Radioactive (90Y) upconversion nanoparticles conjugated with recombinant targeted toxin for synergistic nanotheranostics of cancer

Evgenii L. Guryev; Natalia O. Volodina; Natalia Y. Shilyagina; Sergey V. Gudkov; Irina V. Balalaeva; Arthur B. Volovetskiy; Alexander V. Lyubeshkin; Alexey V. Sen; Sergey A. Ermilov; Vladimir A. Vodeneev; Rem V. Petrov; Andrei V. Zvyagin; Zhores I. Alferov; Sergey M. Deyev

doi:10.1073/pnas.1809258115

Radioactive (⁹⁰Y) upconversion nanoparticles conjugated with recombinant targeted toxin for synergistic nanotheranostics of cancer

Evgenii L. Guryev, Natalia O. Volodina, Natalia Y. Shilyagina, Sergey V. Gudkov, Irina V. Balalaeva, Arthur B. Volovetskiy, Alexander V. Lyubeshkin, Alexey V. Sen, Sergey A. Ermilov, Vladimir A. Vodeneev, Rem V. Petrov, Andrei V. Zvyagin^*, Zhores I. Alferov, Sergey M. Deyev

^*Corresponding author for this work

ARC Centre of Excellence for Nanoscale BioPhotonics (CNBP)

Research output: Contribution to journal › Article › peer-review

57 Citations (Scopus)

Abstract

We report combined therapy using upconversion nanoparticles (UCNP) coupled to two therapeutic agents: beta-emitting radionuclide yttrium-90 (⁹⁰Y) fractionally substituting yttrium in UCNP, and a fragment of the exotoxin A derived from Pseudomonas aeruginosa genetically fused with a targeting designed ankyrin repeat protein (DARPin) specific to HER2 receptors. The resultant hybrid complex UCNP-R-T was tested using human breast adenocarcinoma cells SK-BR-3 overexpressing HER2 receptors and immunodeficient mice, bearing HER2-positive xenograft tumors. The photophysical properties of UCNPs enabled background-free imaging of the UCNP-R-T distribution in cells and animals. Specific binding and uptake of UCNP complexes in SK-BR-3 cells was observed, with separate ⁹⁰Y- and PE40-induced cytotoxic effects characterized by IC₅₀ 140 μg/mL (UCNP-R) and 5.2 μg/mL (UCNP-T), respectively. When both therapeutic agents were combined into UCNP-R-T, the synergetic effect increased markedly, ∼2200-fold, resulting in IC₅₀ = 0.0024 μg/mL. The combined therapy with UCNP-R-T was demonstrated in vivo.

Original language	English
Pages (from-to)	9690-9695
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	115
Issue number	39
DOIs	https://doi.org/10.1073/pnas.1809258115
Publication status	Published - 25 Sept 2018

Keywords

Combined therapy
Nuclear medicine
Targeted therapy
Theranostics
Upconversion nanoparticles

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10.1073/pnas.1809258115

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Guryev, E. L., Volodina, N. O., Shilyagina, N. Y., Gudkov, S. V., Balalaeva, I. V., Volovetskiy, A. B., Lyubeshkin, A. V., Sen, A. V., Ermilov, S. A., Vodeneev, V. A., Petrov, R. V., Zvyagin, A. V., Alferov, Z. I., & Deyev, S. M. (2018). Radioactive (⁹⁰Y) upconversion nanoparticles conjugated with recombinant targeted toxin for synergistic nanotheranostics of cancer. Proceedings of the National Academy of Sciences of the United States of America, 115(39), 9690-9695. https://doi.org/10.1073/pnas.1809258115

@article{ae09aed7ad00456cab71519659970396,

title = "Radioactive (90Y) upconversion nanoparticles conjugated with recombinant targeted toxin for synergistic nanotheranostics of cancer",

abstract = "We report combined therapy using upconversion nanoparticles (UCNP) coupled to two therapeutic agents: beta-emitting radionuclide yttrium-90 (90Y) fractionally substituting yttrium in UCNP, and a fragment of the exotoxin A derived from Pseudomonas aeruginosa genetically fused with a targeting designed ankyrin repeat protein (DARPin) specific to HER2 receptors. The resultant hybrid complex UCNP-R-T was tested using human breast adenocarcinoma cells SK-BR-3 overexpressing HER2 receptors and immunodeficient mice, bearing HER2-positive xenograft tumors. The photophysical properties of UCNPs enabled background-free imaging of the UCNP-R-T distribution in cells and animals. Specific binding and uptake of UCNP complexes in SK-BR-3 cells was observed, with separate 90Y- and PE40-induced cytotoxic effects characterized by IC50 140 μg/mL (UCNP-R) and 5.2 μg/mL (UCNP-T), respectively. When both therapeutic agents were combined into UCNP-R-T, the synergetic effect increased markedly, ∼2200-fold, resulting in IC50 = 0.0024 μg/mL. The combined therapy with UCNP-R-T was demonstrated in vivo.",

keywords = "Combined therapy, Nuclear medicine, Targeted therapy, Theranostics, Upconversion nanoparticles",

