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Visualization of Nanocarriers and Drugs in Cells and Tissue

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Drug Delivery and Targeting

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 284))

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Abstract

In this chapter, the visualization of nanocarriers and drugs in cells and tissue is reviewed. This topic is tightly connected to modern drug delivery, which relies on nanoscopic drug formulation approaches and the ability to probe nanoparticulate systems selectively in cells and tissue using advanced spectroscopic and microscopic techniques. We first give an overview of the breadth of this research field. Then, we mainly focus on topical drug delivery to the skin and discuss selected visualization techniques from spectromicroscopy, such as scanning transmission X-ray microscopy and fluorescence lifetime imaging. These techniques rely on the sensitive and quantitative detection of the topically applied drug delivery systems and active substances, either by exploiting their molecular properties or by introducing environmentally sensitive probes that facilitate their detection.

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Abbreviations

ADC:

Analog-to-digital converter

CARS:

Coherent anti-Stokes Raman scattering

CFD:

Constant-fraction discriminator

CMS-ICC:

ICC-tagged core-multishell nanocarriers

Cy3:

Cyanine-3

D/DE:

Dermis

DL:

Dual label

EDX:

Energy-dispersive X-ray emission

EPR:

Electron paramagnetic resonance

FITC:

Fluorescein isothiocyanate

FLIM:

Fluorescence lifetime imaging microscopy

FRET:

Fluorescence resonance energy transfer

HEC:

Hydroxyethyl cellulose

ICC:

Indocarbocyanine

MALDI:

Matrix-assisted laser desorption ionization

MG-FITC:

FITC-tagged tecto-dendrimer

NC:

Nanocarrier

NIR:

Near-infrared

NMR:

Nuclear magnetic resonance

OPO:

Optical parametric oscillator

PAM:

Photoacoustic microscopy

PCA:

Principal component analysis

PEEM:

Photoemission electron microscopy

ppt:

Parts per trillion

SC:

Stratum corneum

SCC-25:

Human tongue carcinoma cell line

SEM:

Scanning electron microscopy

SIMS:

Secondary ion mass spectrometry

SRS:

Stimulated Raman scattering

s-SNOM:

Scattering-scanning near-field optical microscopy

STXM:

Scanning transmission X-ray microscopy

TAC:

Time-to-amplitude converter

TCSPC:

Time-correlated single photon counting

TEM:

Transmission electron microscopy

TERS:

Tip-enhanced Raman spectroscopy

TEWL:

Transepidermal water loss

TIRFM:

Total internal reflection fluorescence microscopy

TOF:

Time-of-flight

TXM:

Transmission X-ray microscopy

UV:

Ultraviolet

VE:

Viable epidermis

References

  • Ahluwalia A (1998) Topical glucocorticoids and the skin-mechanisms of action: an update. Mediators Inflamm 7:183–193

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Alexander H, Brown S, Danby S, Flohr C (2018) Research techniques made simple: transepidermal water loss measurement as a research tool. J Investig Dermatol 138:2295–2300

    Article  CAS  PubMed  Google Scholar 

  • Alexiev U, Farrens DL (2014) Fluorescence spectroscopy of rhodopsins: insights and approaches. BBA-Bioenergetics 1837:694–709

    Article  CAS  PubMed  Google Scholar 

  • Alexiev U, Volz P, Boreham A, Brodwolf R (2017) Time-resolved fluorescence microscopy (FLIM) as an analytical tool in skin nanomedicine. Eur J Pharm Biopharm 116:111–124

    Article  PubMed  Google Scholar 

  • Alnasif N, Zoschke C, Fleige E, Brodwolf R, Boreham A, Rühl E, Eckl KM, Merk HF, Hennies HC, Alexiev U, Haag R, Küchler S, Schäfer-Korting M (2014) Penetration of normal, damaged and diseased skin - an in vitro study on dendritic core-multishell nanotransporters. J Control Release 185:45–50

    Article  CAS  PubMed  Google Scholar 

  • Alvarez Núñez FA, Yalkowsky SH (1997) Correlation between log P and ClogP for some steroids. J Pharm Sci 86:1187–1189

    Article  PubMed  Google Scholar 

  • Amos WB, White JG (2003) How the confocal laser scanning microscope entered biological research. Biol Cell 95:335–342

    Article  CAS  PubMed  Google Scholar 

  • Ashtikar M, Langelüddecke L, Fahr A, Deckert V (2017) Tip-enhanced Raman scattering for tracking of invasomes in the stratum corneum. BBA-Gen Subjects 1861:2630–2639

    Article  CAS  Google Scholar 

  • Balke J, Volz P, Neumann F, Brodwolf R, Wolf A, Pischon H, Radbruch M, Mundhenk L, Gruber AD, Ma N, Alexiev U (2018) Visualizing oxidative cellular stress induced by nanoparticles in the subcytotoxic range using fluorescence lifetime imaging. Small 14:1800310

    Article  Google Scholar 

  • Becker W (2021) The bh TCSPC handbook (9th edition). Becker and Hickl GmbH. Available on https://www.becker-hickl.com/literature/documents/flim/the-bh-tcspc-handbook/

  • Benson HAE, Grice JE, Mohammed Y, Namjoshi S, Roberts MS (2019) Topical and transdermal drug delivery: from simple potions to smart technologies. Curr Drug Deliv 16:444–460

