Journal of Cancer Therapy, 2013, 4, 25-32
Published Online December 2013 (
Open Access JCT
Enhancement of Tumor Regression by Coulomb
Nanoradiator Effect in Proton Treatment of Iron-Oxide
Nanoparticle-Loaded Orthotopic Rat Glioma Model:
Implication of Novel Particle Induced Radiation Therapy
Seung-Jun Seo1, Jae-Kun Jeon1, Eun-Ju Jeong2, Won-Seok Chang1,3, Gi-Hwan Choi4, Jong-Ki Kim1*
1Department of Biomedical Engineering, School of Medicine, Catholic University of Daegu, 3056-6 Taemyung 4 Dong, Nam-Ku,
Daegu City, South Korea; 2Department of Diagnostic Imaging, School of Medicine, Catholic University of Daegu, 3056-6 Taemyung
4 Dong, Nam-Ku, Daegu City, South Korea; 3Biomedical Engineering, College of Medicine, Kyungpook National University, 680
Gukchaebosang-ro, Daegu, South Korea; 4Department of Neurosurgery, School of Medicine, Catholic University of Daegu, 3056-6
Taemyung 4 Dong, Nam-Ku, Daegu City, South Korea.
Email: *
Received November 12th, 2013; revised December 2nd, 2013; accepted December 9th, 2013
Copyright © 2013 Seung-Jun Seo et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background: Proton-impact metallic nanoparticles, inducing low-energy electrons emission and characteristic X-rays
termed as Coulomb nanoradiator effect (CNR), are known to produce therapeutic enhancement in proton treatment on
experimental tumors. The purpose of this pilot study was to investigate the effect of CNR-based dose enhancement on
tumor growth inhibition in an iron-oxide nanoparticle (FeONP)-loaded orthotopic rat glioma model. Methods: Pro-
ton-induced CNR was exploited to treat glioma-bearing SD rat loaded with FeONP by either fully-absorbed single pris-
tine Bragg peak (APBP) or spread-out Bragg peak (SOBP) 45-MeV proton beam. A selected number of rats were ex-
amined by MRI before and after treatment to obtain the size and position information for adjusting irradiation field.
Tumor regression assay was performed by histological analysis of residual tumor in the sacrificed rats 7 days after
treatment. The results of CNR-treated groups were compared with the proton alone control. Results: Intravenous injec-
tion of FeONP (300 mg/kg) elevated the tumor concentration of iron up to 37 μg of Fe/g tissue, with a tumor-to-normal
ratio of 5, 24 hours after injection. The group receiving FeONP and proton beam showed 65% - 79% smaller tumor
volume dose-dependently compared with the proton alone group. The rats receiving FeONP and controlled irradiation
field by MR imaging demonstrated more than 95% - 99% tumor regression compared with MRI-determined initial tu-
mor size. Conclusions: Proton-impact FeONP produced therapeutic enhancement compared with proton alone in an
orthotopic rat glioma model at a selected temporal point after treatment. Single BP proton beam could induce CNR-
based dose enhancement and produce enhanced tumor regression that was comparable to SOBP treatment despite in-
homogeneous tumor dose in the APBP-treated tumor. These results may suggest emergence of novel Particle Induced
Radiation Therapy (PIRT) on malignant glioma.
Keywords: Proton Therapy; Iron Oxide Nanoparticles; Coulomb Nanoradiator; Malignant Glioma
1. Introduction
Radiation therapy is a mainstay of treatment for patients
with high grade gliomas, including glioblastoma. Radia-
tion therapy in conjunction with surgery has been shown
to prolong survival and, in the short term, improve cog-
nitive function in patients with brain tumors. Over the
longer term, however, radiation can cause fatigue and se-
rious, permanent side effects, including radiation necro-
sis. Proton beam therapy, on the other hand, delivers very
precise, very high doses of radiation to a tumor site, while
sparing the surrounding healthy tissue. Currently, most
glioblastoma patients receive proton therapy with a dose
standard of 60 Gy, with concurrent chemotherapy. How-
ever, clinical trials suggest success and better overall
*Corresponding author.
