulbrich K., Říhová B. HPMA based macromolecular therapeutics: Internalization, intracellular pathway and cell death depend on the character of covalent bond between the drug and the peptidic spacer and also on spacer composition. J. Drug Target. 2006;14:391–403. doi: 10.1080/10611860600833591. PubMed DOI

Machová D., Koziolová E., Chytil P., Venclíková K., Etrych T., Janoušková O. Nanotherapeutics with suitable properties for advanced anticancer therapy based on HPMA copolymer-bound ritonavir via pH-sensitive spacers. Eur. J. Pharm. Biopharm. 2018;131:141–150. doi: 10.1016/j.ejpb.2018.07.023. PubMed DOI

Chen Y., Walsh R.J., Arriaga E.A. Selective determination of the doxorubicin content of individual acidic organelles in impure subcellular fractions. Anal. Chem. 2005;77:2281–2287. doi: 10.1021/ac0480996. PubMed DOI

Shen F., Chu S., Bence A.K., Bailey B., Xue X., Erickson P.A., Montrose M.H., Beck W.T., Erickson L.C. Quantitation of doxorubicin uptake, efflux, and modulation of multidrug resistance (MDR) in MDR human cancer cells. J. Pharmacol. Exp. Ther. 2008;324:95–102. doi: 10.1124/jpet.107.127704. PubMed DOI

Priem B., Tian C., Tang J., Zhao Y., Mulder W.J.M. Fluorescent nanoparticles for the accurate detection of drug delivery. Expert Opin. Drug Deliv. 2015;12:1881–1894. doi: 10.1517/17425247.2015.1074567. PubMed DOI

Nori A., Kopecek J. Intracellular targeting of polymer-bound drugs for cancer chemotherapy. Adv. Drug Deliv. Rev. 2005;57:609–636. doi: 10.1016/j.addr.2004.10.006. PubMed DOI

Chytil P., Koziolová E., Janoušková O., Kostka L., Ulbrich K., Etrych T. Synthesis and Properties of Star HPMA Copolymer Nanocarriers Synthesised by RAFT Polymerisation Designed for Selective Anticancer Drug Delivery and Imaging. Macromol. Biosci. 2015;15:839–850. doi: 10.1002/mabi.201400510. PubMed DOI

Laga R., Janoušková O., Ulbrich K., Pola R., Blažková J., Filippov S.K., Etrych T., Pechar M. Thermoresponsive Polymer Micelles as Potential Nanosized Cancerostatics. Biomacromolecules. 2015;16:2493–2505. doi: 10.1021/acs.biomac.5b00764. PubMed DOI

Braunová A., Kostka L., Sivák L., Cuchalová L., Hvězdová Z., Laga R., Filippov S., Černoch P., Pechar M., Janoušková O., et al. Tumor-targeted micelle-forming block copolymers for overcoming of multidrug resistance. J. Control. Release. 2017;245:41–51. doi: 10.1016/j.jconrel.2016.11.020. PubMed DOI

Zhang R., Yang J., Radford D.C., Fang Y., Kopeček J. FRET Imaging of Enzyme-Responsive HPMA Copolymer Conjugate. Macromol. Biosci. 2017;17:1600125. doi: 10.1002/mabi.201600125. PubMed DOI

Yang J.Y., Zhang R., Radford D.C., Kopecek J. FRET-trackable biodegradable HPMA copolymer-epirubicin conjugates for ovarian carcinoma therapy. J. Control. Release. 2015;218:36–44. doi: 10.1016/j.jconrel.2015.09.045. PubMed DOI PMC

Fan W., Shi W., Zhang W., Jia Y., Zhou Z., Brusnahan S.K., Garrison J.C. Cathepsin S-cleavable, multi-block HPMA copolymers for improved SPECT/CT imaging of pancreatic cancer. Biomaterials. 2016;103:101–115. doi: 10.1016/j.biomaterials.2016.05.036. PubMed DOI PMC