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bloch S, Lesage F, McIntosh L, Gandjbakhche A, Liang KX, Achilefu S (2005) Whole-body fluorescence lifetime imaging of a tumor-targeted near-infrared molecular probe in mice. J Biomed Opt 10:054003

    Article  PubMed  Google Scholar 

  • Böhm D, Moré S, Moré M, Kloner L, Volkmann M, Haag R, Kohn B (2020) Nanocarrier in veterinary medicine – a pilot study for the treatment of feline hyperthyroidism with a nano-carrier based thiamazole ointment. Schweiz Arch Tierheilkd 162:223–234

    Article  PubMed  Google Scholar 

  • Bommannan D, Potts RO, Guy RH (1991) Examination of the effect of ethanol on human stratum corneum in vivo using infrared spectroscopy. J Control Release 16:299–304

    Article  CAS  Google Scholar 

  • Boreham A, Pfaff M, Fleige E, Haag R, Alexiev U (2014) Nanodynamics of dendritic core-multishell nanocarriers. Langmuir 30:1686–1695

    Article  CAS  PubMed  Google Scholar 

  • Boreham A, Pikkemaat J, Volz P, Brodwolf R, Kuehne C, Licha K, Haag R, Dernedde J, Alexiev U (2016) Detecting and quantifying biomolecular interactions of a dendritic polyglycerol sulfate nanoparticle using fluorescence lifetime measurements. Molecules 21:22

    Article  Google Scholar 

  • Boreham A, Brodwolf R, Walker K, Haag R, Alexiev U (2017a) Time-resolved fluorescence spectroscopy and fluorescence lifetime imaging microscopy for characterization of dendritic polymer nanoparticles and applications in nanomedicine. Molecules 22:17

    Article  Google Scholar 

  • Boreham A, Volz P, Peters D, Keck CM, Alexiev U (2017b) Determination of nanostructures and drug distribution in lipid nanoparticles by single molecule microscopy. Eur J Pharm Biopharm 110:31–38

    Article  CAS  PubMed  Google Scholar 

  • Borst JW, Visser A (2010) Fluorescence lifetime imaging microscopy in life sciences. Meas Sci Technol 21:102002

    Article  Google Scholar 

  • Bos JD, Meinardi MMHM (2000) The 500 Dalton rule for the skin penetration of chemical compounds and drugs. Exp Dermatol 9:165–169

    Article  CAS  PubMed  Google Scholar 

  • Bouwstra JA, Honeywell-Nguyen PL, Gooris GS, Ponec M (2003) Structure of the skin barrier and its modulation by vesicular formulations. Prog Lipid Res 42:1–36

    Article  CAS  PubMed  Google Scholar 

  • Brandner JM (2016) Importance of tight junctions in relation to skin barrier function. Curr Probl Dermatol 49:27–37

    Article  PubMed  Google Scholar 

  • Brodwolf R, Volz-Rakebrand P, Stellmacher J, Wolff C, Unbehauen M, Haag R, Schäfer-Korting M, Zoschke C, Alexiev U (2020) Faster, sharper, more precise: automated cluster-FLIM in preclinical testing directly identifies the intracellular fate of theranostics in live cells and tissue. Theranostics 10:6322–6336

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Candi E, Schmidt R, Melino G (2005) The cornified envelope: a model of cell death in the skin. Nat Rev Mol Cell Biol 6:328–340

    Article  CAS  PubMed  Google Scholar 

  • Caprioli RM, Farmer TB, Gile J (1997) Molecular imaging of biological samples: localization of peptides and proteins using MALDI-TOF MS. Anal Chem 69:4751–4760

    Article  CAS  PubMed  Google Scholar 

  • Cruchley AT, Williams DM, Farthing PM, Speight PM, Lesch CA, Squier CA (1994) Langerhans cell density in normal human oral mucosa and skin: relationship to age, smoking and alcohol consumption. J Oral Pathol Med 23:55–59

    Article  CAS  PubMed  Google Scholar 

  • Dazzi A, Prater CB (2017) AFM-IR: technology and applications in nanoscale infrared spectroscopy and chemical imaging. Chem Rev 117:5146–5173

    Article  CAS  PubMed  Google Scholar 

  • Digman MA, Caiolfa VR, Zamai M, Gratton E (2008) The phasor approach to fluorescence lifetime imaging analysis. Biophys J 94:L14–L16

    Article  CAS  PubMed  Google Scholar 

  • Döge N, Hadam S, Volz P, Wolf A, Schönborn KH, Blume-Peytavi U, Alexiev U, Vogt A (2018) Identification of polystyrene nanoparticle penetration across intact skin barrier as rare event at sites of focal particle aggregations. J Biophotonics 11:e201700169

    Article  PubMed  Google Scholar 

  • Dong P, Stellmacher J, Bouchet LM, Nieke M, Kumar A, Osorio-Blanco ER, Nagel G, Lohan SB, Teutloff C, Patzelt A, Schäfer-Korting M, Calderon M, Meinke MC, Alexiev U (2021) A dual fluorescence-spin label probe for visualization and quantification of target molecules in tissue by multiplexed FLIM-EPR spectroscopy. Angew Chem Int Ed Engl 60:14938–14944