Enhancement of Tumor Regression by Coulomb Nanoradiator Effect in Proton
Treatment of Iron-Oxide Nanoparticle-Loaded Orthotopic Rat Glioma Model:
Implication of Novel Particle Induced Radiation Therapy
survival rates with higher dosing [1,2]. The two-year
overall survival rate for patients treated with the current
standard of care is 26.5 percent. However, patients irra-
diated to 90 - 96.6 Gy (RBE) had a two-year overall sur-
vival rate of 34 - 45 percent.
Recently, our laboratory found proton-impact high-Z
nanoparticles produced CNR-based dose enhancement
effect that led to a large therapeutic enhancement on na-
noparticle-loaded mouse tumor model in either SOBP [3]
or traversing Bragg peak irradiation [4]. Other groups
also demonstrated the enhancement of cytotoxicity in their
ion beam-impact in vitro studies on either platinum or
gold-loaded cells [5,6]. Therapeutic enhancement was be-
lieved to have relevance to dose-enhancement effect
from burst emission of low-energy electrons by Auger
cascades of directly-impact ionized atom and interatomic
relaxation process (IRP)-driven ionization from surround-
ing neutral atoms, collectively termed as Coulomb nano-
radiator (CNR) [4,7].
Here, we first report our pilot studies in nanoparticles-
loaded orthotopic rat glioma model with the results of
dose-dependent enhancement of tumor regression effect
by proton-impact CNR. Importantly, a proton beam was
applied in fully-absorbed single Bragg peak (APBP) to
compare the effect of CNR-induction with conventional
SOBP beam. The enhancement of tumor regression by
APBP proton beam was comparable to the SOBP beam
under the same dose. These observations may suggest emer-
gence of novel particle induced radiation therapy (PIRT)
on malignant glioma that may change present fractiona-
tion protocol in proton therapy or overcome the problem
of tumor infiltration and radiation resistant population.
2. Methods
2.1. Metal Nanoparticles
Alginate-coated superparamagnetic magnetite nanoparti-
cles (FeONP) were synthesized by insonating ferrous and
ferric salt solutions, as reported previously [8,9]. Briefly,
FeCl2·4H2O (1.72 g) and FeCl3·6H2O (4.70 g) (8.65
mmol Fe2+/17.30 mmol Fe3+) were dissolved in 80 ml of
distilled water. A black magnetic oxide precipitate was
obtained by heating the solution to 80˚C in argon atmos-
phere, increasing the pH to 10 by adding 28% -30% am-
monium hydroxide to the water, and insonating the mix-
ed iron solution with 20-kHz ultrasound at a power out-
put of 140 W for 1 h. Alginate was used to coat the nano-
particle surface to disperse the particles. Briefly, 2 g of
magnetite nanoparticles were dispersed in 60 ml of saline
and 25 ml of alginic acid solution by heating the solution
to 80˚C while insonating at power output of 50 W for
30 min under nitrogen gas with continuous stirring. The
particles were purified by washing with saline while be-
ing exposed to a strong neodymiummagnet (magnetic
field density; Br = 11,000 Gauss). Finally, a ferrofluid con-
taining 25 mg/ml FeONP was obtained.
2.2. Transmission Electron Microscopy (TEM)
The average particle size, size distribution, and morpho-
logy of FeONP were examined using a Zeiss 902 trans-
mission electron microscope (Carl Zeiss Pte., Ltd., Ober-
kochen, Germany) at a voltage of 80 kV. The aqueous
dispersion of the particles was drop casted onto a carbon-
coated copper grid, and the grid was air dried at room
temperature before microscopic observation.
2.3. Animal Models
Intracranial gliomas were prepared by inoculating 5 ×
106 C6 glioma cells stereotactically 5 mm deep into the
frontal lobe of the left hemisphere of Sprague Darley (SD)
rats after a craniotomy, as described elsewhere [10]. The
animals were anesthetized by intraperitoneal injections of
ketamine and xylazine at 60 mg·kg1. After immobilizing
the rats in a rodent stereotactic frame, an incision was
made in the skin and a burr hole made in the skull. One
million tumor cells were injected at a rate of 1 - 2 micro-
liters/minute using a microsyringe (Hamilton, Reno, NV,
US) mounted on a stereotactic frame (Kopf Instruments,
Tujunga, CA, US), at coordinates of 1 mm lateral and 1
mm posterior to the bregma and 1.5 mm below the dura.