Bhuckory S., Kays J.C., Dennis A.M. In Vivo Biosensing Using Resonance Energy Transfer. Biosensors. 2019;9:76. doi: 10.3390/bios9020076. PubMed DOI PMC

Basuki J.S., Duong H.T.T., Macmillan A., Erlich R.B., Esser L., Akerfeldt M.C., Whan R.M., Kavallaris M., Boyer C., Davis T.P. Using Fluorescence Lifetime Imaging Microscopy to Monitor Theranostic Nanoparticle Uptake and Intracellular Doxorubicin Release. ACS Nano. 2013;7:10175–10189. doi: 10.1021/nn404407g. PubMed DOI

Dai X.W., Yue Z.L., Eccleston M.E., Swartling J., Slater N.K.H., Kaminski C.F. Fluorescence intensity and lifetime imaging of free and micellar-encapsulated doxorubicin in living cells. Nanomed-Nanotechnol. 2008;4:49–56. doi: 10.1016/j.nano.2007.12.002. PubMed DOI

Mansfield J.R., Gossage K.W., Hoyt C.C., Levenson R.M. Autofluorescence removal, multiplexing, and automated analysis methods for in-vivo fluorescence imaging. J. Biomed. Opt. 2005;10:041207. doi: 10.1117/1.2032458. PubMed DOI

Weissleder R. A clearer vision for in vivo imaging. Nat. Biotechnol. 2001;19:316–317. doi: 10.1038/86684. PubMed DOI

Hoffmann S., Caysa H., Kuntsche J., Kreideweiss P., Leimert A., Mueller T., Mäder K. Carbohydrate plasma expanders for passive tumor targeting: In vitro and in vivo studies. Carbohyd. Polym. 2013;95:404–413. doi: 10.1016/j.carbpol.2013.03.033. PubMed DOI

Han Y.-H., Kankala R.K., Wang S.-B., Chen A.-Z. Leveraging Engineering of Indocyanine Green-Encapsulated Polymeric Nanocomposites for Biomedical Applications. Nanomaterials. 2018;8:360. doi: 10.3390/nano8060360. PubMed DOI PMC

Kolitz-Domb M., Grinberg I., Corem-Salkmon E., Margel S. Engineering of near infrared fluorescent proteinoid-poly(L-lactic acid) particles for in vivo colon cancer detection. J. Nanobiotechnol. 2014;12:30. doi: 10.1186/s12951-014-0030-z. PubMed DOI PMC

Hirsjarvi S., Sancey L., Dufort S., Belloche C., Vanpouille-Box C., Garcion E., Coll J.L., Hindre F., Benoit J.P. Effect of particle size on the biodistribution of lipid nanocapsules: Comparison between nuclear and fluorescence imaging and counting. Int. J. Pharm. 2013;453:594–600. doi: 10.1016/j.ijpharm.2013.05.057. PubMed DOI

Studenovský M., Heinrich A.-K., Lucas H., Mueller T., Mäder K., Etrych T. Dual fluorescent N-(2-hydroxypropyl)methacrylamide-based conjugates for passive tumor targeting with reduction-sensitive drug release: Proof of the concept, tumor accumulation, and biodistribution. J. Bioact. Compat. Pol. 2016 doi: 10.1177/0883911515618975. DOI

Pola R., Heinrich A.K., Mueller T., Kostka L., Mäder K., Pechar M., Etrych T. Passive Tumor Targeting of Polymer Therapeutics: In Vivo Imaging of Both the Polymer Carrier and the Enzymatically Cleavable Drug Model. Macromol. Biosci. 2016;16:1577–1582. doi: 10.1002/mabi.201600273. PubMed DOI

Cho H., Kwon G.S. Polymeric Micelles for Neoadjuvant Cancer Therapy and Tumor-Primed Optical Imaging. ACS Nano. 2011;5:8721–8729. doi: 10.1021/nn202676u. PubMed DOI PMC

Pola R., Parnica J., Zuska K., Böhmová E., Filipová M., Pechar M., Pankrác J., Mucksová J., Kalina J., Trefil P., et al. Oligopeptide-targeted polymer nanoprobes for fluorescence-guided endoscopic surgery. Multifunct. Mater. 2019;2:024004. doi: 10.1088/2399-7532/ab159e. DOI

