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

In the present article, we describe a multimodal radiobioconjugatethat contains a chemotherapeutic agent (doxorubicin, DOX), a & beta;-emitter(Au-198), and a guiding vector (trastuzumab, Tmab) for targetedtherapy of cancers overexpressing HER2 receptors. To achieve thisgoal, radioactive gold nanoparticles ((198)AuNPs) with amean diameter of 30 nm were synthesized and coated with a poly(ethyleneglycol) (PEG) linker conjugated to DOX and monoclonal antibody (Tmab)via peptide bond formation. In vitro experiments demonstrated a highaffinity of the radiobioconjugate to HER2 receptors and cell internalization.Cytotoxicity experiments performed using the MTS assay showed a significantdecrease in the viability of SKOV-3 cells. A synergistic cytotoxiceffect due to the simultaneous presence of DOX and (198)Auwas revealed after 48 h of treatment with 2.5 MBq/mL. Flow cytometryanalysis indicated that DOX-(198)AuNPs-Tmab mainly inducedcell cycle arrest in the G2/M phase and late apoptosis. Dose-dependentadditive and synergistic effects of the radiobioconjugate were alsoshown in spheroid models. Ex vivo biodistribution experiments wereperformed in SKOV-3 tumor-bearing mice, investigating different distributionsof the (198)AuNPs-DOX and DOX-(198)AuNPs-Tmab afterintravenous (i.v.) and intratumoral (i.t.) administration. Finally,in vivo therapeutic efficacy studies on the same animal model demonstratedvery promising results, as they showed a significant tumor growtharrest up to 28 days following a single intratumoral injection of10 MBq. Therefore, the proposed multimodal radiobioconjugate showsgreat potential for the local treatment of HER2+ cancers.

Automated summary

In this article, we introduce a multimodal radiobioconjugate composed of doxorubicin, Au-198, and trastuzumab for targeted therapy of HER2+ cancers. The radiobioconjugate showed high affinity to HER2 receptors and induced cell cycle arrest and apoptosis in vitro. In spheroid models, it demonstrated dose-dependent additive and synergistic effects. Biodistribution and therapeutic efficacy studies in tumor-bearing mice exhibited promising results.