Abstract
Photodynamic therapy (PDT) has emerged as an attractive therapeutic modality for the targeted destruction of abnormal cells as it involves the specific generation of reactive oxygen species (ROS) in tissue only in the combined presence of a photosensitizer (PS), incident excitation light, and molecular oxygen. A variety of effective PS molecules have been developed but they are often limited by poor water solubility or a lack of cell-type specificity. We have developed a quantum dot-chlorin e6 (QD-Ce6) nanobioconjugate system where the QD (5 nm diameter) serves simultaneously as a hydrophilic scaffold and an efficient Förster resonance energy transfer (FRET) donor to multiple Ce6 PS acceptors arrayed around the central QD. Decoration of the conjugate with a membrane-tethering peptide stably localizes the ensemble conjugate system on the exofacial leaflet of the plasma membrane of mammalian cells. Excitation of Ce6 in a FRET configuration results in membrane-localized ROS generation resulting in lipid peroxidation, increased membrane permeability, and inhibition of cellular proliferation. We present and discuss our results in the context of the further evolution of QD-based PDT systems.
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References
Andrásfalvy BK, Galiñanes GL, Huber D, Barbic M, Macklin JJ, Susumu K, Delehanty JB, Huston AL, Makara JK, Medintz IL (2014) Quantum dot–based multiphoton fluorescent pipettes for targeted neuronal electrophysiology. Nat Methods 11:1237–1241
Berney C, Danuser G (2003) FRET or no FRET: a quantitative comparison. Biophys J 84:3992–4010
Biel MA (2010) Photodynamic therapy of head and neck cancers. Methods Mol Biol 635:281–293
Boeneman K, Delehanty JB, Blanco-Canosa JB, Susumu K, Stewart MH, Oh E, Huston AL, Dawson G, Ingale S, Walters R, Domowicz M, Deschamps JR, Algar WR, DiMaggio S, Manono J, Spillmann CM, Thompson D, Jennings TL, Dawson PE, Medintz IL (2013) Selecting improved peptidyl motifs for cytosolic delivery of disparate protein and nanoparticle materials. ACS Nano 7:3778–3796
Caglar M, Pandya R, Xiao J, Foster SK, Divitini G, Chen RYS, Greenham NC, Franze K, Rao A, Keyser UF (2019) All-optical detection of neuronal membrane depolarization in live cells using colloidal quantum dots. Nano Lett 19:8539–8549
Chen JJ, Yu BP (1994) Alterations in mitochondrial membrane fluidity by lipid peroxidation products. Free Radic Biol Med 17:411–418
Delehanty JB, Blanco-Canosa JB, Bradburne CE, Susumu K, Stewart MH, Prasuhn DE, Dawson PE, Medintz IL (2013) Site-specific cellular delivery of quantum dots with chemoselectively-assembled modular peptides. Chem Comm 49(72):7878–7880
Dougherty TJ, Gomer CJ, Henderson BW, Jori G, Kessel D, Korbelik M, Moan J, Peng Q (1998) Photodynamic therapy. J Natl Cancer Inst 90:889–905
Farooq MU, Novosad V, Rozhkova EA, Wali H, Ali A, Fateh AA, Neogi PB, Neogi A, Wang Z (2018) Gold nanoparticles-enabled efficient dual delivery of anticancer therapeutics to HeLa cells. Sci Rep 8:2907
Gavrina AI, Shirmanova MV, Aksenova NA, Yuzhakova DV, Snopova LB, Solovieva AB, Timashev PS, Dudenkova VV, Zagaynova EV (2018) Photodynamic therapy of mouse tumor model using chlorin e6- polyvinyl alcohol complex. J Photochem Photobio B 178:614–622