Ko J.Y., Park S., Lee H., Koo H., Kim M.S., Choi K., Kwon I.C., Jeong S.Y., Kim K., Lee D.S. pH-Sensitive Nanoflash for Tumoral Acidic pH Imaging in Live Animals. Small. 2010;6:2539–2544. doi: 10.1002/smll.201001252. PubMed DOI

Gao G.H., Li Y., Lee D.S. Environmental pH-sensitive polymeric micelles for cancer diagnosis and targeted therapy. J. Control. release. 2013;169:180–184. doi: 10.1016/j.jconrel.2012.11.012. PubMed DOI

Etrych T., Daumová L., Pokorná E., Tušková D., Lidický O., Kolářová V., Pankrác J., Šefc L., Chytil P., Klener P. Effective doxorubicin-based nano-therapeutics for simultaneous malignant lymphoma treatment and lymphoma growth imaging. J. Control. Release. 2018;289:44–55. doi: 10.1016/j.jconrel.2018.09.018. PubMed DOI

Berg K., Selbo P.K., Weyergang A., Dietze A., Prasmickaite L., Bonsted A., Engesaeter B.O., Angell-Petersen E., Warloe T., Frandsen N., et al. Porphyrin-related photosensitizers for cancer imaging and therapeutic applications. J. Microsc-Oxford. 2005;218:133–147. doi: 10.1111/j.1365-2818.2005.01471.x. PubMed DOI

Nakamura H., Liao L., Hitaka Y., Tsukigawa K., Šubr V., Fang J., Ulbrich K., Maeda H. Micelles of zinc protoporphyrin conjugated to N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer for imaging and light-induced antitumor effects in vivo. J. Control. Release. 2013;165:191–198. doi: 10.1016/j.jconrel.2012.11.017. PubMed DOI

Hackbarth S., Islam W., Fang J., Šubr V., Röder B., Etrych T., Maeda H. Singlet oxygen phosphorescence detection in vivo identifies PDT-induced anoxia in solid tumors. Photochem. Photobiol. Sci. 2019;18:1304–1314. doi: 10.1039/C8PP00570B. PubMed DOI

Niedre M.J., de Kleine R.H., Aikawa E., Kirsch D.G., Weissleder R., Ntziachristos V. Early photon tomography allows fluorescence detection of lung carcinomas and disease progression in mice in vivo. Proc. Natl. Acad. Sci. USA. 2008;105:19126–19131. doi: 10.1073/pnas.0804798105. PubMed DOI PMC

Hall D., Ma G.B., Lesage F., Yong W. Simple time-domain optical method for estimating the depth and concentration of a fluorescent inclusion in a turbid medium. Opt. Lett. 2004;29:2258–2260. doi: 10.1364/OL.29.002258. PubMed DOI

Swartling J., Svensson J., Bengtsson D., Terike K., Andersson-Engels S. Fluorescence spectra provide information on the depth of fluorescent lesions in tissue. Appl. Opt. 2005;44:1934–1941. doi: 10.1364/AO.44.001934. PubMed DOI

Shi J.W., Liu F., Pu H.S., Zuo S.M., Luo J.W., Bai J. An adaptive support driven reweighted L1-regularization algorithm for fluorescence molecular tomography. Biomed. Opt. Express. 2014;5:4039–4052. doi: 10.1364/BOE.5.004039. PubMed DOI PMC

Favicchio R., Psycharakis S., Schonig K., Bartsch D., Mamalaki C., Papamatheakis J., Ripoll J., Zacharakis G. Quantitative performance characterization of three-dimensional noncontact fluorescence molecular tomography. J. Biomed. Opt. 2016;21:026009. doi: 10.1117/1.JBO.21.2.026009. PubMed DOI

Pian Q., Yao R.Y., Zhao L.L., Intes X. Hyperspectral time-resolved wide-field fluorescence molecular tomography based on structured light and single-pixel detection. Opt. Lett. 2015;40:431–434. doi: 10.1364/OL.40.000431. PubMed DOI PMC