The incision was closed with veterinary adhesive and to-
pical lidocaine was administered.
2.4. Tumoral Uptake of Nanoparticles
To measure nanoparticle uptake in the tumors, nanopar-
ticle doses of either 100 or 300 mg/kg body weight were
administered to the C6 tumor models via the tail vein 1 h
or 24 h prior to surgical removal of the tumors. In addi-
tion, normal brain tissue was also sampled to measure tu-
mor-to-normal ratio. Tumor and normal samples were
placed in tared vials and analyzed for iron using ICP-MS
2.5. MRI Examination
MRI imaging at a 1.5 T MRI unit (GE 1.5 T, US) was
performed on selected rats to confirm the formation of
gliomas seven days after the implantation of the C6 cells.
Brain axial T1-weighted images were acquired using a
wrist coil and a fast spin echo sequence (FSE) to monitor
the formation of the tumor mass after injecting a contrast
agent at a dose of 1 mg/kg. Scan parameters of the FSE
Open Access JCT
Enhancement of Tumor Regression by Coulomb Nanoradiator Effect in Proton
Treatment of Iron-Oxide Nanoparticle-Loaded Orthotopic Rat Glioma Model:
Implication of Novel Particle Induced Radiation Therapy
imaging were set as follows: an echo time of 15 ms, a
repetition time of 450 ms, a field of view (FOV) of 80
mm, an imaging matrix of 320 × 256, a slice thickness of
2 mm, an ETL of 4, and a number of excitations (NEX)
of 4.
2.6. Proton Irradiation Experiments
The 45 MeV proton beam irradiations were conducted in
the animal model using the experimental setup presented
in Figure 1 at the Korea Cancer Center Hospital (Seoul,
Korea) while delivering an average proton dose with a
dose rate of 0.51 - 0.67 Gy/s to the sample. Fifty micro-
liters of iron NPs in saline solution were administered in
the tail vein of the animals 24 h prior to proton irradiation.
The proton beam irradiated the orthotopic rat glioma mo-
del in either SOBP or a fully-absorbed manner with a
single BP (APBP) occurrence at the greatest depth of the
tumor volume as shown in Figure 1 with two-single dos-
es, 20 or 40 Gy. In this single BP irradiation, the proxi-
mal tumor volume was exposed to the plateau dose (PD).
Thus, the tumor mass was treated by CNR plus either BP
or PD.
Three experimental groups of C6 rat glioma models
were prepared for Treatment-APBP and Treatment-SOBP,
respectively, by intravenously injecting FeONPs at 300
Figure 1. The experimental layout describes the appropri-
ate irradiation mode with different Bragg peak positions.
The proton beam energy after the Al window was 40 Me-
Vinthe collimator. For Treatment-APBP, a single pristine
Bragg peak was placed at 6 mm depth of the tumor in the
rat brain. For Treatment-SOBP, 40 Gy was delivered homo-
geneously up to the estimated average tumor depth of 6 mm
andthe tumor area of 4 mm based on a separ ate histological
analysis of initial tumor size; the surrounding normal tis-
sues were shielded using a series of acrylate blocks and a
bolus positioned inside the beam collimator to fit the tumor
mg/kg body weight into the rat. Five proton-alone groups
were also prepared for each proton dose as controls. The
rats were anesthetized by the intraperitoneal injection of
20 mg/kg ketamine and 18.4 mg/kg xylazine. For Treat-
ment-APBP, each animal group was irradiated with a sin-
gle dose proton beam in which either 20 or 40 Gy was
delivered at BP from tumor depth of 6 mm. In Treat-
ment-SOBP, 40 Gy was delivered homogeneously up to
the estimated typical tumor depth of 6 mm and the tumor
area of 4 mm that was determined by histological meas-
urement of average initial tumor size 7 days after im-
planting tumor cell in separate five rats; the surrounding
normal tissues were shielded using a series of acrylate
blocks and a bolus positioned inside the beam collimator
to fit the tumor size. Therefore, homogeneity of proton
dose in Treatment-SOBP was assured only in the central
region of tumor mass, 4 × 6 mm. Radiation dose might
not be delivered in some parts where initial tumor mass
was larger than this estimated typical irradiation field,
because proton beam was not irradiated in stereotactic
manner with guidance by MRI -based tumor position in
each animal. Only selected numbers of rat were examin-
ed using MRI before proton irradiation to fit irradiation
field according to obtained size and depth. In these cases,
initial tumor size before treatment was estimated from
MRI data.
