학술논문
Improvement of the Effectiveness of HER2+ Cancer Therapy by Use of Doxorubicin and Trastuzumab Modified Radioactive Gold Nanoparticles.
Document Type
Academic Journal
Author
Żelechowska-Matysiak K; Centre of Radiochemistry and Nuclear Chemistry, Institute of Nuclear Chemistry and Technology, 03-195 Warsaw, Poland.; Salvanou EA; Institute of Nuclear & Radiological Sciences & Technology, Energy & Safety, N.C.S.R. 'Demokritos', Agia Paraskevi, 15341 Athens, Greece.; Bouziotis P; Institute of Nuclear & Radiological Sciences & Technology, Energy & Safety, N.C.S.R. 'Demokritos', Agia Paraskevi, 15341 Athens, Greece.; Budlewski T; Isotope Therapy Department, National Medical Institute of the Ministry of the Interior and Administration, 02-507 Warsaw, Poland.; Bilewicz A; Centre of Radiochemistry and Nuclear Chemistry, Institute of Nuclear Chemistry and Technology, 03-195 Warsaw, Poland.; Majkowska-Pilip A; Centre of Radiochemistry and Nuclear Chemistry, Institute of Nuclear Chemistry and Technology, 03-195 Warsaw, Poland.; Isotope Therapy Department, National Medical Institute of the Ministry of the Interior and Administration, 02-507 Warsaw, Poland.
Source
Publisher: American Chemical Society Country of Publication: United States NLM ID: 101197791 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1543-8392 (Electronic) Linking ISSN: 15438384 NLM ISO Abbreviation: Mol Pharm Subsets: MEDLINE
Subject
Language
English
Abstract
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.