An Y., Liu J., Zhang G.L., Ye J.Z., Du Y., Mao Y., Chi C.W., Tian J. A Novel Region Reconstruction Method for Fluorescence Molecular Tomography. IEEE Trans. Biomed. Eng. 2015;62:1818–1826. doi: 10.1109/TBME.2015.2404915. PubMed DOI

Chi C., Du Y., Ye J., Kou D., Qiu J., Wang J., Tian J., Chen X. Intraoperative Imaging-Guided Cancer Surgery: From Current Fluorescence Molecular Imaging Methods to Future Multi-Modality Imaging Technology. Theranostics. 2014;4:1072–1084. doi: 10.7150/thno.9899. PubMed DOI PMC

Kelly K., Alencar H., Funovics M., Mahmood U., Weissleder R. Detection of invasive colon cancer using a novel, targeted, library-derived fluorescent peptide. Cancer Res. 2004;64:6247–6251. doi: 10.1158/0008-5472.CAN-04-0817. PubMed DOI

Heffer E., Pera V., Schutz O., Siebold H., Fantini S. Near-infrared imaging of the human breast: Complementing hemoglobin concentration maps with oxygenation images. J. Biomed. Opt. 2004;9:1152–1160. doi: 10.1117/1.1805552. PubMed DOI

Choe R., Corlu A., Lee K., Durduran T., Konecky S.D., Grosicka-Koptyra M., Arridge S.R., Czerniecki B.J., Fraker D.L., DeMichele A., et al. Diffuse optical tomography of breast cancer during neoadjuvant chemotherapy: A case study with comparison to MRI. Medical. Phys. 2005;32:1128–1139. doi: 10.1118/1.1869612. PubMed DOI

Taroni P., Danesini G., Torricelli A., Pifferi A., Spinelli L., Cubeddu R. Clinical trial of time-resolved scanning optical mammography at 4 wavelengths between 683 and 975 nm. J. Biomed. Opt. 2004;9:464–473. doi: 10.1117/1.1695561. PubMed DOI

Corlu A., Choe R., Durduran T., Rosen M.A., Schweiger M., Arridge S.R., Schnall M.D., Yodh A.G. Three-dimensional in vivo fluorescence diffuse optical tomography of breast cancer in humans. Opt. Express. 2007;15:6696–6716. doi: 10.1364/OE.15.006696. PubMed DOI

Intes X., Ripoll J., Chen Y., Nioka S., Yodh A.G., Chance B. In vivo continuous-wave optical breast imaging enhanced with Indocyanine Green. Med. Phys. 2003;30:1039–1047. doi: 10.1118/1.1573791. PubMed DOI

Graves E.E., Ripoll J., Weissleder R., Ntziachristos V. A submillimeter resolution fluorescence molecular imaging system for small animal imaging. Med. Phys. 2003;30:901–911. doi: 10.1118/1.1568977. PubMed DOI

Ntziachristos V., Weissleder R. Experimental three-dimensional fluorescence reconstruction of diffuse media by use of a normalized Born approximation. Opt. Lett. 2001;26:893–895. doi: 10.1364/OL.26.000893. PubMed DOI

Ale A., Ermolayev V., Herzog E., Cohrs C., de Angelis M.H., Ntziachristos V. FMT-XCT: In vivo animal studies with hybrid fluorescence molecular tomography-X-ray computed tomography. Nat. Methods. 2012;9:615–620. doi: 10.1038/nmeth.2014. PubMed DOI

Panizzi P., Nahrendorf M., Figueiredo J.L., Panizzi J., Marinelli B., Iwamoto Y., Keliher E., Maddur A.A., Waterman P., Kroh H.K., et al. In vivo detection of Staphylococcus aureus endocarditis by targeting pathogen-specific prothrombin activation. Nat. Med. 2011;17:1142–1146. doi: 10.1038/nm.2423. PubMed DOI PMC

