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

Abass Khochaiche; Matt Westlake; Alice O'Keefe; Elette Engels; Sarah Vogel; Michael Valceski; Nan Li; Kirrily C Rule; Josip Horvat; Konstantin Konstantinov; Anatoly Rosenfeld; Michael Lerch; Stéphanie Corde; Moeava Tehei

doi:10.1016/j.msec.2021.111970

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

Mater Sci Eng C Mater Biol Appl. 2021 Apr:123:111970. doi: 10.1016/j.msec.2021.111970. Epub 2021 Feb 19.

Authors

Affiliations

¹ Centre for Medical Radiation Physics, University of Wollongong, Wollongong, Australia; School of Physics, University of Wollongong, Wollongong, Australia; Illawarra Health and Medical Research Institute (IHMRI), University of Wollongong, Wollongong, Australia; Molecular Horizons, School of Chemistry and Molecular, Bioscience University of Wollongong, Wollongong, Australia.
² Centre for Medical Radiation Physics, University of Wollongong, Wollongong, Australia; School of Physics, University of Wollongong, Wollongong, Australia; Illawarra Health and Medical Research Institute (IHMRI), University of Wollongong, Wollongong, Australia.
³ Australian Nuclear Science and Technology Organisation, ANSTO, Sydney, Australia.
⁴ School of Physics, University of Wollongong, Wollongong, Australia.
⁵ Illawarra Health and Medical Research Institute (IHMRI), University of Wollongong, Wollongong, Australia; Institute for Superconducting and Electronic Materials (ISEM), University of Wollongong, Wollongong, Australia.
⁶ Centre for Medical Radiation Physics, University of Wollongong, Wollongong, Australia; School of Physics, University of Wollongong, Wollongong, Australia; Illawarra Health and Medical Research Institute (IHMRI), University of Wollongong, Wollongong, Australia; Department of Radiation Oncology, Prince of Wales Hospital, Randwick, Australia.
⁷ Centre for Medical Radiation Physics, University of Wollongong, Wollongong, Australia; School of Physics, University of Wollongong, Wollongong, Australia; Illawarra Health and Medical Research Institute (IHMRI), University of Wollongong, Wollongong, Australia; Molecular Horizons, School of Chemistry and Molecular, Bioscience University of Wollongong, Wollongong, Australia. Electronic address: moeava@uow.edu.au.

PMID: 33812598
DOI: 10.1016/j.msec.2021.111970

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; Nanoparticles; Reactive oxygen species; Selective toxicity; Silver doped LaMnO(3).

MeSH terms

Animals
Dogs
Lanthanum / toxicity
Manganese Compounds
Metal Nanoparticles* / toxicity
Silver*

Substances

Manganese Compounds
manganite
Silver
Lanthanum