Photodynamic therapy (PDT) is a highly selective, clinically approved, minimally invasive technique that effectively eliminates cancer cells. Its effectiveness is limited by poor light penetration into tissue and the hydrophobic nature of photosensitizers, highlighting the need for new approaches to treatment. Here, a theranostic upconversion nanoplatform, consisting of a NaYF4:Yb,Er,Tm,Fe core and a NaHoF4 shell codoped with Yb, Nd, Gd and Tb ions, was designed to enhance PDT outcomes by integrating multi-wavelength upconversion luminescence, T2-weighted magnetic resonance imaging (MRI) and PDT. The synthesized core-shell upconversion nanoparticles (CS-UCNPs) were coated with new verteporfin (VP)-conjugated alendronate-terminated poly(N,N-dimethylacrylamide-co-2-aminoethyl acrylate) [Ale-P(DMA-AEA)] grafted with poly(ethylene glycol) (PEG). Under 980 nm NIR irradiation, CS-UCNP@Ale-P(DMA-AEA)-PEG-VP nanoparticles generated reactive oxygen species (ROS) due to the efficient energy transfer between CS-UCNPs and VP. In a pilot preclinical study, intratumoral administration of nanoparticle conjugates to mice, followed by exposure to NIR light, induced necrosis of pancreatic tumor and suppressed its growth.

Center for Advanced Preclinical Imaging 1st Faculty of Medicine Charles University Salmovská 3 120 00 Prague Czech Republic

Institute of Biophysics and Informatics 1st Faculty of Medicine Charles University Salmovská 1 120 00 Prague Czech Republic

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

NanoBioMedical Centre Adam Mickiewicz University Wszechnicy Piastowskiej 3 61 614 Poznań Poland

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Siegel R.L., Kratzer T.B., Giaquinto A.N., Sung H., Jemal A. Cancer statistics. CA Cancer J. Clin. 2025;75:10–45. doi: 10.3322/caac.21871. PubMed DOI PMC

Abdullah K.M., Sharma G., Singh A.P., Siddiqui J.A. Nanomedicine in cancer therapeutics: Current perspectives from bench to bedside. Mol. Cancer. 2025;24:169. doi: 10.1186/s12943-025-02368-w. PubMed DOI PMC

Papa V., Furci F., Minciullo P.L., Casciaro M., Allegra A., Gangemi S. Photodynamic therapy in cancer: Insights into cellular and molecular pathways. Curr. Issues Mol. Biol. 2025;47:69. doi: 10.3390/cimb47020069. PubMed DOI PMC

Overchuk M., Weersink R.A., Wilson B.C., Zheng G. Photodynamic and photothermal therapies: Synergy opportunities for nanomedicine. ACS Nano. 2023;17:7979–8003. doi: 10.1021/acsnano.3c00891. PubMed DOI PMC

Chambre L., Saw W.S., Ekineker G., Kiew L.V., Chong W.Y., Lee H.B., Chung L.Y., Bretonnière Y., Dumoulin F., Sanyal A. Surfactant-free direct access to porphyrin-cross-linked nanogels for photodynamic and photothermal therapy. Bioconjug. Chem. 2018;29:4149–4159. doi: 10.1021/acs.bioconjchem.8b00787. PubMed DOI

Bartusik-Aebisher D., Woźnicki P., Dynarowicz K., Aebisher D. Photosensitizers for photodynamic therapy of brain cancers—A review. Brain Sci. 2023;13:1299. doi: 10.3390/brainsci13091299. PubMed DOI PMC

Kawasaki R., Eto T., Kono N., Ohdake R., Yamana K., Hirano H., Kawamura S., Tarutani N., Katagiri K., Ikeda A. Photodynamic therapy using hybrid nanoparticles comprising of upconversion nanoparticles and chlorin e6-bearing pullulan. Biomater. Sci. 2024;12:5766–5774. doi: 10.1039/D4BM00769G. PubMed DOI