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Emergency Use Authorization (Eua) of the Pfizer-Biontech Covid-19 Vaccine to Prevent Coronavirus Disease (2019) (COVID-19) in individuals 16 years of age and older. https://www.fda.gov/media/144414/download. Accessed 28 Nov 2022

  • Evans CL, Potma EO, Puoris'haag M, Cote D, Lin CP, Xie XS (2005) Chemical imaging of tissue in vivo with video-rate coherent anti-stokes Raman scattering microscopy. Proc Natl Acad Sci U S A 102:16807–16812

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Frazer B, Gilbert B, De Stasio G (2002) X-ray absorption microscopy of aqueous samples. Rev Sci Instrum 73:1373–1375

    Article  CAS  Google Scholar 

  • Frazer BH, Girasole M, Wiese LM, Franz T, De Stasio G (2004) Spectromicro scope for the photoelectron imaging of nanostructures with X-rays (SPHINX): performance in biology, medicine and geology. Ultramicroscopy 99:87–94

    Article  CAS  PubMed  Google Scholar 

  • Freudiger CW, Min W, Saar BG, Lu S, Holtom GR, He CW, Tsai JC, Kang JX, Xie XS (2008) Label-free biomedical imaging with high sensitivity by stimulated Raman scattering microscopy. Science 322:1857–1861

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Frombach J, Lohan SB, Lemm D, Gruner P, Hasler J, Ahlberg S, Blume-Peytavi U, Unbehauen M, Haag R, Meinke MC, Vogt A (2018) Protease-mediated inflammation: an in vitro human keratinocyte-based screening tool for anti-inflammatory drug nanocarrier systems. Z Phys Chem 232:919–933

    Article  CAS  Google Scholar 

  • Frombach J, Unbehauen M, Kurniasih IN, Schumacher F, Volz P, Hadam S, Rancan F, Blume-Peytavi U, Kleuser B, Haag R, Alexiev U, Vogt A (2019) Core-multishell nanocarriers enhance drug penetration and reach keratinocytes and antigen-presenting cells in intact human skin. J Control Release 299:138–148

    Article  CAS  PubMed  Google Scholar 

  • Fu D, Lu FK, Zhang X, Freudiger C, Pernik DR, Holtom G, Xie XS (2012) Quantitative chemical imaging with multiplex stimulated Raman scattering microscopy. J Am Chem Soc 134:3623–3626

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Germer G, Ohigashi T, Yuzawa H, Kosugi N, Flesch R, Rancan F, Vogt A, Rühl E (2021) Improved skin permeability after topical treatment with serine protease: probing the penetration of rapamycin by scanning transmission X-ray microscopy. ACS Omega 6:12213–12222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gorzelanny C, Mess C, Schneider SW, Huck V, Brandner JM (2020) Skin barriers in dermal drug delivery: which barriers have to be overcome and how can we measure them? Pharmaceutics 12:684

    Article  PubMed  PubMed Central  Google Scholar 

  • Graf C, Rühl E (2019) Imaging techniques for probing nanoparticles in cells and skin. In: Gehr P, Zellner R (eds) Biological responses to nanoscale particles: molecular and cellular aspects and methodological approaches. Springer, Cham, pp 213–239

    Google Scholar 

  • Gregoire S, Luengo GS, Hallegot P, Pena AM, Chen XQ, Bornschlogl T, Chan KF, Pence I, Obeidy P, Feizpour A, Jeong S, Evans CL (2020) Imaging and quantifying drug delivery in skin - part 1: autoradiography and mass spectrometry imaging. Adv Drug Deliv Rev 153:137–146

    Article  CAS  PubMed  Google Scholar 

  • Gröger D, Paulus F, Licha K, Welker P, Weinhart M, Holzhausen C, Mundhenk L, Gruber AD, Abram U, Haag R (2013) Synthesis and biological evaluation of radio and dye labeled amino functionalized dendritic polyglycerol sulfates as multivalent anti-inflammatory compounds. Bioconjug Chem 24:1507–1514

    Article  PubMed  Google Scholar 

  • Gronbach L, Wolff C, Klinghammer K, Stellmacher J, Jurmeister P, Alexiev U, Schäfer-Korting M, Tinhofer I, Keilholz U, Zoschke C (2020) A multilayered epithelial mucosa model of head neck squamous cell carcinoma for analysis of tumor-microenvironment interactions and drug development. Biomaterials 258:120277

    Article  CAS  PubMed  Google Scholar 

  • Gupta M, Agrawal U, Vyas SP (2012) Nanocarrier-based topical drug delivery for the treatment of skin diseases. Expert Opin Drug Deliv 9:783–804

    Article  CAS  PubMed  Google Scholar 

  • Gupta S, Bansal R, Gupta S, Jindal N, Jindal A (2013) Nanocarriers and nanoparticles for skin care and dermatological treatments. Indian Dermatol Online J 4:267–272

    Article  PubMed  PubMed Central  Google Scholar 

  • Guttmann P, Bittencourt C (2015) Overview of nanoscale NEXAFS performed with soft X-ray microscopes. Beilstein J Nanotechnol 6:595–604

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hegenbarth R, Steinmann A, Mastel S, Amarie S, Huber AJ, Hillenbrand R, Sarkisov SY, Giessen H (2014) High-power femtosecond mid-IR sources for s-SNOM applications. J Opt 16:094003

