Design of Cerenkov-assisted Photoactivation of TiO2...

Design of Cerenkov-assisted Photoactivation of TiO2 Nanoparticles and Reactive Oxygen

Species Generation for Cancer Treatment

Shalinee Kavadiya1 and Pratim Biswas1, *

Revision version submitted to Journal of Nuclear Medicine

September 17, 2018

1 Aerosol and Air Quality Research Laboratory

Center of Aerosol Science and Engineering

Department of Energy, Environmental and Chemical Engineering

Washington University in St. Louis, 63130, USA

Running title: Cerenkov-assisted Cancer Treatment

Pratim Biswas (Corresponding author) One Brookings Drive, Campus Box 1180 Washington University in St. Louis, St. Louis, MO 63130 Tel: +1-314-935-5548 Fax: +1-314-935-5464 Email address: [email protected] Shalinee Kavadiya (First author) One Brookings Drive, Campus Box 1180 Washington University in St. Louis, St. Louis, MO 63130 Tel: +1-314-825-9488 Email address: [email protected] Manuscript word count: 5497

Journal of Nuclear Medicine, published on October 5, 2018 as doi:10.2967/jnumed.118.215608by on June 12, 2020. For personal use only. jnm.snmjournals.org Downloaded from

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ABSTRACT

The use of Cerenkov radiation (CR) to activate nanoparticles in situ has recently been shown to

control cancerous tumor growth. While the methodology has been demonstrated to work, to

better understand the mechanistic steps, we develop a mathematical model that integrates

Cerenkov physics, light interaction with matter, and photocatalytic reaction engineering. The

model describes a detailed pathway for localized reactive oxygen species (ROS) generation from

the Cerenkov-assisted photocatalytic activity of TiO2. The model predictions are verified by

comparing to the experimental reports in the literature. It is then used to investigate the effect of

various parameters - size of TiO2 nanoparticles, concentration of TiO2 nanoparticles, and activity

of the radionuclide [2-deoxy-2-18F-fluoro-D-glucose (18F-FDG)] on the number of photons and

ROS generation. The importance of nanoparticle size on ROS generation for cancerous tumor

growth control is elucidated, and an optimal size is proposed. The model presented here can be

used for other radionuclides and nanoparticles and can provide guidance to the concentration and

size of TiO2 nanoparticles and activity of radionuclide needed for efficient cancer therapy.

Keywords Cancer treatment, Cerenkov radiation, Nuclear decay, Photocatalysis, Photodynamic

therapy

by on June 12, 2020. For personal use only. jnm.snmjournals.org Downloaded from


INTRODUCTION

Radionuclides are being used for various medical applications, from imaging for diseases

diagnosis to therapy. Therapeutic uses include tumor growth control for cancer, in which the

high-intensity radiation from the nuclide kills the cancer cells. A recent development has

employed another exciting property of the radionuclides, production of Cerenkov Radiation

(CR), for imaging (1-6). CR is electromagnetic radiation produced when a charged particle

travels in a medium with speed larger than that of light in that medium (7). The fast-moving

charged ion polarizes the medium along its direction of movement, resulting in the small

displacement of the electrons. When the electrons relax, spherical waveforms generate along the

ion track, which interfere constructively at a specific angle to the direction of movement and

produces electromagnetic radiation (8,9). CR has a broadband emission in which the intensity

decreases with increasing wavelength. Moreover, the radiation is generated locally within a

given tissue, improving the signal-to-noise ratio for imaging applications. However, CR

produces low light intensity, and thus it is often challenging to detect the signal. To overcome

this issue, varieties of fluorophores, such as small molecules (10), quantum dots (11,12), and

nanoparticles (13) are used to convert the Cerenkov light into long wavelength radiation.

Recently, CR has also been utilized as a light source for chemical and therapeutic applications

(14-16). In 2015, Kotagiri et al. (15) demonstrated the use of CR generated by the 18F-FDG

radionuclide to activate TiO2 nanoparticles in vivo to produce reactive oxygen species (ROS) and

suppress the growth of cancer cells. Since then, there has been a growing interest in the

Cerenkov-assisted photodynamic therapy (PDT). TiO2 has been a known photocatalyst for

energy (17-20), and environmental (21,22) applications. It has a band gap of 3.2 eV and absorbs

UV light efficiently, which matches with the high-intensity regime of CR. Kamkaew et al.



reported a system with 89Zr radionuclide (Cerenkov source) and chlorine e6 (Ce6)

(photocatalyst) and demonstrated its advantage in ROS generation though CR (16). Recent

studies study published early this year demonstrated two radionuclides, 68Ga and 18F, for their

cellular uptake and effectiveness in cancer treatment (23,24)

