Sisin, Noor Nabilah Talik
(2021)
Synergetic radiosensitization effects of bismuth oxide nanoparticles, cisplatin and baicalein-rich fraction from oroxylum indicum combinations for clinical radiotherapy.
PhD thesis, Universiti Sains Malaysia.
Abstract
Multimodal strategies of cancer treatment aim to eradicate complex malignant
disease with enhanced therapeutic outcome with combined synergetic effects in
contrast to individual techniques that might exhibits some limitations.
Chemotherapeutic drug such as cisplatin have been applied to increase radiation doses
at target tissues in radiotherapy. However, commercial chemo-drugs toxicities had
compelled the researchers to evaluate alternatives for non-toxic agents and
radiosensitizers, potentially from natural derivatives or metal-based nanoparticles
(NPs). Integration of novel nanomaterials and natural product as radiosensitizer to
increase the anti-tumors efficacy are also promising to enhance the treatment
performance. This study aimed to investigate the synergetic radiosensitization effects
of bismuth oxide NPs (BiONPs), cisplatin (Cis) and a baicalein-rich fraction (BRF)
from Oroxylum indicum (OI) leaves extract under clinical radiotherapy of High Dose
Rate (HDR) brachytherapy, photon, and electron beams. The cytotoxicity, cellular
uptake, and reactive oxygen species (ROS) generation induced by BiONPs were
initially investigated on MCF-7 and MDA-MB-231 breast cancer as well as NIH/3T3
normal fibroblast cell lines in elucidating the BiONPs feasibility for radiotherapy
application. The safe concentration of Cis and BRF were also determined prior
irradiation. Quantification of radiosensitization effects and ROS generation were
conducted with individual BiONPs, Cis, and BRF, as well as BiONPs-Cis (BC),
BiONPs-BRF (BB) and BiONPs-Cis-BRF (BCB) combinations for High Dose Rate
(HDR) brachytherapy, photon, and electron beams. Raman Spectroscopy and
apoptosis analysis were conducted to elucidate the subcellular biochemical changes
and cells death mechanism. The cytotoxicity results provide that the BiONPs induced
minimal cell deaths constituting less than 20% on average while ROS production by
BiONPs was negligible. The increment of NPs cellular uptake indicated that BiONPs
were internalized and bound to the cellular surfaces. Consequently, 0.5 mM of 60 nm
BiONPs was found to be an optimum concentration and size for radiotherapy
application. The lowest values of the 25% of inhibition concentration by individual
Cis and BRF obtained were 1.30 μM and 0.76 μg/ml, respectively, and utilized for the
subsequent experiments. Investigation of the radiosensitization effects among the
treatment components indicated the highest SER value by BC combination in MCF-7
cells, followed by BCB and BB treatments. The effects were more prominent for Ir-
192 of γ-radiation compared to photon and electron beams. Meanwhile, the
combination treatments present the higher ROS levels for photon beam than
brachytherapy and electron beam. The highest ROS enhancement was attributed to the
presence of BC combination in MDA-MB-231 cells. Interestingly, the BCB
combination also showed a high SER but collaterally affected the normal cells. The
BC combination of MCF-7 cells showed potential as an effective radiosensitizer for
brachytherapy with the early apoptosis predominantly occurred within 40 hours after
irradiation. Finally, the finding from Raman spectroscopy demonstrated that the
BiONPs-Cis and brachytherapy combination would affect the glycolysis process, the
amino acid structure arrangement and the DNA/RNA stability that would suggest the
enhancement of radiation effects on cancer cells. In conclusion, this study suggests the
potential of BiONPs, Cis and BRF as radiosensitizer that could improve the efficiency
of radiotherapy to eradicate the cancer cells. The combination of these potent
radiosensitizers could produce synergetic effects that will elevate the therapeutic
impact of clinical radiotherapy.
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