Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 39, Pages 9690-9695Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1809258115
Keywords
theranostics; targeted therapy; combined therapy; nuclear medicine; upconversion nanoparticles
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Funding
- Ministry of Education and Science of the Russian Federation [14.Z50.31.0022]
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We report combined therapy using upconversion nanoparticles (UCNP) coupled to two therapeutic agents: beta-emitting radionuclide yttrium-90 (Y-90) 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 Y-90-and PE40-induced cytotoxic effects characterized by IC50 140 mu g/mL (UCNP-R) and 5.2 mu g/mL (UCNP-T), respectively. When both therapeutic agents were combined into UCNPR- T, the synergetic effect increased markedly, similar to 2200-fold, resulting in IC50 = 0.0024 mu g/mL. The combined therapy with UCNP-R-T was demonstrated in vivo.
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