Improvement of the Effectiveness of HER2+ Cancer Therapy by Use of Doxorubicin and Trastuzumab Modified Radioactive Gold Nanoparticles

• Published in: Molecular pharmaceutics 2023-09, Vol.20 (9), p.4676-4686
• Main Authors: Żelechowska-Matysiak, Kinga, Salvanou, Evangelia-Alexandra, Bouziotis, Penelope, Budlewski, Tadeusz, Bilewicz, Aleksander, Majkowska-Pilip, Agnieszka
• Format: Article
• Language: English
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/acs.molpharmaceut.3c00414

In the present article, we describe a multimodal radiobioconjugate that contains a chemotherapeutic agent (doxorubicin, DOX), a β-emitter (198Au), and a guiding vector (trastuzumab, Tmab) for targeted therapy of cancers overexpressing HER2 receptors. To achieve this goal, radioactive gold nanoparticles (198AuNPs) with a mean diameter of 30 nm were synthesized and coated with a poly­(ethylene glycol) (PEG) linker conjugated to DOX and monoclonal antibody (Tmab) via peptide bond formation. In vitro experiments demonstrated a high affinity of the radiobioconjugate to HER2 receptors and cell internalization. Cytotoxicity experiments performed using the MTS assay showed a significant decrease in the viability of SKOV-3 cells. A synergistic cytotoxic effect due to the simultaneous presence of DOX and 198Au was revealed after 48 h of treatment with 2.5 MBq/mL. Flow cytometry analysis indicated that DOX-198AuNPs-Tmab mainly induced cell cycle arrest in the G2/M phase and late apoptosis. Dose-dependent additive and synergistic effects of the radiobioconjugate were also shown in spheroid models. Ex vivo biodistribution experiments were performed in SKOV-3 tumor-bearing mice, investigating different distributions of the 198AuNPs-DOX and DOX-198AuNPs-Tmab after intravenous (i.v.) and intratumoral (i.t.) administration. Finally, in vivo therapeutic efficacy studies on the same animal model demonstrated very promising results, as they showed a significant tumor growth arrest up to 28 days following a single intratumoral injection of 10 MBq. Therefore, the proposed multimodal radiobioconjugate shows great potential for the local treatment of HER2+ cancers.