    Article  CAS  Google Scholar 

  • Henke BL, Gullikson EM, Davis JC (1993) X-ray interactions - photoabsorption, scattering, transmission, and reflection at E=50-30,000 eV, Z=1-92. At Data Nucl Data Tables 54:181–342

    Article  CAS  Google Scholar 

  • Hirvonen LM, Suhling K (2020) Fast timing techniques in FLIM applications. Front Physiol 8:161

    Article  Google Scholar 

  • Hirvonen LM, Nedbal J, Almutairi N, Phillips TA, Becker W, Conneely T, Milnes J, Cox S, Sturzenbaum S, Suhling K (2020) Lightsheet fluorescence lifetime imaging microscopy with wide-field time-correlated single photon counting. J Biophotonics 13:e201960099

    Article  PubMed  Google Scholar 

  • Jeong WY, Kwon M, Choi HE, Kim KS (2021) Recent advances in transdermal drug delivery systems: a review. Biomater Res 25:24

    Article  PubMed  PubMed Central  Google Scholar 

  • Jo JA, Fang QY, Marcu L (2005) Ultrafast method for the analysis of fluorescence lifetime imaging microscopy data based on the Laguerre expansion technique. IEEE J Quantum Electron 11:835–845

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kaeokhamloed N, Legeay S, Roger E (2022) FRET as the tool for in vivo nanomedicine tracking. J Control Release 349:156–173

    Article  CAS  PubMed  Google Scholar 

  • Kanevche K, Burr D, Elsaesser A, Hass PK, Nuernberg D, Heberle J (2021) Infrared nanoscopy and tomography of intracellular structures. Commun Biol 4:1341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kästner B, Johnson CM, Hermann P, Kruskopf M, Pierz K, Hoehl A, Hornemann A, Ulrich G, Fehmel J, Patoka P, Rühl E, Ulm G (2018) Infrared nanospectroscopy of phospholipid and surfactin monolayer domains. ACS Omega 3:4141–4147

    Article  PubMed  PubMed Central  Google Scholar 

  • Keilmann F, Huber AJ, Hillenbrand R (2009) Nanoscale conductivity contrast by scattering-type near-field optical microscopy in the visible, infrared and THz domains. J Infrared Millim Terahertz Waves 30:1255–1268

    CAS  Google Scholar 

  • Kirchberg K, Kim TY, Möller M, Skegro D, Raju GD, Granzin J, Büldt G, Schlesinger R, Alexiev U (2011) Conformational dynamics of helix 8 in the GPCR rhodopsin controls arrestin activation in the desensitization process. Proc Natl Acad Sci U S A 108:18690–18695

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kirejev V, Guldbrand S, Borglin J, Simonsson C, Ericson MB, Multiphoton microscopy. (2012) A powerful tool in skin research and topical drug delivery science. J Drug Deliv Sci Technol 22:250–259

    Article  CAS  Google Scholar 

  • Klossek A, Thierbach S, Rancan F, Vogt A, Blume-Peytavi U, Rühl E (2017) Studies for improved understanding of lipid distributions in human skin by combining stimulated and spontaneous Raman microscopy. Eur J Pharm Biopharm 116:76–84

    Article  CAS  PubMed  Google Scholar 

  • Koehler MJ, Zimmermann S, Springer S, Elsner P, Koenig K, Kaatz M (2011) Keratinocyte morphology of human skin evaluated by in vivo multiphoton laser tomography. Skin Res Technol 17:479–486

    Article  CAS  PubMed  Google Scholar 

  • König K (2020) Review: clinical in vivo multiphoton FLIM tomography. Methods Appl Fluoresc 8:034002

    Article  PubMed  Google Scholar 

  • Koprinarov IN, Hitchcock AP, McCrory CT, Childs RF (2002) Quantitative mapping of structured polymeric systems using singular value decomposition analysis of soft X-ray images. J Phys Chem B 106:5358–5364

    Article  CAS  Google Scholar 

  • Krüger HR, Schütz I, Justies A, Licha K, Welker P, Haucke V, Calderon M (2014) Imaging of doxorubicin release from theranostic macromolecular prodrugs via fluorescence resonance energy transfer. J Control Release 194:189–196

    Article  PubMed  Google Scholar 

  • Kurniasih IN, Keilitz J, Haag R (2015) Dendritic nanocarriers based on hyperbranched polymers. Chem Soc Rev 44:4145–4164

    Article  CAS  PubMed  Google Scholar 

  • Kuschewski F, von Ribbeck HG, Döring J, Winnerl S, Eng LM, Kehr SC (2016) Narrow-band near-field nanoscopy in the spectral range from 1.3 to 8.5 THz. Appl Phys Lett 108: 113102

    Google Scholar 

  • Lademann J, Caspers PJ, van der Pol A, Richter H, Patzelt A, Zastrow L, Darvin M, Sterry W, Fluhr JW (2009) In vivo Raman spectroscopy detects increased epidermal antioxidative potential with topically applied carotenoids. Laser Phys Lett 6:76–79