Palanikumar L., Kalmouni M., Houhou T., Abdullah O., Ali L., Pasricha R., Straubinger R., Thomas S., Afzal A.J., Barrera F.N., et al. pH-Responsive upconversion mesoporous silica nanospheres for combined multimodal diagnostic imaging and targeted photodynamic and photothermal cancer therapy. ACS Nano. 2023;17:18979–18999. doi: 10.1021/acsnano.3c04564. PubMed DOI PMC

Singh S.K., Parihar S., Jain S., Ho J.A., Vankayala R. Light-responsive functional nanomaterials as pioneering therapeutics: A paradigm shift to combat age-related disorders. J. Mater. Chem. B. 2024;12:8212–8234. doi: 10.1039/D4TB00578C. PubMed DOI

Gao C., Bhattarai P., Chen M., Zhang N., Hameed S., Yue X., Dai Z. Amphiphilic drug conjugates as nanomedicines for combined cancer therapy. Bioconjug. Chem. 2018;29:3967–3981. doi: 10.1021/acs.bioconjchem.8b00692. PubMed DOI

Singh A., Maheshwari S., Vishwakarma V.K., Prajapati B. Upconversion core-shell nanoconstructs for cancer theragnostics. In: Patel J.K., Dhas N., Saraogi G.K., editors. Core-Shell Nano Constructs for Cancer Theragnostic. Springer; Singapore: 2025. pp. 545–573. DOI

Hamblin M.R. Upconversion in photodynamic therapy: Plumbing the depths. Dalton Trans. 2018;47:8571–8580. doi: 10.1039/C8DT00087E. PubMed DOI PMC

Liu X., Qian H., Ji Y., Li Z., Shao Y., Hu Y., Tong G., Li L., Guo W., Guo H. Mesoporous silica-coated NaYF4 nanocrystals: Facile synthesis, in vitro bioimaging and photodynamic therapy of cancer cells. RSC Adv. 2012;2:12263–12268. doi: 10.1039/c2ra21688d. DOI

Wang H., Liu Z., Wang S., Dong C., Gong X., Zhao P., Chang J. MC540 and upconverting nanocrystal coloaded polymeric liposome for near-infrared light-triggered photodynamic therapy and cell fluorescent imaging. ACS Appl. Mater. Interfaces. 2014;6:3219–3225. doi: 10.1021/am500097f. PubMed DOI

Wang H., Dong C., Zhao P., Wang S., Liu Z., Chang J. Lipid coated upconverting nanoparticles as NIR remote controlled transducer for simultaneous photodynamic therapy and cell imaging. Int. J. Pharm. 2014;466:307–313. doi: 10.1016/j.ijpharm.2014.03.029. PubMed DOI

Chen X., Zhao Z., Jiang M., Que D., Shi S., Zheng N. Preparation and photodynamic therapy application of NaYF4:Yb,Tm–NaYF4:Yb,Er multifunctional upconverting nanoparticles. New J. Chem. 2013;37:1782–1788. doi: 10.1039/c3nj00065f. DOI

Rostami I., Rezvani H., Hu Z., Shahmoradian S.H. Breakthroughs in medicine and bioimaging with up-conversion nanoparticles. Int. J. Nanomed. 2019;14:7759–7780. doi: 10.2147/IJN.S221433. PubMed DOI PMC

Chu H., Cao T., Dai G., Liu B., Duan H., Kong C., Tian N., Hou D., Sun Z. Recent advances in functionalized upconversion nanoparticles for light-activated tumor therapy. RSC Adv. 2021;11:35472–35488. doi: 10.1039/D1RA05638G. PubMed DOI PMC

Satpathy A., Su T.-Y., Huang W.-T., Chiang C.J., Liu R.-S. Versatile nanoplatforms for bioimaging and therapy using upconversion nanoparticles. ACS Appl. Opt. Mater. 2024;2:1790–1802. doi: 10.1021/acsaom.4c00012. DOI