While there has been experimental validation of locally generating ROS in the vicinity of

tumors using CR (25), there is a need for a mechanistic understanding to better optimize the

process which will then result in wider clinical deployment. In this regard, it is crucial to

establish a quantitative correlation between the Cerenkov-produced light signal and the amount

of ROS generation. Previous works have modeled the CR yield of various radionuclides using

the Frank-Tamm equation and Monte-Carlo simulation (26-30). However, there has been no

work on modeling the efficiency of CR activation of TiO2 nanoparticles and the corresponding

amount of ROS generation. The photoactivity of TiO2 nanoparticles and the subsequent reaction

for ROS generation has been studied previously, but primarily under activation by an external

constant light source (21,31). However, systems containing time-dependent light sources

distributed around the TiO2 nanoparticle, such as CR generated from distributed radionuclides, is

more complex and has not been explored earlier.

That said, we develop a mathematical model that integrates Cerenkov physics, light

extinction, and photocatalytic reaction engineering to identify the mechanistic steps involved in

cancer cell destruction in the presence of radionuclides and semiconducting TiO2 nanoparticles.

We first calculate the amount of CR generated by the 18F-FDG radionuclide. Second, we

determine the light radiation absorbed by the TiO2 nanoparticles. Finally, we calculate the

amount of ROS (hydroxyl and superoxide) generated with time. The model predictions are

validated with experimental results from the literature. Additionally, we study the effect of



parameters, such as the radioactivity of 18F-FDG and the concentration and size of TiO2

nanoparticles on the amount of ROS. With the help of this model, the dose of radionuclides and

TiO2 nanoparticles of a particular size to suppress cancer cell growth can be optimized.

METHODS

Fig. 1 presents a schematic description of the PDT. The system consists of 18F-FDG

radionuclide (CR source), TiO2 nanoparticles (CR absorber), and cancer cells in a biological

fluid. The model primarily accounts for cell death by ROS generated from the activation of

photocatalyst by Cerenkov radiation. Other mechanisms because of the radionuclide-

nanoparticle interaction such as ionization and excitation of the nanoparticle by ionizing

radiation are not considered. The effect of these mechanisms on the model is described later in

discussion section. Moreover, radiolysis of water is negligible under the used value of

radioactivity (32). Different parts of the integrated model are described next.

Cerenkov Physics

The number concentration of TiO2 nanoparticles (2TiON , #/cm3) is calculated from the

concentration (2TiOC , mol/L) and the size of TiO2 nanoparticles

2

2

2

,TiOTiO

TiO p

CN

v (1)

where 2TiO is the density and pv is the volume of one TiO2 nanoparticle of diameter pd . 18F

decays to a stable 18O nuclei and releases one β particle with 97% probability, considered as the

source of CR. The number of β subatomic particle ( )N generated per second is related to the

radioactivity of the 18F-FDG radionuclide ( A , Bq), which decreases with time (half-life of 18F =

109.7 min).



N A (2)

TiO2 nanoparticles and 18F-FDG molecules are considered uniformly dispersed, and the

average distance ( avgx ) between the point of generation of β particles and TiO2 is determined by:

2

1/3

1.avg

TiO

xN N

(3)

If the β particle travels in the medium faster than the speed of light, it generates CR. The

number of Cerenkov photons/second from a β particle is described by the Frank-Tamm Eq. (33):

2

2 2 2

1 12 1 , 1,phd N

ndld n

(4a)

cos 1/ ,n (4b)

1/222

221 .

o

o

m c

E m c

(4c)

Here, l is the β particle pathlength, α is a structure constant (1/137), β is the ratio of the

velocity of charged particles to the velocity of light in vacuum (vp/c), n is the refractive index of

the medium (assumed constant), is the wavelength, om is the rest mass of the β particle, and E

is the energy of β particle. The Cerenkov photons originating from a β particle move at an angle

from the trajectory of the β particle.

Number of photons are calculated at each step along the β particle trajectory. As the β

particle travels, the loss in its energy is determined from the range-energy relationship (34), and

the energy is updated at every step in its path. Since all the β particles have different initial

energies and follow an energy spectrum, the Eq. 4a for phN is weighted by the relative

probability of a β particle of given energy being emitted by the radionuclide, and then summed



across all the energies. The probability of each energy was taken from the β energy spectrum

available at the Lund/LBNL Nuclear Data Search Website (35). The pathlength ( l ) depends on

avgx , which is a function of 2TiOC , A , pd . Therefore, phN is a function of

2, ,TiO pC A d , and .