    Article  CAS  Google Scholar 

  • Lawrence JR, Swerhone GDW, Dynes JJ, Korber DR, Hitchcock AP (2016) Soft X-ray spectromicroscopy for speciation, quantitation and nano-eco-toxicology of nanomaterials. J Microsc 261:130–147

    Article  CAS  PubMed  Google Scholar 

  • Le Marois A, Labouesse S, Suhling K, Heintzmann R (2017) Noise-corrected principal component analysis of fluorescence lifetime imaging data. J Biophotonics 10:1124–1133

    Article  PubMed  Google Scholar 

  • Lee SC, Kim K, Kim J, Lee S, Yi JH, Kim SW, Ha KS, Cheong C (2001) One micrometer resolution NMR microscopy. J Magn Reson 150:207–213

    Article  CAS  PubMed  Google Scholar 

  • Legall H et al (2012) Compact x-ray microscope for the water window based on a high brightness laser plasma source. Opt Express 20:18362–18369

    Article  CAS  PubMed  Google Scholar 

  • Lemaster JE, Jokerst JV (2017) What is new in nanoparticle-based photoacoustic imaging? Wiley Interdiscip Rev Nanomed Nanobiotechnol 9:e1404

    Article  Google Scholar 

  • Lerotic M, Mak R, Wirick S, Meirer F, Jacobsen C (2014) MANTiS: a program for the analysis of X-ray spectromicroscopy data. J Synchrotron Radiat 21:1206–1212

    Article  CAS  PubMed  Google Scholar 

  • Leung BO, Chou KC (2011) Review of super-resolution fluorescence microscopy for biology. Appl Spectrosc 65:967–980

    Article  CAS  PubMed  Google Scholar 

  • Liu LX, Yang QQ, Zhang ML, Wu ZQ, Xue P (2019) Fluorescence lifetime imaging microscopy and its applications in skin cancer diagnosis. J Innov Opt Health Sci 12:1930004

    Article  CAS  Google Scholar 

  • Lu FK, Basu S, Igras V, Hoang MP, Ji MB, Fu D, Holtom GR, Neel VA, Freudiger CW, Fisher DE, Xie XS (2015) Label-free DNA imaging in vivo with stimulated Raman scattering microscopy. Proc Natl Acad Sci U S A 112:11624–11629

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ma X, Fernandez FM (2022) Advances in mass spectrometry imaging for spatial cancer metabolomics. Mass Spectrom Rev:e21804

    Google Scholar 

  • Mannam V, Zhang YD, Yuan XT, Ravasio C, Howard SS (2020) Machine learning for faster and smarter fluorescence lifetime imaging microscopy. J Phys 2:042005

    Google Scholar 

  • Mao G, Flach CR, Mendelsohn R, Walters RM (2012) Imaging the distribution of sodium dodecyl sulfate in skin by confocal Raman and infrared microspectroscopy. Pharm Res 29:2189–2201

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mathurin J, Deniset-Besseau A, Bazin D, Dartois E, Wagner M, Dazzi A (2022) Photothermal AFM-IR spectroscopy and imaging: status, challenges, and trends. J Appl Phys 131:010901

    Article  CAS  Google Scholar 

  • Mirakovski D, Damevska K, Simeonovski V, Nikolovska S, Boev B, Petrov A, Sijakova Ivanova T, Zendelska A, Hadzi-Nikolova M, Boev I, Dimov G, Darlenski R, Kazandjieva J, Damevska S, Situm M (2022) Use of SEM/EDX methods for the analysis of ambient particulate matter adhering to the skin surface. J Eur Acad Dermatol Venereol 36:1376–1381

    Article  CAS  PubMed  Google Scholar 

  • Mitchell MJ, Billingsley MM, Haley RM, Wechsler ME, Peppas NA, Langer R (2021) Engineering precision nanoparticles for drug delivery. Nat Rev Drug Discov 20:101–124

    Article  CAS  PubMed  Google Scholar 

  • Mitragotri S, Burke PA, Langer R (2014) Overcoming the challenges in administering biopharmaceuticals: formulation and delivery strategies. Nat Rev Drug Discov 13:655–672

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nagano S, Sadeghi M, Balke J, Fleck M, Heckmann N, Psakis G, Alexiev U (2022) Improved fluorescent phytochromes for in situ imaging. Sci Rep 12:5587

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nastiti C, Ponto T, Abd E, Grice JE, Benson HAE, Roberts MS (2017) Topical nano and microemulsions for skin delivery. Pharmaceutics 9:37

    Article  PubMed  PubMed Central  Google Scholar 

  • Niehaus M, Soltwisch J, Belov ME, Dreisewerd K (2019) Transmission-mode MALDI-2 mass spectrometry imaging of cells and tissues at subcellular resolution. Nat Methods 16:925–931

    Article  CAS  PubMed  Google Scholar 

  • Noun M, Akoumeh R, Abbas I (2022) Cell and tissue imaging by TOF-SIMS and MALDI-TOF: an overview for biological and pharmaceutical analysis. Microsc Microanal 28:1–26

    Article  CAS  PubMed  Google Scholar 

  • Ober K, Volz-Rakebrand P, Stellmacher J, Brodwolf R, Licha K, Haag R, Alexiev U (2019) Expanding the scope of reporting nanoparticles: sensing of lipid phase transitions and nanoviscosities in lipid membranes. Langmuir 35:11422–11434

