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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UR - http://www.scopus.com/inward/citedby.url?scp=85053941613&partnerID=8YFLogxK
U2 - 10.1073/pnas.1809258115
DO - 10.1073/pnas.1809258115
M3 - Article
C2 - 30194234
AN - SCOPUS:85053941613
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
SN - 0027-8424
IS - 39
ER -