Iodine containing porous organosilica nanoparticles trigger tumor spheroids destruction upon monochromatic X-ray irradiation: DNA breaks and K-edge energy X-ray

AbstractX-ray irradiation of high Z elements causes photoelectric effects that include the release of Auger electrons that can induce localized DNA breaks. We have previously established a tumor spheroid-based assay that used gadolinium containing mesoporous silica nanoparticles and synchrotron-generated monochromatic X-rays. In this work, we focused on iodine and synthesized iodine-containing porous organosilica (IPO) nanoparticles. IPO were loaded onto tumor spheroids and the spheroids were irradiated with 33.2 keV monochromatic X-ray. After incubation in CO2 incubator, destruction of tumor spheroids was observed which was accompanied by apoptosis induction, as determined by the TUNEL assay. By employing the γH2AX assay, we detected double strand DNA cleavages immediately after the irradiation. These results suggest that IPO first generate double strand DNA breaks upon X-ray irradiation followed by apoptosis induction of cancer cells. Use of three different monochromatic X-rays having energy levels of 33.0, 33.2 and 33.4 keV as well as X-rays with 0.1 keV energy intervals showed that the optimum effect of all three events (spheroid destruction, apoptosis induction and generation of double strand DNA breaks) occurred with a 33.2 keV monochromatic X-ray. These results uncover the preferential effect of K-edge energy X-ray for tumor spheroid destruction mediated by iodine containing nanoparticles.

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Destruction of tumor mass by gadolinium-loaded nanoparticles irradiated with monochromatic X-rays: Implications for the Auger therapy

Scientific Reports ◽

10.1038/s41598-019-49978-1 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 5

Author(s):

Kotaro Matsumoto ◽

Hiroyuki Saitoh ◽

Tan Le Hoang Doan ◽

Ayumi Shiro ◽

Keigo Nakai ◽

...

Keyword(s):

Mesoporous Silica Nanoparticles ◽

X Rays ◽

Tumor Spheroids ◽

Tumor Mass ◽

X Ray ◽

Complete Destruction ◽

New Type ◽

Efficient Uptake ◽

A Site ◽

Shell Energy

Abstract Synchrotron generated monochromatic X-rays can be precisely tuned to the K-shell energy of high Z materials resulting in the release of the Auger electrons. In this work, we have employed this mechanism to destruct tumor spheroids. We first loaded gadolinium onto the surface of mesoporous silica nanoparticles (MSNs) producing gadolinium-loaded MSN (Gd-MSN). When Gd-MSN was added to the tumor spheroids, we observed efficient uptake and uniform distribution of Gd-MSN. Gd-MSN also can be taken up into cancer cells and localize to a site just outside of the cell nucleus. Exposure of the Gd-MSN containing tumor spheroids to monochromatic X-ray beams resulted in almost complete destruction. Importantly, this effect was observed at an energy level of 50.25 keV, but not with 50.0 keV. These results suggest that it is possible to use precisely tuned monochromatic X-rays to destruct tumor mass loaded with high Z materials, while sparing other cells. Our experiments point to the importance of nanoparticles to facilitate loading of gadolinium to tumor spheroids and to localize at a site close to the nucleus. Because the nanoparticles can target to tumor, our study opens up the possibility of developing a new type of radiation therapy for cancer.

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Convergence of the Study on Monochromatic X-rays and the Research on Nanoparticles Opens Up a Possibility to Develop a New Type of Radiation Therapy

10.20944/preprints202003.0391.v1 ◽

2020 ◽

Author(s):

Fuyuhiko Tamanoi ◽

Kotaro Matsumoto ◽

Tan Le Hoang Doan ◽

Ayumi Shiro ◽

Hiroyuki Saitoh

Keyword(s):

