First extensive study of silver-doped lanthanum manganite nanoparticles for inducing selective chemotherapy and radio-toxicity enhancement

doi:10.1016/j.msec.2021.111970

Materials Science and Engineering: C

Volume 123, April 2021, 111970

https://doi.org/10.1016/j.msec.2021.111970 Get rights and content

Highlights

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Brain cancer treatment outcomes could be improved with better selectivity.
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Silver doped lanthanum manganite is a cancer cell selective nanoparticle.
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Causes cancer cell death via reactive oxygen species, promotes healthy cell growth.
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Nanoparticles according to silver doping can raise its Curie temperature.
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Nanoparticles offer synergistic cancer treatments.

Abstract

Nanoparticles have a great potential to increase the therapeutic efficiency of several cancer therapies. This research examines the potential for silver-doped lanthanum manganite nanoparticles to enhance radiation therapy to target radioresistant brain cancer cells, and their potential in combinational therapy with magnetic hyperthermia. Magnetic and structural characterisation found all dopings of nanoparticles (NPs) to be pure and single phase with an average crystallite size of approximately 15 nm for undoped NPs and 20 nm for silver doped NPs. Additionally, neutron diffraction reveals that La_0.9Ag_0.1MnO₃ (10%-LAGMO) NPs exhibit residual ferromagnetism at 300 K that is not present in lower doped NPs studied in this work, indicating that the Curie temperature may be manipulated according to silver doping. This radiobiological study reveals a completely cancer-cell selective treatment for LaMnO₃, La_0.975Ag_0.025MnO₃ and La_0.95Ag_0.05MnO₃ (0, 2.5 and 5%-LAGMO) and also uncovers a potent combination of undoped lanthanum manganite with orthovoltage radiation. Cell viability assays and real time imaging results indicated that a concentration of 50 μg/mL of the aforementioned nanoparticles do not affect the growth of Madin-Darby Canine Kidney (MDCK) non-cancerous cells over time, but stimulate its metabolism for overgrowth, while being highly toxic to 9L gliosarcoma (9LGS). This is not the case for 10%-LAGMO nanoparticles, which were toxic to both non-cancerous and cancer cell lines. The nanoparticles also exhibited a level of toxicity that was regulated by the overproduction of free radicals, such as reactive oxygen species, amplified when silver ions are involved. With the aid of fluorescent imaging, the drastic effects of these reactive oxygen species were visualised, where nucleus cleavage (an apoptotic indicator) was identified as a major consequence. The genotoxic response of this effect for 9LGS and MDCK due to 10%-LAGMO NPs indicates that it is also causing DNA double strand breaks within the cell nucleus. Using 125 kVp orthovoltage radiation, in combination with an appropriate amount of NP-induced cell death, identified undoped lanthanum manganite as the most ideal treatment. Real-time imaging following the combination treatment of undoped lanthanum manganite nanoparticles and radiation, highlighted a hinderance of growth for 9LGS, while MDCK growth was boosted. The clonogenic assay following incubation with undoped lanthanum manganite nanoparticles combined with a relatively low dose of radiation (2 Gy) decreased the surviving fraction to an exceptionally low (0.6 ± 6.7)%. To our knowledge, these results present the first biological in-depth analysis on silver-doped lanthanum manganite as a brain cancer selective chemotherapeutic and radiation dose enhancer and as a result will propel its first in vivo investigation.

Keywords

Cancer therapy

Selective toxicity

Silver doped LaMnO₃

Nanoparticles

Reactive oxygen species

Cited by (0)

Abass Khochaiche is a Master of Philosophy (Medical Radiation Physics) graduate at the University of Wollongong. He completed this with special commendation for an outstanding thesis. Abass's research was primarily on the ground-breaking studies of new nanoparticles, silver-doped lanthanum manganite. His studies have shown potential for a completely cancer cell selective treatment strategy of deadly brain cancers that may be used in combination with many therapy techniques such as hyperthermia. His expertise in cell assays, microscopy, flow cytometry and small animal monitoring and handling has allowed him to continue to discover the limits of his nanoparticles as a PhD candidate.

Matt Westlake graduated at the top of his class from the University of Wollongong with honours in advanced physics. He then completed a PhD focused on the characterisation of silver doped lanthanum manganite.

Alice O'Keefe is a medical physicist investigating materials for use in the novel cancer therapy that is Magnetic Hyperthermia. Alice is a researcher at the University of Wollongong where she has completed her Master of Research in medical physics, with a focus on solid state materials and nano-fabrication. Alice is a PhD candidate working in the Targeted Nano-Therapies team for UOW's Centre for Medical Radiation Physics. Her PhD is on the analysis of lanthanum manganite as a nano-material for use in cancer therapies.

Elette Engels is a PhD student with the Targeted Nano-Therapies Theme of the Centre for Medical Radiation Physics at the University of Wollongong. She holds a Bachelor of Medical Radiation Physics (Advanced) with First Class Honours in 2015. Elette investigates image-guided radiotherapy and synchrotron Microbeam Radiotherapy with nanoparticles, which has been recognised with postgraduate prizes from the Australian Institute of Physics (NSW branch) and Australasian College of Physical Scientists & Engineers in Medicine (NSW branch). Elette has expertise in Geant4 simulation, cell assay, flow cytometry and microscopy studies, synchrotron science, dosimetry, CT imaging, and small animal handling and surgery.