2.7. Tumor Regression Assay and Statistical
Each animal group was killed 7 days after the treatment
by an overdose injection of sodium pentobarbital. The
brains were removed, fixed in 10% formaldehyde, paraf-
fin embedded, and sectioned through the area of irradia-
tion. The 5-μm-thick sections were stained with hemato-
xylin and eosin, and the tumor was examined microsco-
pically. For each rat, the largest lesion area was measured
by a microscope with image analysis software (Axitophot,
Zeiss, Germany). The tumor shape was assumed to appro-
ximate a spheroid. The volume was calculated using the
formula 4π/3 × x/2 × y/2 × z/2: x and y are the dimen-
sions of the largest lesion area while z is the height of
each section (5-μm) multiplied by the number of sections
containing the tumor tissue. In case residual tumor was
minimal and irregular, the area of each tumor section was
calculated using image analysis software to integrate for
total tumor volume. The therapeutic response was evalu-
ated by histological assay, measuring the tumor size of
each experimental group after the animals were sacri-
ficed and compared with the average tumor size before
treatment and the proton alone group. The differences
between the groups were assessed with a one-way
ANOVA followed by the Bonferroni multiple compari-
Open Access JCT
Enhancement of Tumor Regression by Coulomb Nanoradiator Effect in Proton
Treatment of Iron-Oxide Nanoparticle-Loaded Orthotopic Rat Glioma Model:
Implication of Novel Particle Induced Radiation Therapy
Open Access JCT
son test. A p value of <0.05 was considered the level of
significance for all of our tests. All data were analyzed
using a contemporary statistical software package (Graph-
Pad Prism; GraphPad Software, Inc., San Diego, CA,
3. Results
3.1. Size Distribution Studies by TEM
The average size of the particles was determined by TEM,
by using measurements of the size of approximately 200
particles. The particles had a globular shape and an ap-
proximate size of 10.6 nm with a standard deviation of
0.78 nm. The size of the particles after coating was 13 -
15 nm in diameter.
3.2. Tumor Uptake
ICP-MS data are summarized in Table 1. Tumor concen-
trations of FeONP 24 h after injection with a dose of 300
mg/kg were 37.6 ± 6.3 μg·Fe/g tissue, while the corre-
sponding normal were 7.4 ± 3.7 μg·Fe/g tissue. The tu-
mor-to-normal FeONP ratio was about 5 after 24-hour
post-injection. When iron nanoparticles were injected,
less than 1% of the injected dose was taken by tumor in a
given time interval after injection.
3.3. Tumor Regression Effect of Proton-Impact
Nanoparticles on FeONP Rats
The mean tumor sizes of various groups were summariz-
ed for each treatment group in Table 2. The average tu-
mor size was significantly different in the rat receiving
only proton radiation and those receiving FeONP fol-
lowed by either SOBP (p < 0.05) or APBP (p < 0.02)
proton irradiation, as shown in Table 2. The FeONP-
SOBP rat demonstrated smallest average tumor size among
experimental groups 7 days after treatment and signifi-
cantly (p < 0.05) smaller tumor size compared to the
SOBP-proton alone rat. The FeONP-APBP rat also show-
ed comparable (but statistically insignificant) tumor vo-
lume regression to the FeONP-SOBP rat after irradiation
with 40 Gy, and the average tumor size decreased dose-
dependently between 20 - 40 Gy.
Although only small numbers of rats were examined
by MRI before treatment to measure the tumor size and
position, enabling conformal energy delivery by fitting
the irradiation field to the tumor volume information, the
FeONP-MRI rats showed much better tumor regression
compared with corresponding un-examined groups
shown in Table 2. T1-weighted MRI-data of some se-
Table 1. Results of tumor uptake following the injection of iron-oxide nanoparticles injection dose.
Tissue 300 mg/kg 100 mg/kg
1 h 24 h 24 h
Tumor 26.2 ± 4.1 37.6 ± 6.3 19.6 ± 5.4
Tissue concentration (μg of Fe/g tissue)
Normal 12.5 ± 3.8 7.4 ± 3.7
Uptake/injection (%) 0.6
Data are presented as average ± standard deviation (n = 3).