author = "Guryev, {Evgenii L.} and Volodina, {Natalia O.} and Shilyagina, {Natalia Y.} and Gudkov, {Sergey V.} and Balalaeva, {Irina V.} and Volovetskiy, {Arthur B.} and Lyubeshkin, {Alexander V.} and Sen, {Alexey V.} and Ermilov, {Sergey A.} and Vodeneev, {Vladimir A.} and Petrov, {Rem V.} and Zvyagin, {Andrei V.} and Alferov, {Zhores I.} and Deyev, {Sergey M.}",

year = "2018",

month = sep,

day = "25",

doi = "10.1073/pnas.1809258115",

language = "English",

volume = "115",

pages = "9690--9695",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

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Guryev, EL, Volodina, NO, Shilyagina, NY, Gudkov, SV, Balalaeva, IV, Volovetskiy, AB, Lyubeshkin, AV, Sen, AV, Ermilov, SA, Vodeneev, VA, Petrov, RV, Zvyagin, AV, Alferov, ZI & Deyev, SM 2018, 'Radioactive (⁹⁰Y) upconversion nanoparticles conjugated with recombinant targeted toxin for synergistic nanotheranostics of cancer', Proceedings of the National Academy of Sciences of the United States of America, vol. 115, no. 39, pp. 9690-9695. https://doi.org/10.1073/pnas.1809258115

Radioactive (⁹⁰Y) upconversion nanoparticles conjugated with recombinant targeted toxin for synergistic nanotheranostics of cancer. / Guryev, Evgenii L.; Volodina, Natalia O.; Shilyagina, Natalia Y. et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 39, 25.09.2018, p. 9690-9695.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Radioactive (90Y) upconversion nanoparticles conjugated with recombinant targeted toxin for synergistic nanotheranostics of cancer

AU - Guryev, Evgenii L.

AU - Volodina, Natalia O.

AU - Shilyagina, Natalia Y.

AU - Gudkov, Sergey V.

AU - Balalaeva, Irina V.

AU - Volovetskiy, Arthur B.

AU - Lyubeshkin, Alexander V.

AU - Sen, Alexey V.

AU - Ermilov, Sergey A.

AU - Vodeneev, Vladimir A.

AU - Petrov, Rem V.

AU - Zvyagin, Andrei V.

AU - Alferov, Zhores I.

AU - Deyev, Sergey M.

PY - 2018/9/25

Y1 - 2018/9/25

N2 - We report combined therapy using upconversion nanoparticles (UCNP) coupled to two therapeutic agents: beta-emitting radionuclide yttrium-90 (90Y) fractionally substituting yttrium in UCNP, and a fragment of the exotoxin A derived from Pseudomonas aeruginosa genetically fused with a targeting designed ankyrin repeat protein (DARPin) specific to HER2 receptors. The resultant hybrid complex UCNP-R-T was tested using human breast adenocarcinoma cells SK-BR-3 overexpressing HER2 receptors and immunodeficient mice, bearing HER2-positive xenograft tumors. The photophysical properties of UCNPs enabled background-free imaging of the UCNP-R-T distribution in cells and animals. Specific binding and uptake of UCNP complexes in SK-BR-3 cells was observed, with separate 90Y- and PE40-induced cytotoxic effects characterized by IC50 140 μg/mL (UCNP-R) and 5.2 μg/mL (UCNP-T), respectively. When both therapeutic agents were combined into UCNP-R-T, the synergetic effect increased markedly, ∼2200-fold, resulting in IC50 = 0.0024 μg/mL. The combined therapy with UCNP-R-T was demonstrated in vivo.

AB - We report combined therapy using upconversion nanoparticles (UCNP) coupled to two therapeutic agents: beta-emitting radionuclide yttrium-90 (90Y) fractionally substituting yttrium in UCNP, and a fragment of the exotoxin A derived from Pseudomonas aeruginosa genetically fused with a targeting designed ankyrin repeat protein (DARPin) specific to HER2 receptors. The resultant hybrid complex UCNP-R-T was tested using human breast adenocarcinoma cells SK-BR-3 overexpressing HER2 receptors and immunodeficient mice, bearing HER2-positive xenograft tumors. The photophysical properties of UCNPs enabled background-free imaging of the UCNP-R-T distribution in cells and animals. Specific binding and uptake of UCNP complexes in SK-BR-3 cells was observed, with separate 90Y- and PE40-induced cytotoxic effects characterized by IC50 140 μg/mL (UCNP-R) and 5.2 μg/mL (UCNP-T), respectively. When both therapeutic agents were combined into UCNP-R-T, the synergetic effect increased markedly, ∼2200-fold, resulting in IC50 = 0.0024 μg/mL. The combined therapy with UCNP-R-T was demonstrated in vivo.

KW - Combined therapy

KW - Nuclear medicine

KW - Targeted therapy

KW - Theranostics

KW - Upconversion nanoparticles

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U2 - 10.1073/pnas.1809258115

DO - 10.1073/pnas.1809258115

M3 - Article

C2 - 30194234

AN - SCOPUS:85053941613

SN - 0027-8424

VL - 115

SP - 9690

EP - 9695

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 39

ER -

Radioactive (⁹⁰Y) upconversion nanoparticles conjugated with recombinant targeted toxin for synergistic nanotheranostics of cancer

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