An international research team, involving researchers from National Research Nuclear University MEPhI, has developed a new cancer theranostics strategy, which makes it possible to increase diagnostics efficiency and greatly reduce the effective concentration of drugs used in cancer chemotherapy. The research results were published on ACS Nano website.
https://pubs.acs.org/doi/10.1021/acsnano.0c03421
According to the authors of the new strategy, when combined with immunotherapy, image-guided targeted delivery of chemotherapeutic agents is a promising direction for combination cancer theranostics, but this approach has so far produced only limited success due to a lack of molecular targets on the cell surface and low therapeutic index of conventional chemotherapy.
“Our team has developed a synergistic strategy of combination immuno/chemotherapy: two different drugs were directed toward different domains of the single cell-surface receptor – HER2 oncomarker.HER2 is a clinically relevantoncomarker, whose overexpression is often correlatedwith resistance to chemotherapy, high metastasis, and a negative prognosis,” Victoria Shipunova, researcher at the Laboratory of Bionanophotonicsof the Institute of Engineering Physics for Biomedicine of MEPhI, one of the publication’s authors, said.
The dual targeting strategy used two distinct drugsi) PLGA (polylactide-co-glycolide) nanoparticles loaded with a chemotherapeutic drug (doxorubicin), modified with an affibody recognition molecule and an imaging diagnostic fluorescent dye (Nile Red); ii) bifunctional genetically engineered DARP-LoPE immunotoxin, consisting of a low-immunogenic modification of therapeutic Pseudomonas exotoxin A (LoPE) and a scaffold targeting protein, DARPin9.29.
According to the proposed strategy, the first chemotherapeutic nanoagent PLGA, with the affibody recognition molecule, targets subdomains III and IV of the HER2 receptor with a 60-fold specificity compared to non-targeted nanoparticles, while the second immunotoxin effectively targets subdomain I of the HER2 receptor by the DARPin molecule.
“By using the combination strategy with two targeted superstructures, we’ve managed to in vitro reduce the concentration of active substances by 1000 times to achieve the same therapeutic effect. Moreover, the combination of these drugs acts synergistically, with substance significantly enhancing the effect of the other. This synergy has made it possible to significantly increase the effectiveness of therapy for HER2-positive tumorsin vivo and completely prevent metastases,” Victoria Shipunova said.
The authors of the study believe that the proposed synergistic dual targeting strategy will make it possible to develop effective methods to treat aggressive tumors. In addition, according to the scientists, the proposed technology makes possible highly effective treatment in a very short period of time, which is very important to prevent metastases in rapidly developing neoplasms.
The study involved scientists from the Laboratory of Molecular Immunology of Shemyakin − Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Institute of Engineering Physics for Biomedicine of MEPhI, Institute for Lasers, Photonics and Biophotonics, University at Buffalo (USA) and Aix Marseille University (France).
The study was supported -by the Russian Science Foundation grants ? 17-74-20146 (particle synthesis and characterization, in vivo studies) and 19-72-30012 (electron microscopy study), and by the Russian Foundation for Basic Research grant ? 20-34-70136 (theranostic immunotoxin purification) and 19-29-04012 (in vitro toxicity studies).