Vonwil D., Christensen J., Fischer S., Ronneberger O., Shastri V.P. Validation of Fluorescence Molecular Tomography/Micro-CT Multimodal Imaging In Vivo in Rats. Mol. Imaging Biol. 2014;16:350–361. doi: 10.1007/s11307-013-0698-8. PubMed DOI

Schulz R.B., Ale A., Sarantopoulos A., Freyer M., Soehngen E., Zientkowska M., Ntziachristos V. Hybrid System for Simultaneous Fluorescence and X-Ray Computed Tomography. IEEE Trans. Med. Imaging. 2010;29:465–473. doi: 10.1109/TMI.2009.2035310. PubMed DOI

Nahrendorf M., Keliher E., Marinelli B., Waterman P., Feruglio P.F., Fexon L., Pivovarov M., Swirski F.K., Pittet M.J., Vinegoni C., et al. Hybrid PET-optical imaging using targeted probes. Proc. Natl. Acad. Sci. USA. 2010;107:7910–7915. doi: 10.1073/pnas.0915163107. PubMed DOI PMC

Ma X., Phi Van V., Kimm M.A., Prakash J., Kessler H., Kosanke K., Feuchtinger A., Aichler M., Gupta A., Rummeny E.J., et al. Integrin-Targeted Hybrid Fluorescence Molecular Tomography/X-ray Computed Tomography for Imaging Tumor Progression and Early Response in Non-Small Cell Lung Cancer. Neoplasia. 2017;19:8–16. doi: 10.1016/j.neo.2016.11.009. PubMed DOI PMC

Kunjachan S., Gremse F., Theek B., Koczera P., Pola R., Pechar M., Etrych T., Ulbrich K., Storm G., Kiessling F., et al. Noninvasive Optical Imaging of Nanomedicine Biodistribution. ACS Nano. 2013;7:252–262. doi: 10.1021/nn303955n. PubMed DOI PMC

Kunjachan S., Pola R., Gremse F., Theek B., Ehling J., Moeckel D., Hermanns-Sachweh B., Pechar M., Ulbrich K., Hennink W.E., et al. Passive versus Active Tumor Targeting Using RGD- and NGR-Modified Polymeric Nanomedicines. Nano. Lett. 2014;14:972–981. doi: 10.1021/nl404391r. PubMed DOI PMC

Giddabasappa A., Gupta V.R., Norberg R., Gupta P., Spilker M.E., Wentland J., Rago B., Eswaraka J., Leal M., Sapra P. Biodistribution and Targeting of Anti-5T4 Antibody-Drug Conjugate Using Fluorescence Molecular Tomography. Mol. Cancer Ther. 2016;15:2530–2540. doi: 10.1158/1535-7163.MCT-15-1012. PubMed DOI

Theek B., Baues M., Gremse F., Pola R., Pechar M., Negwer I., Koynov K., Weber B., Barz M., Jahnen-Dechent W., et al. Histidine-rich glycoprotein-induced vascular normalization improves EPR-mediated drug targeting to and into tumors. J. Control. Release. 2018;282:25–34. doi: 10.1016/j.jconrel.2018.05.002. PubMed DOI PMC

Lee H., Lytton-Jean A.K.R., Chen Y., Love K.T., Park A.I., Karagiannis E.D., Sehgal A., Querbes W., Zurenko C.S., Jayaraman M., et al. Molecularly self-assembled nucleic acid nanoparticles for targeted in vivo siRNA delivery. Nat. Nanotechnol. 2012;7:389–393. doi: 10.1038/nnano.2012.73. PubMed DOI PMC

Novobrantseva T.I., Borodovsky A., Wong J., Klebanov B., Zafari M., Yucius K., Querbes W., Ge P., Ruda V.M., Milstein S., et al. Systemic RNAi-mediated Gene Silencing in Nonhuman Primate and Rodent Myeloid Cells. Mol. Ther-Nucl Acids. 2012;1:e4. doi: 10.1038/mtna.2011.3. PubMed DOI PMC