Jiménez-Munguía I, Fedorov AK, Abdulaeva IA, Birin KP, Ermakov YA, Batishchev OV, Gorbunova YG, Sokolov VS (2019) Lipid membrane adsorption determines photodynamic efficiency of β-imidazolyl-substituted porphyrins. Biomolecules 9:853
Jurkiewicz P, Olżyńska A, Cwiklik L, Conte E, Jungwirth P, Megli FM, Hof M (2012) Biophysics of lipid bilayers containing oxidatively modified phospholipids: insights from fluorescence and EPR experiments and from MD simulations. Biochimica et Biophysica Acta (BBA) - Biomembranes 1818:2388–2402
Karabanovas V, Skripka A, Valanciunaite J, Kubiliute R, Poderys V, Rotomskis R (2014) Formation of self-assembled quantum dot–chlorin e6 complex: influence of nanoparticles phospholipid coating. J Nanopart Res 16:2508
Kim J, Santos OA, Park JH (2014) Selective photosensitizer delivery into plasma membrane for effective photodynamic therapy. J Control Release 191:98–104
Kou J, Dou D, Yang L (2017) Porphyrin photosensitizers in photodynamic therapy and its applications. Oncotarget 8:81591–81603
Larson DR, Zipfel WR, Williams RM, Clark SW, Bruchez MP, Wise FW, Webb WW (2003) Water-soluble quantum dots for multiphoton fluorescence imaging in vivo. Science 300:1434–1436
Lavi A, Weitman H, Holmes RT, Smith KM, Ehrenberg B (2002) The depth of porphyrin in a membrane and the membrane’s physical properties affect the photosensitizing efficiency. Biophys J 82:2101–2110
Li P-T, Ke E-S, Chiang P-C, Tsai T (2015) ALA- or Ce6-PDT induced phenotypic change and suppressed migration in surviving cancer cells. J Dent Sci 10:74–80
Luke-Marshall NR, Hansen LA, Shafirstein G, Campagnari AA (2020) Antimicrobial photodynamic therapy with chlorin e6 is bactericidal against biofilms of the primary human otopathogens. mSphere 5:e00492-00420
Mattoussi H, Mauro JM, Goldman ER, Anderson GP, Sundar VC, Mikulec FV, Bawendi MG (2000) Self-assembly of CdSe−ZnS quantum dot bioconjugates using an engineered recombinant protein. J Am Chem Soc 122:12142–12150
McCann JJ, Choi UB, Zheng L, Weninger K, Bowen ME (2010) Optimizing methods to recover absolute FRET efficiency from immobilized single molecules. Biophys J 99:961–970
McLaurin EJ, Greytak AB, Bawendi MG, Nocera DG (2009) Two-photon absorbing nanocrystal sensors for ratiometric detection of oxygen. J Am Chem Soc 131:12994–13001
Medintz IL, Clapp AR, Brunel FM, Tiefenbrunn T, Tetsuo Uyeda H, Chang EL, Deschamps JR, Dawson PE, Mattoussi H (2006) Proteolytic activity monitored by fluorescence resonance energy transfer through quantum-dot–peptide conjugates. Nat Mater 5:581–589
Mei BC, Susumu K, Medintz IL, Mattoussi H (2009) Polyethylene glycol-based bidentate ligands to enhance quantum dot and gold nanoparticle stability in biological media. Nat Protoc 4:412–423
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
Moisenovich MM, Ol’shevskaya VA, Rokitskaya TI, Ramonova AA, Nikitina RG, Savchenko AN, Tatarskiy VV Jr, Kaplan MA, Kalinin VN, Kotova EA, Uvarov OV, Agapov II, Antonenko YN, Shtil AA (2010) Novel photosensitizers trigger rapid death of malignant human cells and rodent tumor transplants via lipid photodamage and membrane permeabilization. PLoS One 5:e12717
Nafiujjaman M, Revuri V, Park H-K, Kwon IK, Cho K-J, Lee Y-K (2016) Enhanced photodynamic properties of graphene quantum dot conjugated Ce6 nanoparticles for targeted cancer therapy and imaging. Chem Lett 45:997–999