    Article  CAS  PubMed  Google Scholar 

  • Okay S (2020) Single-molecule characterization of drug delivery systems. Assay Drug Dev Technol 18:56–63

    Article  CAS  PubMed  Google Scholar 

  • Patra JK, Das G, Fraceto LF, Campos EVR, Rodriguez-Torres MDP, Acosta-Torres LS, Diaz-Torres LA, Grillo R, Swamy MK, Sharma S, Habtemariam S, Shin HS (2018) Nano based drug delivery systems: recent developments and future prospects. J Nanobiotechnol 16:71

    Article  Google Scholar 

  • Paturi J, Kim HD, Chakraborty B, Friden PM, Banga AK (2010) Transdermal and intradermal iontophoretic delivery of dexamethasone sodium phosphate: quantification of the drug localized in skin. J Drug Target 18:134–140

    Article  CAS  PubMed  Google Scholar 

  • Pelkmans L, Helenius A (2002) Endocytosis via caveolae. Traffic 3:311–320

    Article  CAS  PubMed  Google Scholar 

  • Pena A-M, Chen X, Pence IJ, Bornschlögl T, Jeong S, Grégoire S, Luengo GS, Hallegot P, Obeidy P, Feizpour A, Chan KF, Evans CL (2020) Imaging and quantifying drug delivery in skin – part 2: fluorescence and vibrational spectroscopic imaging methods. Adv Drug Deliv Rev 153:147–168

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pischon H, Radbruch M, Ostrowski A, Volz P, Gerecke C, Unbehauen M, Hönzke S, Hedtrich S, Fluhr JW, Haag R, Kleuser B, Alexiev U, Gruber AD, Mundhenk L (2017) Stratum corneum targeting by dendritic core-multishell-nanocarriers in a mouse model of psoriasis. Nanomedicine 13:317–327

    Article  CAS  PubMed  Google Scholar 

  • Poudel C, Mela I, Kaminski CF (2020) High-throughput, multi-parametric, and correlative fluorescence lifetime imaging. Methods and Applications in Fluorescence 8:024005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rajes K, Walker KA, Hadam S, Zabihi F, Ibrahim-Bacha J, Germer G, Patoka P, Wassermann B, Rancan F, Rühl E, Vogt A, Haag R (2021) Oxidation-sensitive core-multishell nanocarriers for the controlled delivery of hydrophobic drugs. ACS Biomater Sci Eng 7:2485–2495

    Article  CAS  PubMed  Google Scholar 

  • Richter C, Schneider C, Quick MT, Volz P, Mahrwald R, Hughes J, Dick B, Alexiev U, Ernsting NP (2015) Dual-fluorescence pH probe for bio-labelling. Phys Chem Chem Phys 17:30590–30597

    Article  CAS  PubMed  Google Scholar 

  • Ruman U, Fakurazi S, Masarudin MJ, Hussein MZ (2020) Nanocarrier-based therapeutics and theranostics drug delivery systems for next generation of liver cancer nanodrug modalities. Int J Nanomedicine 15:1437–1456

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sahu KS, Raj R, Raj MP, Alpana R (2020) Topical lipid based drug delivery systems for skin diseases: a review. Curr Drug Ther 15:283–298

    CAS  Google Scholar 

  • Schäfer-Korting M, Zoschke C (2021) How qualification of 3D disease models cuts the Gordian knot in preclinical drug development. Handb Exp Pharmacol 265:29–56

    Article  PubMed  Google Scholar 

  • Schmitt MV, Lienau P, Fricker G, Reichel A (2019) Quantitation of lysosomal trapping of basic lipophilic compounds using in vitro assays and in silico predictions based on the determination of the full pH profile of the endo−/lysosomal system in rat hepatocytes. Drug Metab Dispos 47:49–57

    Article  CAS  PubMed  Google Scholar 

  • Schnell M, Goikoetxea M, Amenabar I, Carney PS, Hillenbrand R (2020) Rapid infrared spectroscopic nanoimaging with nano-FTIR holography. ACS Photonics 7:2878–2885

    Article  CAS  Google Scholar 

  • Schulz R, Yamamoto K, Klossek A, Flesch R, Hönzke S, Rancan F, Vogt A, Blume-Peytavi U, Hedtrich S, Schäfer-Korting M, Rühl E, Netz RR (2017) Data-based modeling of drug penetration relates human skin barrier function to the interplay of diffusivity and free-energy profiles. Proc Natl Acad Sci U S A 114:3631–3636

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Scimeca M, Bischetti S, Lamsira HK, Bonfiglio R, Bonanno E (2018) Energy dispersive X-ray (EDX) microanalysis: a powerful tool in biomedical research and diagnosis. Eur J Histochem 62:88–97

    Google Scholar 

  • Sersa I (2021) Magnetic resonance microscopy of samples with translational symmetry with FOVs smaller than sample size. Sci Rep 11:541

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shapiro DA et al (2020) An ultrahigh-resolution soft x-ray microscope for quantitative analysis of chemically heterogeneous nanomaterials. Sci Adv 6:eabc4904

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sheppard CJR (2020) Multiphoton microscopy: a personal historical review, with some future predictions. J Biomed Opt 25:1–11