Nahorniak M., Pop-Georgievski O., Velychkivska N., Filipová M., Rydvalová E., Gunár K., Matouš P., Kostiv U., Horák D. Rose bengal-modified upconverting nanoparticles: Synthesis, characterization, and biological evaluation. Life. 2022;12:1383. doi: 10.3390/life12091383. PubMed DOI PMC

Liu K., Liu X., Zeng Q., Zhang Y., Tu L., Liu T., Kong X., Wang Y., Cao F., Lambrechts S.A., et al. Covalently assembled NIR nanoplatform for simultaneous fluorescence imaging and photodynamic therapy of cancer cells. ACS Nano. 2012;6:4054–4062. doi: 10.1021/nn300436b. PubMed DOI

Xia L., Kong X., Liu X., Tu L., Zhang Y., Chang Y., Liu K., Shen D., Zhao H., Zhang H. An upconversion nanoparticle—Zinc phthalocyanine based nanophotosensitizer for photodynamic therapy. Biomaterials. 2014;35:4146–4156. doi: 10.1016/j.biomaterials.2014.01.068. PubMed DOI

Ai X., Hu M., Wang Z., Lyu L., Zhang W., Li J., Yang H., Lin J., Xing B. Enhanced cellular ablation by attenuating hypoxia status and reprogramming tumor-associated macrophages via NIR light-responsive upconversion nanocrystals. Bioconjug. Chem. 2018;29:928–938. doi: 10.1021/acs.bioconjchem.8b00068. PubMed DOI

Fan W., Shen B., Bu W., Chen F., He Q., Zhao K., Zhang S., Zhou L., Peng W., Xiao Q., et al. A smart upconversion-based mesoporous silica nanotheranostic system for synergetic chemo-/radio-/photodynamic therapy and simultaneous MR/UCL imaging. Biomaterials. 2014;35:8992–9002. doi: 10.1016/j.biomaterials.2014.07.024. PubMed DOI

Sun X., Zhang P., Hou Y., Li Y., Huang X., Wang Z., Jing L., Gao M. Upconversion luminescence mediated photodynamic therapy through hydrophilically engineered porphyrin. Chem. Eng. Process.-Process Intensif. 2019;142:107551. doi: 10.1016/j.cep.2019.107551. DOI

Mohanty S., Kaczmarek A.M. Unravelling the benefits of transition-metal-co-doping in lanthanide upconversion nanoparticles. Chem. Soc. Rev. 2022;51:6893–6908. doi: 10.1039/D2CS00495J. PubMed DOI

Ezerskyte E., Butkiene G., Katelnikovas A., Klimkevicius V. Development of biocompatible, UV and NIR excitable nanoparticles with multiwavelength emission and enhanced colloidal stability. ACS Mater. Au. 2025;5:353–364. doi: 10.1021/acsmaterialsau.4c00151. PubMed DOI PMC

Cheng X., Tu D., Zheng W., Chen X. Energy transfer designing in lanthanide-doped upconversion nanoparticles. Chem. Commun. 2020;56:15118–15132. doi: 10.1039/D0CC05878E. PubMed DOI

Chandwani M., Agrawal R., Singh B.P., Momin M., Ningthoujam R.S. Upconversion and energy transfer processes, synthesis of upconversion nanoparticles and its application as an effective nano theranostic approach for the management of cancer. J. Mol. Struct. 2025;1348:143413. doi: 10.1016/j.molstruc.2025.143413. DOI

Wei Z., Liu Y., Li B., Li J., Lu S., Xing X., Liu K., Wang F., Zhang H. Rare-earth based materials: An effective toolbox for brain imaging, therapy, monitoring and neuromodulation. Light Sci. Appl. 2022;11:175. doi: 10.1038/s41377-022-00864-y. PubMed DOI PMC