Pipparelli A, Arsenijevic Y, Thuret G, Gain P, Nicolas M, Majo F (2013) ROCK inhibitor enhances adhesion and wound healing of human corneal endothelial cells. PLoS One 8(4):e62095
Richter C (1987) Biophysical consequences of lipid peroxidation in membranes. Chem Phys Lipids 44(2–4):175–189
Sangtani A, Nag OK, Field LD, Breger JC, Delehanty JB (2017) Multifunctional nanoparticle composites: progress in the use of soft and hard nanoparticles for drug delivery and imaging. Wiley Interdiscip Rev Nanomed Nanobiotechnol 9: e1466
Sangtani A, Petryayeva E, Wu M, Susumu K, Oh E, Huston AL, Lasarte-Aragones G, Medintz IL, Algar WR, Delehanty JB (2018) Intracellularly actuated quantum dot–peptide–doxorubicin nanobioconjugates for controlled drug delivery via the endocytic pathway. Bioconjug Chem 29:136–148
Sangtani A, Petryayeva E, Susumu K, Oh E, Huston AL, Lasarte-Aragones G, Medintz IL, Algar WR, Delehanty JB (2019) Nanoparticle-peptide-drug bioconjugates for unassisted defeat of multidrug resistance in a model cancer cell line. Bioconjug Chem 30:525–530
Sharma S, Lamichhane N, Parul S, T., Roy, I. (2021) Iron oxide nanoparticles conjugated with organic optical probes for in vivo diagnostic and therapeutic applications. Nanomed 16:943–962
Skripka A, Valanciunaite J, Dauderis G, Poderys V, Kubiliute R, Rotomskis R (2013) Two-photon excited quantum dots as energy donors for photosensitizer chlorin e6. J Biomed Opt 18:078002
Skripka A, Dapkute D, Valanciunaite J, Karabanovas V, Rotomskis R (2019) Impact of quantum dot surface on complex formation with chlorin e6 and photodynamic therapy. Nanomaterials 9:9
Susumu K, Uyeda HT, Medintz IL, Pons T, Delehanty JB, Mattoussi H (2007) Enhancing the stability and biological functionalities of quantum dots via compact multifunctional ligands. J Am Chem Soc 129:13987–13996
Susumu K, Field LD, Oh E, Hunt M, Delehanty JB, Palomo V, Dawson PE, Huston AL, Medintz IL (2017) Purple-, blue-, and green-emitting multishell alloyed quantum dots: synthesis, characterization, and application for ratiometric extracellular ph sensing. Chem Mater 29:7330–7344
Valanciunaite J, Klymchenko AS, Skripka A, Richert L, Steponkiene S, Streckyte G, Mely Y, Rotomskis R (2014) A non-covalent complex of quantum dots and chlorin e6: efficient energy transfer and remarkable stability in living cells revealed by FLIM. RSC Adv 4:52270–52278
Wallace B, Atzberger PJ (2017) Förster resonance energy transfer: role of diffusion of fluorophore orientation and separation in observed shifts of FRET efficiency. PLoS One 12:e0177122
Zhang KY, Song L, Gu T, Wang H, Yang C, Zhou H, Gao P, Liu S, Zhao Q (2020) Cell-membrane staining properties and photocytotoxicity of a ruthenium(ii) photosensitizer. Eur J Inorg Chem 2020:3996–4001
Acknowledgements
A.S. was a Ph.D. candidate in the Fischell Department of Bioengineering, University of Maryland College Park, MD.
The authors acknowledge the NRL Base Funding Program and the NRL Institute for Nanoscience for financial support.
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Sangtani, A., Nag, O.K., Oh, E. et al. Quantum dot-enabled membrane-tethering and enhanced photoactivation of chlorin-e6. J Nanopart Res 23, 159 (2021). https://doi.org/10.1007/s11051-021-05297-z
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DOI: https://doi.org/10.1007/s11051-021-05297-z