Au@Pt Core-Shell Nanoparticle Bioconjugates for the Therapy of HER2+ Breast Cancer and Hepatocellular Carcinoma. Model Studies on the Applicability of 193mPt and 195mPt Radionuclides in Auger Electron Therapy

Abstract

193mPt and 195mPt radionuclides are therapeutically attractive Auger electron emitters with notably high Auger electron yield per decay. The present paper summarizes the first step of research on the applications of core-shell (Au@Pt) nanoparticles for electron Auger therapy of HER2+ (human epidermal growth factor receptor 2) breast cancer and hepatocellular carcinoma. Gold nanoparticles (30 nm) were synthesized covered with a platinum shell at high efficiency (>80%) and were further evaluated for in vitro studies such as binding affinity, internalization and cytotoxicity. To find the mechanism(s) responsible for platinum cytotoxicity in HepG2 cells, the platinum concentration in isolated cell nuclei and cytoplasm was determined using ICP-MS (inductively coupled plasma mass spectrometry). Lack of platinum in cell nuclei suggests that the cytotoxic effect is associated with the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Studies carried out on the SKOV-3 cell line with the use of a synthesized targeting bioconjugate (Au@Pt-PEG-trastuzumab) revealed a high affinity of this preparation to HER2+ cells, its internalization, its placement in the perinuclear area and partial intranuclear location. The specific binding for HER2 negative cells, MDA-MB-231, was negligible and Au@Pt-PEG-trastuzumab did not enter these cells. The results obtained are promising and warrant future investigation of Auger electron therapy using 193mPt and 195mPt based radiopharmaceuticals.

Doxorubicin- and Trastuzumab-Modified Gold Nanoparticles as Potential Multimodal Agents for Targeted Therapy of HER2+ Cancers

“…These results demonstrated that DOX–PEG–AuNPs–PEG–([ 131 I]Tmab) bioconjugate binds specifically to HER2 receptors expressed on SKOV-3 cells with high affinity. Our findings were in good agreement with other publications, where various NPs conjugated with Tmab were studied for receptor-binding properties [ 19 , 20 , 21 ].…”

“…This was due to the detected radioactivities being close to the background which confirmed the lack of specific binding to MDA-MB-231 cells. Similar results were obtained by Wawrowicz et al [ 19 ], where receptor affinity for Au@Pt-PEG–[ 131 I]Tmab was studied.…”

Oxidative Status as an Attribute for Selective Antitumor Activity of Platinum-Containing Nanoparticles against Hepatocellular Carcinoma

“…Since we observed a marked, time-dependent increase in ROS production, we asked whether redox stress triggered by Au@Pt and PtNPs refers to the particle-dependent, apoptotic changes in HCC. The typical, molecular hallmarks of apoptosis, such as chromatin condensation and apoptotic body formation, have been previously confirmed with confocal imaging of HCCs after treatment with Au@Pt [ 31 ]. To extend that research, here, we employed Annexin-V assay.…”

“…The following supporting information can be downloaded at: . References [ 31 , 38 , 39 , 40 , 41 ] are cited in Supplementary Materials.…”

Nanostructures as Radionuclide Carriers in Auger Electron Therapy

“…Anticancer drug delivery systems represent a widely investigated research area in the context of nanoparticles medical application. The surface of nanoparticles can be modified with proper vectors (such as antibodies, peptides, or small biologically active molecules) which have high affinity to the receptors on tumor cells, and the number of these targeting ligands bound to one nanoparticle can be much more than one [16]. Specific binding to transmembrane receptors improves the delivery of radioactivity to the targeted tissue, which leads to improved therapeutic efficacy.…”