Sarah Vogel holds an Honours Degree in Medical and Radiation Physics and is a PhD candidate at the University of Wollongong. Her focus is on the enhancement of synchrotron microbeam radiation using novel nanoparticles. Her expertise includes cell culture, flow cytometry, confocal imaging, nanoparticle toxicity, kilovoltage and microbeam radiation, computed tomography imaging and rodent animal studies (including surgery).

Michael Valceski is a PhD student with the University of Wollongong, previously completing Honours Class I in a B. of Medical Radiation Physics (Advanced) in 2018. His PhD thesis investigates novel, multi-modal, theranostic combination therapies, utilizing nanoparticles, halogenated-pyrimidine's, chemotherapeutic drugs and new radiobiological techniques. He has experience with cell culture and a variety of in vitro techniques, including clonogenic assay, flow cytometry, fluorescent & confocal microscopy, and biological assays. He has further experience with a variety of pre-clinical in vivo techniques, including rat handling/monitoring, stereotaxic surgery assistance, IP and SC injections, euthanasia and necropsy, and anaesthesia administration.

Nan Li, after completing a PhD in protein structural biology in the University of Sydney, joined Prof Nick Dixon's group in School of Chemistry, University of Wollongong to study the DNA replication machinery in E. coli, Acinetobacter spp. and Staphylococcus aureus using X-ray crystallography. Nan later joined the Targeted Nano-Therapies group led by Dr Moeava Tehei in School of Physics, UOW to study the radiation enhancement in both conventional and synchrotron radiations along with anti-cancer drugs polo-like kinase 1 inhibitors and nanoparticles. Some of the results were published in Biomedical Physics & Engineering Express, 2019.

Kirrily C. Rule is a neutron scatterer at ANSTO, operating the thermal triple axis spectrometer, TAIPAN. She is an Associate Professor at the University of Wollongong and the national Honorary Secretary of the Australian Institute of Physics. Kirrily's scientific focus is to measure dynamics in materials using inelastic neutron scattering techniques. Her research interests are on novel and low dimensional magnetic materials. Kirrily studied a combined Arts/Science degree at Monash University before progressing onto a year of Honours research and then a PhD in Physics.

Josip Horvat received PhD in Physics at Monash University, Australia. He is currently employed as Associate Professor at School of Physics, University of Wollongong. His research interests have been applied superconductivity, magnetic nanoparticles, terahertz spectroscopy, DFT modelling.

Konstantin Konstantinov obtained his MSc and PhD (PhD in Chemistry) degrees from the University of Chemical Technology and Metallurgy in Sofia, Bulgaria. Since 1985 Konstantin has had above 30 years of an international research and academic career and he is a recognised expert in design, study and application of nano-ceramic materials and composites for energy storage and health protection applications as well as advanced nano-technologies. He moved to the University of Wollongong in 2000 and he is currently the Program Coordinator on Nanostructured Materials at the Institute for Superconducting & Electronic Materials.

Anatoly Rosenfeld is Distinguished Professor and Director of Centre for Medical Radiation Physics University of Wollongong to which he was a founder. His major expertise is in design and fabrication of semiconductor radiation detectors with application in radiation medicine and space for radiation protection of astronauts and radiation damage of electronics prediction. He is an immediate past Chair of International Solid State Dosimetry Organization and Member of ICRU Committee for microdosimetry report preparation. Anatoly has published more than 400 peer review papers, holds 18 patents and is actively involved in their commercialization.

Michael Lerch graduated with a PhD in solid state physics (1998). He is a founding member of the Centre for Medical Radiation Physics (CMRP) at the University of Wollongong (UOW) and Head of the UOW School of Physics. Michael applies his expertise of electronic properties of semiconductors to the development of novel, solid-state based sensors and instrumentation for application in radiation medicine. He is interested in the real-world implementation of real-time devices designed to operate in-vivo for targeted diagnostic imaging and radiotherapy. Michael contributes to research in optimization of radiation medicine using the physical and semiconducting properties of engineered nano-ceramics and semiconductor devices.

Stéphanie Corde is Deputy Director of Radiation Oncology Medical Physics at Prince of Wales Hospital, Randwick and Honorary Principal Fellow at Centre for Medical Radiation Physics, University of Wollongong (Australia). She has been qualified as a clinical medical physicist specialist since 1998. In 2002, she graduated with a PhD in Biomedical Engineering from the Joseph Fourier University (Grenoble, France) for her work on new applications of synchrotron radiation in medicine and in particular medical imaging and radiation oncology. She has worked in different clinical radiation oncology departments worldwide. Her ongoing research interests aim at improving radiotherapy treatment quality and efficiency.

Moeava Tehei is scientific leader in the theme Targeted Nano Therapies at the Centre for Medical Radiation Physics at the University of Wollongong. He leads the new advances in targeted nanoparticle dose enhanced image guided research topic with a goal to ultimately translate this research to clinical practise. He has international collaborations in cancer treatments and nanotheranostics, and he is internationally recognised expert in those research topics. Tehei is convenor of conferences that aim at unifying the diverse scientific communities working with radiations. He supervised and mentored about 20 PhD students and research assistants in multimodal cancer treatments and theranostics.

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