Radiation Therapy ◽

Cancer Cells ◽

Mesoporous Silica Nanoparticles ◽

Energy Levels ◽

Cancer Therapies ◽

X Rays ◽

X Ray ◽

Conventional Radiation ◽

Combined Use ◽

New Type

Conventional radiation therapy uses white X-rays that consist of a mixture of X-ray waves with various energy levels. In contrast, a monochromatic X-ray (monoenergetic X-ray) has a single energy level. Irradiation of high Z elements with a synchrotron generated monochromatic X-ray with the energy at or higher than the K-edge energy of the element results in the production of the Auger electrons that cause DNA damage leading to cell killing. Delivery of high Z elements into cancer cells and tumor mass can be facilitated by the use of nanoparticles. Mesoporous silica nanoparticles (MSNs) have been shown to be effective in delivering high Z elements to cancer cells. A proof of principle experiment was reported that demonstrated the feasibility of this approach. This opens up a possibility to pursue the Auger cancer therapy by the combined use of MSNs loaded with high Z elements and monochromatic X-rays. Similar cancer therapies using other types of quantum beams such as neutron, proton and carbon ion beams can be envisioned.

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Use of a ring chromosome and pulsed-field gels to study interhomolog recombination, double-strand DNA breaks and sister-chromatid exchange in yeast.

Genetics ◽

10.1093/genetics/123.4.695 ◽

1989 ◽

Vol 123 (4) ◽

pp. 695-713 ◽

Cited By ~ 4

Author(s):

J C Game ◽

K C Sitney ◽

V E Cook ◽

R K Mortimer

Keyword(s):

Sister Chromatid ◽

Meiotic Recombination ◽

Sister Chromatid Exchange ◽

Recombinant Dna ◽

Ring Chromosome ◽

X Rays ◽

Dna Breaks ◽

Pulsed Field ◽

Double Strand Dna Breaks ◽

Double Strand Dna

Abstract We describe a system that uses pulsed-field gels for the physical detection of recombinant DNA molecules, double-strand DNA breaks (DSB) and sister-chromatid exchange in the yeast Saccharomyces cerevisiae. The system makes use of a circular variant of chromosome III (Chr. III). Meiotic recombination between this ring chromosome and a linear homolog produces new molecules of sizes distinguishable on gels from either parental molecule. We demonstrate that these recombinant molecules are not present either in strains with two linear Chr. III molecules or in rad50 mutants, which are defective in meiotic recombination. In conjunction with the molecular endpoints, we present data on the timing of commitment to meiotic recombination scored genetically. We have used x-rays to linearize circular Chr. III, both to develop a sensitive method for measuring frequency of DSB and as a means of detecting double-sized circles originating in part from sister-chromatid exchange, which we find to be frequent during meiosis.

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Fine-Structure Mapping of Meiosis-Specific Double-Strand DNA Breaks at a Recombination Hotspot Associated With an Insertion of Telomeric Sequences Upstream of the HIS4 Locus in Yeast

Genetics ◽

10.1093/genetics/143.3.1115 ◽

1996 ◽

Vol 143 (3) ◽

pp. 1115-1125 ◽

Cited By ~ 3

Author(s):

Fei Xu ◽

Thomas D Petes

Keyword(s):

Meiotic Recombination ◽

Hydroxyl Groups ◽

Sequence Specificity ◽

Structure Mapping ◽

Dna Breaks ◽

Exonuclease Iii ◽

Recombination Hotspot ◽

Telomeric Sequences ◽

Double Strand Dna Breaks ◽

Double Strand Dna

Abstract Meiotic recombination in Saccharomyces cerevisiae is initiated by double-strand DNA breaks (DSBs). Using two approaches, we mapped the position of DSBs associated with a recombination hotspot created by insertion of telomeric sequences into the region upstream of HIS4. We found that the breaks have no obvious sequence specificity and localize to a region of ~50 bp adjacent to the telomeric insertion. By mapping the breaks and by studies of the exonuclease III sensitivity of the broken ends, we conclude that most of the broken DNA molecules have blunt ends with 3′-hydroxyl groups.