Once the CR is generated, it travels in the system and undergoes extinction (absorption and

scattering) by TiO2 nanoparticles, explained in detail in the next section. Radiation is absorbed

by the TiO2 nanoparticles, leading to the generation of electron and hole pairs [Fig. 1B].

Electrons and holes react with oxygen, and water molecules adsorbed on the nanoparticle

surface, and produce ROS, superoxide, and hydroxyl radical, respectively. ROS further attack

the cancer cells in the system and destroy them.

Light Extinction

To quantitatively model the photon flux to TiO2 nanoparticles, we consider the case of

one β particle and one TiO2 particle, where the β particle travels at an angle from the line

joining the origin of β particle and TiO2 nanoparticle (Fig. 2A). The probability of β particle

moving in the direction is considered while calculating phN . Since Cerenkov photons in this

system move at = 41˚ with respect to the β particle, only photons generated within the ABl part

of the pathlength [illustrated in Fig. 2A], will intersect with the TiO2 and be absorbed. ABl and

OAl are given by

,sin

pAB

dl

(5a)

1sin( ) ,

sinOA avg P Pl x R R (5b)

It is important to note that OAl depends on avgx and pd , but ABl depends only on pd . In

other words, the photons of interest are generated in a constant length segment ( ABl ) but the



location of that length segment and is different for all the β particles, depending on their distance

from the TiO2 and their trajectory (or angle). Once the photons are produced in the length

segment ABl , they travel in the medium and undergo scattering and absorption phenomena, and

therefore, the final number of photons reaching the TiO2 is less. The photons produced at each

step travel different distances ( tl ) to reach the TiO2 (Fig. 2B), as described below:

cos( )cos ,

cos sin( )avg P

t OA AB AB

x Rl l l l l

(6)

Since the photons move at an angle with respect to the path of the β particle, there is

an angular range of , beyond which there is no influence of β particle on the TiO2. In other

words, the Cerenkov photons do not reach the TiO2. Thus, only the β particles moving within

the angular range (Fig. 2C) will contribute to the photon flux.

12 tan .p

p avg

RAngularRange

R x

(7)

The photon flux (#/s.cm2) reaching the TiO2 nanoparticle is calculated at each step using

Eq. 8, taking into account the light extinction. Additionally, TiO2 absorbs only below 380 nm,

thus, the photon flux of interest is defined as 2int ( , , , , )TiO pN C A d with < 380 nm.

2

2int

( , , , , )( , , , , ) exp( ),ph TiO p

TiO p tp

N C A dN C A d bl

A

(8)

The extinction coefficient,b , is

2( ),TiO p abs scab N A Q Q (9a)

2

2

4 1Im ,

2p

abs a p

d mQ k d

m

(9b)



24 4 24

4 2

8 1Re .

3 2p

sca s p

d mQ k d

m

(9c)

here, absQ and scaQ are the efficiencies of absorption and scattering, respectively. m is the

refractive index of TiO2 in water. ak and sk are the absorption and scattering coefficients,

respectively. To account for all the β particles, their individual contributions to phN are

summed. Once the photon flux to the TiO2 particle is obtained, the amount of ROS generation is

determined.

Catalytic Reactions and ROS Production

The photocatalytic generation of free radicals is described by the following reaction

mechanism (21). The TiO2 nanoparticles absorb Cerenkov photons and generate electron (e-)

and hole (h+) pair (reaction 10a). There is a possibility that electron and hole can recombine and

produce heat (reaction 10b). Alternatively, the electrons react with the oxygen molecules

adsorbed on the TiO2 surface and produce superoxide radicals (reaction 10c), and the holes react

with water molecules and produce hydroxyl radicals (reaction 10d).

2

'2 1 int, ( , , , , ) ( , ),h

avg TiO p p pTiO e h G k N C A d A d (10a)

2 2, [ ][ ] ,se h heat R k e h a (10b)

2 2

'2, 2 3 3 , 3, [ ] [ ] ,ads O ads s Oe O O R k e C a k e C (10c)

2 2

'2 4 4 , 4, [ ] [ ] ,ads H O ads s H Oh H O OH H R k h C a k h C (10d)

The rate of electron-hole pair formation (reaction 10a) depends on the photon flux and

the optoelectronic properties of the TiO2 nanoparticle. In the expressions above,

2 2

10 3 6 1 ' 19 3 ' 8 31 2 3 3 4 44.37 10 , 7.14 10 , 10 / , 10 /O H Ok cm k s k k K cm s k k K cm s are the



rate constants of reactions, taken from the literature (36,37). 2OK and

2H OK are the adsorption

rate constants of O2 and H2O, respectively. [e-] and [h+] are the electron and hole concentrations