    Article  PubMed  Google Scholar 

  • Shin CS, Dunnam CR, Borbat PP, Dzikovski B, Barth ED, Halpern HJ, Freed JH (2011) ESR microscopy for biological and biomedical applications. Nanosci Nanotechnol Lett 3:561–567

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smith JT, Yao RY, Sinsuebphon N, Rudkouskaya A, Un N, Mazurkiewicz J, Barroso M, Yan PK, Intes X (2019) Fast fit-free analysis of fluorescence lifetime imaging via deep learning. Proc Natl Acad Sci U S A 116:24019–24030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stöhr J (1992) NEXAFS sepctroscopy. Springer, Berlin

    Book  Google Scholar 

  • Stojanov K, Zuhorn IS, Dierckx RAJO, de Vries EFJ (2012) Imaging of cells and nanoparticles: implications for drug delivery to the brain. Pharm Res 29:3213–3234

    Article  CAS  PubMed  Google Scholar 

  • Tanaka R, Ichimura Y, Kubota N, Konishi R, Nakamura Y, Mizuno S, Takahashi S, Fujimoto M, Nomura T, Okiyama N (2022) The role of PD-L1 on langerhans cells in the regulation of psoriasis. J Investig Dermatol 142:3167–3174.e9

    Article  CAS  PubMed  Google Scholar 

  • Tenchov R, Bird R, Curtze AE, Zhou QQ (2021) Lipid nanoparticles-from liposomes to mRNA vaccine delivery, a landscape of research diversity and advancement. ACS Nano 15:16982–17015

    Article  CAS  PubMed  Google Scholar 

  • Ustione A, Piston DW (2011) A simple introduction to multiphoton microscopy. J Microsc 243:221–226

    Article  CAS  PubMed  Google Scholar 

  • Valli J, Sanderson J (2021) Super-resolution fluorescence microscopy methods for assessing mouse biology. Curr Protoc 1:e224

    Article  CAS  PubMed  Google Scholar 

  • van Smeden J, Bouwstra JA (2016) Stratum Corneum lipids: their role for the skin barrier function in healthy subjects and atopic dermatitis patients. Curr Probl Dermatol 49:8–26

    Article  PubMed  Google Scholar 

  • Vogt A, Wischke C, Neffe AT, Ma N, Alexiev U, Lendlein A (2016) Nanocarriers for drug delivery into and through the skin - do existing technologies match clinical challenges? J Control Release 242:3–15

    Article  CAS  PubMed  Google Scholar 

  • Volz P, Boreham A, Wolf A, Kim T-Y, Balke J, Frombach J, Hadam S, Afraz Z, Rancan F, Blume-Peytavi U, Vogt A, Alexiev U (2015) Application of single molecule fluorescence microscopy to characterize the penetration of a large amphiphilic molecule in the Stratum Corneum of human skin. Int J Mol Sci 16:6960–6977

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Volz P, Schilrreff P, Brodwolf R, Wolff C, Stellmacher J, Balke J, Morilla MJ, Zoschke C, Schäfer-Korting M, Alexiev U (2017) Pitfalls in using fluorescence tagging of nanomaterials: tecto-dendrimers in skin tissue as investigated by cluster-FLIM. Ann N Y Acad Sci 1405:202–214

    Article  CAS  PubMed  Google Scholar 

  • Volz P, Brodwolf R, Zoschke C, Haag R, Schäfer-Korting M, Alexiev U (2018) White-light supercontinuum laser-based multiple wavelength excitation for TCSPC-FLIM of cutaneous nanocarrier uptake. Z Phys Chem 232:671–688

    Article  CAS  Google Scholar 

  • Wang LV, Hu S (2012) Photoacoustic tomography: in vivo imaging from organelles to organs. Science 335:1458–1462

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wanjiku B, Yamamoto K, Klossek A, Schumacher F, Pischon H, Mundhenk L, Rancan F, Judd MM, Ahmed M, Zoschke C, Kleuser B, Rühl E, Schäfer-Korting M (2019) Qualifying X-ray and stimulated Raman spectromicroscopy for mapping cutaneous drug penetration. Anal Chem 91:7208–7214

    Article  CAS  PubMed  Google Scholar 

  • Weissleder R, Ntziachristos V (2003) Shedding light onto live molecular targets. Nat Med 9:123–128

    Article  CAS  PubMed  Google Scholar 

  • Wirth KG, Linnenbank H, Steinle T, Banszerus L, Icking E, Stampfer C, Giessen H, Taubner T (2021) Tunable s-SNOM for nanoscale infrared optical measurement of electronic properties of bilayer graphene. ACS Photonics 8:418–423

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wolf A, Volz-Rakebrand P, Balke J, Alexiev U (2023) Diffusion analysis of NAnoscopic ensembles: a tracking-free diffusivity analysis for nanoscopic ensembles in biological samples and nanotechnology. Small 19:e2206722

    Article  PubMed  Google Scholar 

  • Wong CH, Siah KW, Lo AW (2019) Estimation of clinical trial success rates and related parameters. Biostatistics 20:273–286

    Article  PubMed  Google Scholar 

  • Working PK, Dayan AD (1996) Pharmacological-toxicological expert report - Caelyx(TM) - (Stealth(R) liposomal doxorubicin HCl) - foreword. Hum Exp Toxicol 15:751–785