Viswanathan S., Kovacs Z., Green K.N., Ratnakar S.J., Sherry A.D. Alternatives to gadolinium-based metal chelates for magnetic resonance imaging. Chem. Rev. 2010;110:2960–3018. doi: 10.1021/cr900284a. PubMed DOI PMC

Ezerskyte E., Morkvenas A., Venius J., Sakirzanovas S., Karabanovas V., Katelnikovas A., Klimkevicius V. Biocompatible upconverting nanoprobes for dual-modal imaging and temperature sensing. ACS Appl. Nano Mater. 2024;7:6185–6195. doi: 10.1021/acsanm.3c06111. PubMed DOI PMC

Vasylyshyn T., Huntošová V., Patsula V., Olejárová S., Slabý C., Jurašeková Z., Bánó G., Kubacková J., Šlouf M., Shapoval O., et al. Surface-engineered core-shell upconversion nanoparticles for effective hypericin delivery and multimodal imaging. Nanoscale. 2025;17:5838–5857. doi: 10.1039/D4NR05348F. PubMed DOI

Shapoval O., Patsula V., Větvička D., Oleksa V., Kabešová M., Vasylyshyn T., Poučková P., Horák D. Temoporfin-conjugated PEGylated poly(N,N-dimethylacrylamide)-stabilized upconversion colloid for NIR-induced photodynamic therapy of pancreatic cancer. Biomacromolecules. 2024;25:5771–5785. doi: 10.1021/acs.biomac.4c00317. PubMed DOI PMC

Shapoval O., Brandmeier J.C., Nahorniak M., Oleksa V., Makhneva E., Gorris H.H., Farka Z., Horák D. PMVEMA-coated upconverting nanoparticles for upconversion-linked immunoassay of cardiac troponin. Talanta. 2022;244:123400. doi: 10.1016/j.talanta.2022.123400. PubMed DOI

Šlouf M., Sikorová P., Pavlova E., Swietek M., Lartigue L., Skoupý R., Krzyžánek V. 4D-STEM-in-SEM: Changing an SEM microscope to a user-friendly powder electron diffractometer. Microsc. Microanal. 2025;31:ozaf045. doi: 10.1093/mam/ozaf045. PubMed DOI

Shapoval O., Engstová H., Šlouf M., Kočková O., Dlasková A., Jabůrek M., Halili A., Mozheitová A., Jirák D., Ježek P., et al. Liraglutide-conjugated poly(methyl vinyl ether-alt-maleic acid)-coated core-shell upconversion nanoparticles for theranostics of diabetes. ACS Appl. Mater. Interfaces. 2025;17:42863–42876. doi: 10.1021/acsami.5c11275. PubMed DOI PMC

Lanthanum Hexaboride Powder Line Position and Line Shape Standard for Powder Diffraction. US National Institute of Standards and Technology; Gaithersburg, MD, USA: 2000.

Muniz F.T.L., Miranda M.A.R., Santos C.M., Sasaki J.M. The Scherrer equation and the dynamical theory of X-ray diffraction. Acta Cryst. A. 2016;72:385–390. doi: 10.1107/S205327331600365X. PubMed DOI

Quinlan J.A., Inglut C.T., Srivastava P., Rahman I., Stabile J., Gaitan B., Arnau Del Valle C., Baumiller K., Gaur A., Chiou W.A., et al. Carrier-free, amorphous verteporfin nanodrug for enhanced photodynamic cancer therapy and brain drug delivery. Adv. Sci. 2024;11:2302872. doi: 10.1002/advs.202302872. PubMed DOI PMC

Schindelin J., Arganda-Carreras I., Frise E., Kaynig V., Longair M., Pietzsch T., Preibisch S., Rueden C., Saalfeld S., Schmid B., et al. Fiji: An open-source platform for biological-image analysis. Nat. Methods. 2012;9:676–682. doi: 10.1038/nmeth.2019. PubMed DOI PMC