Al Rawashdeh W., Zuo S., Melle A., Appold L., Koletnik S., Tsvetkova Y., Beztsinna N., Pich A., Lammers T., Kiessling F., et al. Noninvasive Assessment of Elimination and Retention using CT-FMT and Kinetic Whole-body Modeling. Theranostics. 2017;7:1499–1510. doi: 10.7150/thno.17263. PubMed DOI PMC

Li B.Q., Maafi F., Berti R., Pouliot P., Rheaume E., Tardif J.C., Lesage F. Hybrid FMT-MRI applied to in vivo atherosclerosis imaging. Biomed. Opt. Express. 2014;5:1664–1676. doi: 10.1364/BOE.5.001664. PubMed DOI PMC

Sosnovik D.E., Nahrendorf M., Deliolanis N., Novikov M., Aikawa E., Josephson L., Rosenzweig A., Weissleder R., Ntziachristos V. Fluorescence tomography and magnetic resonance imaging of myocardial macrophage infiltration in infarcted myocardium in vivo. Circulation. 2007;115:1384–1391. doi: 10.1161/CIRCULATIONAHA.106.663351. PubMed DOI

Zhang Y., Zhang B., Liu F., Luo J.W., Bai J. In vivo tomographic imaging with fluorescence and MRI using tumor-targeted dual-labeled nanoparticles. Int. J. Nanomed. 2014;9:33–41. doi: 10.2147/IJN.S52492. PubMed DOI PMC

Gaedicke S., Braun F., Prasad S., Machein M., Firat E., Hettich M., Gudihal R., Zhu X., Klingner K., Schüler J., et al. Noninvasive positron emission tomography and fluorescence imaging of CD133+ tumor stem cells. Proc. Natl. Acad. Sci. USA. 2014;111:E692–E701. doi: 10.1073/pnas.1314189111. PubMed DOI PMC

Boutet J., Herve L., Debourdeau M., Guyon L., Peltie P., Dinten J.M., Saroul L., Duboeuf F., Vray D. Bimodal ultrasound and fluorescence approach for prostate cancer diagnosis. J. Biomed. Opt. 2009;14:064001. doi: 10.1117/1.3257236. PubMed DOI

Laidevant A., Herve L., Debourdeau M., Boutet J., Grenier N., Dinten J.M. Fluorescence time-resolved imaging system embedded in an ultrasound prostate probe. Biomed. Opt. Express. 2011;2:194–206. doi: 10.1364/BOE.2.000194. PubMed DOI PMC

Theek B., Gremse F., Kunjachan S., Fokong S., Pola R., Pechar M., Deckers R., Storm G., Ehling J., Kiessling F., et al. Characterizing EPR-mediated passive drug targeting using contrast-enhanced functional ultrasound imaging. J. Control. Release. 2014;182:83–89. doi: 10.1016/j.jconrel.2014.03.007. PubMed DOI PMC

McCann C.M., Waterman P., Figueiredo J.L., Aikawa E., Weissleder R., Chen J.W. Combined magnetic resonance and fluorescence imaging of the living mouse brain reveals glioma response to chemotherapy. Neuroimage. 2009;45:360–369. doi: 10.1016/j.neuroimage.2008.12.022. PubMed DOI PMC

Penet M.F., Mikhaylova M., Li C., Krishnamachary B., Glunde K., Pathak A.P., Bhujwalla Z.M. Applications of molecular MRI and optical imaging in cancer. Future Med. Chem. 2010;2:975–988. doi: 10.4155/fmc.10.25. PubMed DOI PMC

Mikhaylova M., Stasinopoulos I., Kato Y., Artemov D., Bhujwalla Z.M. Imaging of cationic multifunctional liposome-mediated delivery of COX-2 siRNA. Cancer Gene Ther. 2009;16:217–226. doi: 10.1038/cgt.2008.79. PubMed DOI PMC

Medarova Z., Pham W., Farrar C., Petkova V., Moore A. In vivo imaging of siRNA delivery and silencing in tumors. Nat. Med. 2007;13:372–377. doi: 10.1038/nm1486. PubMed DOI