Table 2. The mean tumor sizes were summarized for each treatment group.
Mean TV Proton dose (at BP)
0 40 Gy (SOBP) 40 Gy (APBP) 20 GY (APBP) P*
FeONP (mg/kg)
Baseline 50.2 ± 25.2 (n = 5)
0 (proton alone) 21.3 ± 7.2 (n=5)38.1 ± 20.2 (n = 6) 52.7 ± 21.7 (n = 6) 0.007
300 3.1 ± 2.6 (n=5) 8.6 ± 6.6 (n = 5) 18.9 ± 10.2 (n = 5)
(MRI-ex) Baseline 76.8 49.2 ± 16.6 58.5 ± 8.4
(MRI-ex) 300 1.5 (n = 1) 0.8 ± 0.9 (n = 2) 9.3 ± 5.6 (n = 2)
p 0.036 0.013 0.021
The p value refers to the significance of the difference among two or three rat groups treated with Treatment-APBP or Treatment-SOBP across columns or
ows*, respectively using ANOVA analysis. MRI-rats were not included in calculating p value across column. r
Enhancement of Tumor Regression by Coulomb Nanoradiator Effect in Proton
Treatment of Iron-Oxide Nanoparticle-Loaded Orthotopic Rat Glioma Model:
Implication of Novel Particle Induced Radiation Therapy
lected FeONP-rats using contrast agent showed the hy-
per-intense tumor area in pre-treatment MRI that were
minimal or reduced clearly in post-treatment MRI of the
FeONP rats by three different treatments; APBP-20 Gy,
APBP-40 Gy, SOBP-40 Gy as shown in Figure 2. Each
histological image, obtained from sacrificed rats after
treatment, demonstrated the correspondence with its MRI
4. Discussion
Despite potent unmatched tumor dose distribution to ac-
tual tumor size in this non-stereotactic proton irradiation
studies on orthotopic glioma model, it was attempted to
elucidate the effect of proton-impact nanoparticles within
tumor mass on tumor regression by comparing the com-
bined nanoparticle and proton experiment with the proton
alone experiment at a given days after treatment. Statis-
tically-significant enhanced growth inhibition effect from
the FeONP rats indicates that this protocol was able to
produce CNR effect, enabling the rapeutic enhancement
at clinically-relevant proton dose despite insufficient pre-
cision in delivering tumor dose. However, relatively
smaller fluctuation in average tumor size was observed in
CNR-producing experimental group compared with the
proton alone groups. MRI-examined FeONP rats demon-
strated more than 90% tumor regression 7 days after
treatment that may be attributed to relatively well-ma-
tched tumor dose to the tumor size and position. Other
FeONP rats showed more than 60% smaller average re-
sidual tumor size compared with the proton alone, led to
more than 62% tumor regression with respect to the av-
erage initial tumor size. Conversely, growth retardation
or 24% - 50% regression effect was observed in the pro-
ton alone group. Dose-dependently decreased tumor size
after Treatment-APBP on the FeONP rats suggested that
CNR-mediated therapeutic effects increased also dose-
dependently as observed in previous studies with mice
Xenograft tumor model [4]. Comparable tumor regres-
sion effect of the APBP-FeONP rats to the SOBP proton
alone suggested that single BP proton beam combined
with CNR could deliver effectively similar tumor dose
with SOBP proton beam. This effect may be exploited to
modify current fractionation protocol in proton treatment
of brain tumor without enhanced entrance dose. Such en-
hancement under the inhomogeneous distribution of tu-
mor dose may be attributed to both low-energy CNR
electrons (0 - 1000 eV) and concomitant enhancement of
ROS generation with energy-dependent migration mobil-
ity of related ROS molecules [4]. Low energy electrons
can transport up to several hundred nm, while converted
ROS diffuse up to about several μ [11].
