Radioactive (90Y) upconversion nanoparticles conjugated with recombinant targeted toxin for synergistic nanotheranostics of cancer
Menée in vitro et à l'aide de xénogreffes d'adénocarcinome mammaire HER2+ sur un modèle murin, cette étude analyse les effets thérapeutiques de l'injection intratumorale d'un nanocomplexe photoluminescent dans le proche infrarouge, chargé en yttrium-90 et comportant à sa surface une protéine de fusion associant un fragment de l'exotoxine A dérivée de la bactérie Pseudomonas aeruginosa et une protéine spécifique des récepteurs HER2
Emerging cancer nanotechnology enables targeted delivery of substantial payloads of drugs to cancer sites with concomitant reduction of side effects due to the lesser accumulation in the critical organs. This prompts loading of nanocarriers with therapeutic cargo and contrast agents, allowing combined cancer therapy and tumor visualization, respectively. This paper reports the realization of such combined therapy using conjugates of radionuclide yttrium-90–doped upconversion nanoparticles and targeted toxin. The resultant hybrid complex showed high therapeutic efficacy and high imaging contrast both in vitro and in vivo.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.