Ni D., Zhang J., Bu W., Zhang C., Yao Z., Xing H., Wang J., Duan F., Liu Y., Fan W., et al. PEGylated NaHoF4 nanoparticles as contrast agents for both X-ray computed tomography and ultra-high field magnetic resonance imaging. Biomaterials. 2016;76:218–225. doi: 10.1016/j.biomaterials.2015.10.063. PubMed DOI

Shapoval O., Engstová H., Jirák D., Drahokoupil J., Sulková K., Pop-Georgievski O., Ježek P., Horák D. Poly(4-styrenesulfonic acid-co-maleic anhydride)-coated NaGdF4:Yb,Tb,Nd nanoparticles with luminescent and magnetic properties for pancreatic β-cell and Langerhans islet imaging. ACS Appl. Mater. Interfaces. 2022;14:18233–18247. doi: 10.1021/acsami.2c04274. PubMed DOI

Wang Y.-F., Liu G.-Y., Sun L.-D., Xiao J.-W., Zhou J.-C., Yan C.-H. Nd3+-sensitized upconversion nanophosphors: Efficient in vivo bioimaging probes with minimized heating effect. ACS Nano. 2013;7:7200–7206. doi: 10.1021/nn402601d. PubMed DOI

Shen J., Chen G., Vu A.-M., Fan W., Bilsel O.S., Chang C.-C., Han G. Engineering the upconversion nanoparticle excitation wavelength: Cascade sensitization of tri-doped upconversion colloidal nanoparticles at 800 nm. Adv. Opt. Mater. 2013;1:644–650. doi: 10.1002/adom.201300160. DOI

Kostiv U., Kučka J., Lobaz V., Kotov N., Janoušková O., Šlouf M., Krajnik B., Podhorodecki A., Francová P., Šefc L., et al. Highly colloidally stable trimodal 125I-radiolabeled PEG-neridronate-coated upconversion/magnetic bioimaging nanoprobes. Sci. Rep. 2020;10:20016. doi: 10.1038/s41598-020-77112-z. PubMed DOI PMC

Andrews K.W., Dyson D.J., Keown S.R. Interpretation of Electron Diffraction Patterns. 2nd ed. Springer; New York, NY, USA: 1967. DOI

Auzel F. Upconversion and anti-stokes processes with f and d ions in solids. Chem. Rev. 2004;104:139–173. doi: 10.1021/cr020357g. PubMed DOI

Xue X., Thitsa M., Cheng T., Gao W., Deng D., Suzuki T., Ohishi Y. Laser power density dependent energy transfer between Tm3+ and Tb3+: Tunable upconversion emissions in NaYF4:Tm3+, Tb3+, Yb3+ microcrystals. Opt. Express. 2016;24:26307–26321. doi: 10.1364/OE.24.026307. PubMed DOI

Bloembergen N., Morgan L.O. Proton relaxation times in paramagnetic solutions: Effects of electron spin relaxation. J. Chem. Phys. 1961;34:842–850. doi: 10.1063/1.1731684. DOI

Norek M., Peters J.A. MRI contrast agents based on dysprosium or holmium. Prog. Nucl. Magn. Reson. Spectrosc. 2011;59:64–82. doi: 10.1016/j.pnmrs.2010.08.002. PubMed DOI

Caspani S., Magalhães R., Araújo J.P., Sousa C.T. Magnetic nanomaterials as contrast agents for MRI. Materials. 2020;13:2586. doi: 10.3390/ma13112586. PubMed DOI PMC

Molaei M.J. Gadolinium-doped fluorescent carbon quantum dots as MRI contrast agents and fluorescent probes. Sci. Rep. 2022;12:17681. doi: 10.1038/s41598-022-22518-0. PubMed DOI PMC

Feng Y., Xiao Q., Zhang Y., Li F., Li Y., Li C., Wang Q., Shi L., Lin H. Neodymium-doped NaHoF4 nanoparticles as near-infrared luminescent/T2-weighted MR dual-modal imaging agents in vivo. J. Mater. Chem. B. 2017;5:504–510. doi: 10.1039/C6TB01961G. PubMed DOI