The CNR effects under a low dose primary irradiation
suggests not only dose enhancement within the tumor but
also less side effects to the surrounding normal compared
to therapeutic high-dose irradiation alone, effectively tu-
mor-specific. This enhanced tumor dose with less normal
dose may provide an novel Particle Induced Radiation
Therapy (PIRT) with important therapeutic outcome such
as longer survival and less side effects in proton treat-
ment of brain tumor where radiation treatment interferes
with many neuronal function and pediatric brain devel-
opment. In addition, PIRT may modulate greatly present
fractionation scheme, leading to shortening total treat-
ment period. The efficiency of radiation therapy is often
hindered by diffusively invasive characteristic of brain
tumor as well as emergence of radiation-resistant popula-
tion. On the other hand, PIRT with traversing Bragg peak
can be exploited potentially to treat the tumor spreading
in normal as long as iron nanoparticles are preferentially
taken in tumor cell, which are under way in our labora-
tory. Present tumor-to-normal ratio of iron-oxide NP in
this study could be obtained from either EPR effect or
facilitated BBB crossing by macrophage-uptake of NP
[12,13]. Although concentration of nanoparticles with
about 40 μg·Fe/g tissue was achieved injection-dose de-
pendently in this study, less than 1% of total dose was
taken up in brain tumor. Thus intravenous injection of
300 mg/kg would be too much for clinical practice in hu-
man. In this regard, targeted NP with BBB-crossing and
radiation-enhanced BBB disruption [14] may further
increase tumoral uptake of NP even in the tumor infiltra-
tion of malignant glioma where it often occurs at intact-
BBB normal tissue. This advance in nanotechnology
combined with energy-delivery by high-energy ion beam
may enable tumor control of malignant glioma without
side effects.
Nanoradiator effect can be obtained from either Cou-
lomb collision with ion beam or photoelectric absorption
of X-ray photon. However, ion-beam irradiation may pro-
vide much better way in the energy delivery as well as
Z-value independent interaction with nanoparticles com-
pared with X-ray photon under the normal tissue toler-
ance [5,15].
5. Conclusion
In conclusion, proton-impact FeONP produced therapeu-
tic enhancement in an orthotopic rat glioma model by
either conventional SOBP or single pristine Bragg peak
irradiation. The results suggested emergence of novel
Particle Induced Radiation Therapy (PIRT) on malignant
glioma that may enable treatment of tumor infiltration or
shortening current fractionation period without radiation
resistant population.
Open Access JCT
Enhancement of Tumor Regression by Coulomb Nanoradiator Effect in Proton
Treatment of Iron-Oxide Nanoparticle-Loaded Orthotopic Rat Glioma Model:
Implication of Novel Particle Induced Radiation Therapy
(a) APBP 20Gy + FeONP
Figure 2. MRI-data of some selected FeONP-rats were acquired one day before and 7 days after proton tre atment using con-
trast agent-based T1-weighted imaging, leading to hyper-intense tumor area. This enhanced tumor region in pre-treatment
MRI were minimal or reduced clearly in post-treatment MRI of three different treatments; APBP-20 Gy (a), APBP-40 Gy (b),
SOBP-40 Gy on the FeONP rat. Each histological image was obtained from sacrificed rats after treatment and MRI exami-
ation. n
Open Access JCT
Enhancement of Tumor Regression by Coulomb Nanoradiator Effect in Proton
Treatment of Iron-Oxide Nanoparticle-Loaded Orthotopic Rat Glioma Model:
Implication of Novel Particle Induced Radiation Therapy
6. Acknowledgments
This research was supported by Atomic foundation ex-
pansion program, the National Research Foundation of
Korea (NRF-2012M2B2A4029568) funded by the Min-
istry of Education, Science and Technology, and partially
by the Catholic University of Daegu (20135001).
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Open Access JCT
Enhancement of Tumor Regression by Coulomb Nanoradiator Effect in Proton
Treatment of Iron-Oxide Nanoparticle-Loaded Orthotopic Rat Glioma Model:
Implication of Novel Particle Induced Radiation Therapy
NP: Nanoparticle;
CTR: Complete Tumor Regression;
ROS: Reactive Oxygen Species;
CNR: Coulomb Nanoradiator Effect;
PIR: Particle Induced Radiation;
PIRT: PIR Therapy;
SOBP: Spread-Out Bragg Peak;
BP: Bragg Peak;
APBP: Fully Absorbed Pristine Bragg Peak;
Treatment-APBP: PIRT with Fully Absorbed Single
Bragg Peak;
Treatment-SOBP: PIRT with Spread-Out Bragg Peak;
IRP: Interatomic Relaxation Process.
Open Access JCT