Improvement of the Effectiveness of HER2+ Cancer Therapy by Use of Doxorubicin and Trastuzumab Modified Radioactive Gold Nanoparticles.
Kinga Żelechowska-MatysiakEvangelia-Alexandra SalvanouPenelope BouziotisTadeusz BudlewskiAleksander BilewiczAgnieszka Majkowska-PilipPublished in: Molecular pharmaceutics (2023)
In the present article, we describe a multimodal radiobioconjugate that contains a chemotherapeutic agent (doxorubicin, DOX), a β-emitter ( 198 Au), and a guiding vector (trastuzumab, Tmab) for targeted therapy of cancers overexpressing HER2 receptors. To achieve this goal, radioactive gold nanoparticles ( 198 AuNPs) 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 198 Au was revealed after 48 h of treatment with 2.5 MBq/mL. Flow cytometry analysis indicated that DOX- 198 AuNPs-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 198 AuNPs-DOX and DOX- 198 AuNPs-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.
Keyphrases
- cell cycle arrest
- cancer therapy
- gold nanoparticles
- cell death
- drug delivery
- pi k akt
- flow cytometry
- reduced graphene oxide
- monoclonal antibody
- photodynamic therapy
- randomized controlled trial
- single cell
- induced apoptosis
- oxidative stress
- sensitive detection
- endoplasmic reticulum stress
- high dose
- metabolic syndrome
- low dose
- high throughput
- signaling pathway
- cell proliferation
- pain management
- type diabetes
- cell therapy
- smoking cessation
- human health
- endothelial cells
- diabetic rats
- metastatic breast cancer
- anti inflammatory
- pet imaging
- quantum dots
- stress induced