Nahorniak M., Patsula V., Mareková D., Matouš P., Shapoval O., Oleksa V., Vosmanská M., Machová Urdzíková L., Jendelová P., Herynek V., et al. Chemical and colloidal stability of polymer-coated NaYF4:Yb,Er nanoparticles in aqueous media and viability of cells: The effect of a protective coating. Int. J. Mol. Sci. 2023;24:2724. doi: 10.3390/ijms24032724. PubMed DOI PMC

Patsula V., Mareková D., Jendelová P., Nahorniak M., Shapoval O., Matouš P., Oleksa V., Konefał R., Vosmanská M., Machová-Urdziková L., et al. Polymer-coated hexagonal upconverting nanoparticles: Chemical stability and cytotoxicity. Front. Chem. 2023;11:1207984. doi: 10.3389/fchem.2023.1207984. PubMed DOI PMC

Németh Z., Csóka I., Semnani J.R., Sipos B., Haspel H., Kozma G., Kónya Z., Dobó D.G. Quality by design-driven zeta potential optimisation study of liposomes with charge imparting membrane additives. Pharmaceutics. 2022;14:1798. doi: 10.3390/pharmaceutics14091798. PubMed DOI PMC

Miletto I., Gionco C., Paganini M.C., Cerrato E., Marchese L., Gianotti E. Red upconverter nanocrystals functionalized with verteporfin for photodynamic therapy triggered by upconversion. Int. J. Mol. Sci. 2022;23:6951. doi: 10.3390/ijms23136951. PubMed DOI PMC

Ong K.J., MacCormack T.J., Clark R.J., Ede J.D., Ortega V.A., Felix L.C., Dang M.K., Ma G., Fenniri H., Veinot J.G., et al. Widespread nanoparticle-assay interference: Implications for nanotoxicity testing. PLoS ONE. 2014;9:e90650. doi: 10.1371/journal.pone.0090650. PubMed DOI PMC

Iavicoli I., Leso V., Fontana L., Calabrese E.J. Nanoparticle exposure and hormetic dose-responses: An update. Int. J. Mol. Sci. 2018;19:805. doi: 10.3390/ijms19030805. PubMed DOI PMC

Samkoe K.S., Chen A., Rizvi I., O’Hara J.A., Hoopes P.J., Pereira S.P., Hasan T., Pogue B.W. Imaging tumor variation in response to photodynamic therapy in pancreatic cancer xenograft models. Int. J. Radiat. Oncol. Biol. Phys. 2010;76:251–259. doi: 10.1016/j.ijrobp.2009.08.041. PubMed DOI PMC

Huggett M.T., Jermyn M., Gillams A., Illing R., Mosse S., Novelli M., Kent E., Bown S.G., Hasan T., Pogue B.W., et al. Phase I/II study of verteporfin photodynamic therapy in locally advanced pancreatic cancer. Br. J. Cancer. 2014;110:1698–1704. doi: 10.1038/bjc.2014.95. PubMed DOI PMC

Michy T., Massias T., Bernard C., Vanwonterghem L., Henry M., Guidetti M., Royal G., Coll J.L., Texier I., Josserand V., et al. Verteporfin-loaded lipid nanoparticles improve ovarian cancer photodynamic therapy in vitro and in vivo. Cancers. 2019;11:1760. doi: 10.3390/cancers11111760. PubMed DOI PMC

Clemente N., Miletto I., Gianotti E., Invernizzi M., Marchese L., Dianzani U., Renò F. Verteporfin-loaded mesoporous silica nanoparticles inhibit mouse melanoma proliferation in vitro and in vivo. Photochem. Photobiol. B. 2019;197:111533. doi: 10.1016/j.jphotobiol.2019.111533. PubMed DOI