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Expression of double strand DNA breaks repair genes in pterygium

Ophthalmic Genetics ◽

10.3109/13816810.2010.524907 ◽

2010 ◽

Vol 32 (1) ◽

pp. 39-47 ◽

Cited By ~ 4

Author(s):

Anna Łękawa–Ilczuk ◽

Halina Antosz ◽

Beata Rymgayłło–Jankowska ◽

Tomasz Żarnowski

Keyword(s):

Dna Breaks ◽

Double Strand Dna Breaks ◽

Repair Genes ◽

Double Strand Dna

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Inside Back Cover: Double-Strand DNA Breaks Induced by Paracyclophane Gold(I) Complexes (Chem. Eur. J. 26/2017)

Chemistry - A European Journal ◽

10.1002/chem.201700517 ◽

2017 ◽

Vol 23 (26) ◽

pp. 6459-6459

Author(s):

Sebastian Bestgen ◽

Carmen Seidl ◽

Thomas Wiesner ◽

Andreas Zimmer ◽

Martina Falk ◽

...

Keyword(s):

Dna Breaks ◽

Back Cover ◽

Double Strand Dna Breaks ◽

Double Strand Dna

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Nucleosomes Suppress the Formation of Double-strand DNA Breaks during Attempted Base Excision Repair of Clustered Oxidative Damages

Journal of Biological Chemistry ◽

10.1074/jbc.m114.571588 ◽

2014 ◽

Vol 289 (29) ◽

pp. 19881-19893 ◽

Cited By ~ 28

Author(s):

Wendy J. Cannan ◽

Betty P. Tsang ◽

Susan S. Wallace ◽

David S. Pederson

Keyword(s):

Base Excision Repair ◽

Excision Repair ◽

Dna Breaks ◽

Oxidative Damages ◽

Double Strand Dna Breaks ◽

Base Excision ◽

Double Strand Dna

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Roles of Caenorhabditis elegans WRN Helicase in DNA Damage Responses, and a Comparison with Its Mammalian Homolog: A Mini-Review

Gerontology ◽

10.1159/000439200 ◽

2015 ◽

Vol 62 (3) ◽

pp. 296-303 ◽

Cited By ~ 6

Author(s):

Jin-Sun Ryu ◽

Hyeon-Sook Koo

Keyword(s):

Dna Damage ◽

Caenorhabditis Elegans ◽

Werner Syndrome ◽

Model Organisms ◽

Current Status ◽

Helicase Domain ◽

Replication Forks ◽

Dna Breaks ◽

Double Strand Dna Breaks ◽

Double Strand Dna

Werner syndrome protein (WRN) is unusual among RecQ family DNA helicases in having an additional exonuclease activity. WRN is involved in the repair of double-strand DNA breaks via the homologous recombination and nonhomologous end joining pathways, and also in the base excision repair pathway. In addition, the protein promotes the recovery of stalled replication forks. The helicase activity is thought to unwind DNA duplexes, thereby moving replication forks or Holliday junctions. The targets of the exonuclease could be the nascent DNA strands at a replication fork or the ends of double-strand DNA breaks. However, it is not clear which enzyme activities are essential for repairing different types of DNA damage. Model organisms such as mice, flies, and worms deficient in WRN homologs have been investigated to understand the physiological results of defects in WRN activity. Premature aging, the most remarkable characteristic of Werner syndrome, is also seen in the mutant mice and worms, and hypersensitivity to DNA damage has been observed in WRN mutants of all three model organisms, pointing to conservation of the functions of WRN. In the nematode Caenorhabditis elegans, the WRN homolog contains a helicase domain but no exonuclease domain, so that this animal is very useful for studying the in vivo functions of the helicase without interference from the activity of the exonuclease. Here, we review the current status of investigations of C. elegans WRN-1 and discuss its functional differences from the mammalian homologs.

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