    CAS  PubMed  Google Scholar 

  • Xia J, Yao JJ, Wang LV (2014) Photoacoustic tomography: principles and advances. Prog Electromagn Res 147:1–22

    Article  Google Scholar 

  • Yamamoto K, Flesch R, Ohigashi T, Hedtrich S, Klossek A, Patoka P, Ulrich G, Ahlberg S, Rancan F, Vogt A, Blume-Peytavi U, Schrade P, Bachmann S, Schäfer-Korting M, Kosugi N, Rühl E (2015) Selective probing of the penetration of dexamethasone into human skin by soft X-ray spectromicroscopy. Anal Chem 87:6173–6179

    Article  CAS  PubMed  Google Scholar 

  • Yamamoto K, Klossek A, Flesch R, Ohigashi T, Fleige E, Rancan F, Frombach J, Vogt A, Blume-Peytavi U, Schrade P, Bachmann S, Haag R, Hedtrich S, Schäfer-Korting M, Kosugi N, Rühl E (2016) Core-multishell nanocarriers: transport and release of dexamethasone probed by soft X-ray spectromicroscopy. J Control Release 242:64–70

    Article  CAS  PubMed  Google Scholar 

  • Yamamoto K, Klossek A, Flesch A, Rancan F, Weigand M, Bykova I, Bechtel M, Ahlberg S, Vogt A, Blume-Peytavi U, Schrade P, Bachmann S, Hedtrich S, Schäfer-Korting M, Rühl E (2017) Influence of the skin barrier on the penetration of topically-applied dexamethasone probed by soft X-ray spectromicroscopy. Eur J Pharm Biopharm 118:30–37

    Article  CAS  PubMed  Google Scholar 

  • Yamamoto K, Klossek A, Fuchs K, Watts B, Raabe J, Flesch R, Rancan F, Pischon H, Radbruch M, Gruber AD, Mundhenk L, Vogt A, Blume-Peytavi U, Schrade P, Bachmann S, Gurny R, Rühl E (2019) Soft X-ray microscopy for probing of topical tacrolimus delivery via micelles. Eur J Pharm Biopharm 139:68–75

    Article  CAS  PubMed  Google Scholar 

  • Zavalin A, Todd EM, Rawhouser PD, Yang JH, Norris JL, Caprioli RM (2012) Direct imaging of single cells and tissue at sub-cellular spatial resolution using transmission geometry MALDI MS. J Mass Spectrom 47:1473–1481

    Article  PubMed  Google Scholar 

  • Zavalin A, Yang JH, Haase A, Holle A, Caprioli R (2014) Implementation of a Gaussian beam laser and aspheric optics for high spatial resolution MALDI imaging MS. J Am Soc Mass Spectrom 25:1079–1082

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang GJ, Moore DJ, Flach CR, Mendelsohn R (2007) Vibrational microscopy and imaging of skin: from single cells to intact tissue. Anal Bioanal Chem 387:1591–1599

    Article  CAS  PubMed  Google Scholar 

  • Zhang QH, Flach CR, Mendelsohn R, Page L, Whitson S, Bettex MB (2020) Visualization of epidermal reservoir formation from topical diclofenac gels by Raman spectroscopy. J Pain Res 13:1621–1627

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhang X, Li X, Wang Y, Chen Y, Hu Y, Guo C, Yu Z, Xu P, Ding Y, Mi Q-S, Wu J, Gu J, Shi Y (2022) Abnormal lipid metabolism in epidermal Langerhans cells mediates psoriasis-like dermatitis. JCI Insight 7:e15022

    Article  Google Scholar 

  • Zheng FF, Xiong WW, Sun SS, Zhang PH, Zhu JJ (2019) Recent advances in drug release monitoring. Nanophotonics 8:391–413

    Article  CAS  Google Scholar 

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Acknowledgments

Financial support by the German Research Foundation (DFG, a.o. SFB 1112 and SFB 1449 project ID 431232613, and RU 420/12-1) and Freie Universität Berlin is gratefully acknowledged. Beam time for STXM studies at the UVSOR III synchrotron facility (Institute for Molecular Science, Okazaku, Japan) and BESSY II (Helmholtz Zentrum Berlin, Germany) is also gratefully acknowledged.

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Authors and Affiliations

  1. Fachbereich Physik, Freie Universität Berlin, Berlin, Germany

    Ulrike Alexiev

  2. Physikalische Chemie, Freie Universität Berlin, Berlin, Germany

    Eckart Rühl

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  1. Ulrike Alexiev
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  2. Eckart Rühl
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Correspondence to Ulrike Alexiev or Eckart Rühl .

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Editors and Affiliations

  1. Pharmacology and Toxicology, Freie Universität Berlin, Berlin, Germany

    Monika Schäfer-Korting

  2. Laboratory of Organic and Macromolecular Chemistry (IOMC), Friedrich Schiller University Jena, Jena, Germany

    Ulrich S. Schubert

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Alexiev, U., Rühl, E. (2023). Visualization of Nanocarriers and Drugs in Cells and Tissue. In: Schäfer-Korting, M., Schubert, U.S. (eds) Drug Delivery and Targeting. Handbook of Experimental Pharmacology, vol 284. Springer, Cham. https://doi.org/10.1007/164_2023_684

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