(ions per unit surface area of the TiO2 nanoparticle), and 2H OC and

2OC (mM) are the

concentrations of water and dissolved oxygen, respectively. These rates are used to derive the

relationship between the concentration of ROS and the various parameters (2, , ,TiO pC A d , and

). The rates of formation of both radicals (superoxide and hydroxyl) are given by:

2 2

'23

[ ][ ] ,O s TiO

d Ok e C a N

dt

(11a)

2 2

'4

[ ][ ] .H O s TiO

d OHk h C a N

dt

(11b)

We assume that the spatial dimension of the system is big enough that any change in the

concentration of water resulting from reactions 10a-d is not significant. Simultaneously,

dissolved oxygen is assumed to be available, so 2OC also remains constant. It is assumed that the

adsorption equilibrium occurs instantaneously. Concentration of electrons and holes are

calculated by applying a mass balance on them:

2

'2 3

[ ][ ][ ] [ ] ,avg s O

d eG k e h a k e C

dt

(12a)

2

'2 4

[ ][ ][ ] [ ] ,avg s H O

d hG k e h a k h C

dt

(12b)

At steady state, the rate of generation of electrons (or holes) is equal to the rate of their

consumption. Solving the above two Eqs. (12a and b) to derive an expression for the

concentration of photogenerated electrons yields:

2

2

2

'2 '2 3

3'4

[ ] [ ] 0,OO avg

H O

Ck ke k C e G

k C (13)



here 2

'1 int ( , , , , ) ( , )avg TiO p p pG k N C A d A d . Substituting the expression for from Eq. 13

in the expression for the rate of ROS generation, we obtain

2

2 2

2 2 '1 int 22

( , , , , ) ( , )[ ] [ ]( , ).

2

TiO p p p

p TiO TiO p

b b ak N C A d d dd O d OHb d N C d

dt dt a

(14)

here a and b are constants: 2

2

'2 3

'4

,O

H O

Ck ka

k C and

2

'3 .Ob k C

Hence, the rate of ROS generation depends on pd , 2TiOC , and A . The equation is solved

to determine a time variation of the ROS species concentration, which can be correlated to the

tumor cell viability.

RESULTS

Fig. 3A shows the CR spectrum, number of Cerenkov photons/second with 7.4 MBq/mL

radioactivity and 2.5 μg/mL TiO2 nanoparticles of size 10 nm. The spectrum follows the 1/λ2

relation with the wavelength, which agrees with the Frank-Tamm equation (Eq. 4). The

Cerenkov yield per decay from the present study is 1.38 over the wavelength range of 400-800

nm, close to the reported value of 1.3 over the same range (28). In this section, we will discuss

the role of various system parameters on ROS generation, with the goal of determining the

specifications (concentration and size) of TiO2 and activity of radionuclide to terminate cancer

cell growth.

Model Validation by Comparing to Experimental Results

Comparison of the model prediction to the experimental results from Kotagiri et al. (15)

and Duan et al. (23) is presented in Fig. 3B. (23)). Kotagiri et al. (15) used TiO2 nanoparticles



of size 25 nm at a concentration of 2.5 μg/mL; with four different radioactivity (A) levels

of 31.45, 14.80, 7.40 and 0.37 MBq. Duan et al. used 100 μg/mL TiO2 of size ≈ 30 nm and

14.8, 7.4, and 3.7 MBq of 18F-FDG. Experimental results in both the studies show tumor cell

viability (% of control) as a function of 18F-FDG dose (Fig. 3a and b in reference (15) and Fig.

4b in reference (23)). Fractional decreases in the tumor cell viability were then converted into

equivalent intracellular ROS generation using a constant scaling factor (different for both the

studies but same for all the data points of one study). To validate the model, the experimental

parameters mentioned above were used to calculate the ROS concentration from the model.

ROS production predicted from the model (solid line) agree well with the experimental data

(solid symbols) for both the studies.

Effect of Radioactivity (or Decay Time)

The effect of radioactivity or decay time is similar because the radioactivity decreases

with time according to the formula given below:

' '0

1/2

ln 2exp( ), .A A t

t (15)

here, 0A is the initial activity of the radionuclide, A is the activity at any time t, ' is the decay

constant, and 1/ 2t is the half-life. The radioactivity decreases exponentially with time, therefore

by keeping the TiO2 nanoparticles size constant at 10 nm and concentration at 2.5 μg/mL, the

number of photons ( , #/phN s ) and photon flux ( 2int , #/ .N cm s ) (Fig. 4A), and ROS concentration

(Fig. 4B) also decrease exponentially with decay time.



Effect of TiO2 Concentration

The effect of TiO2 concentration was investigated (Fig. 5) by keeping the pd constant at

10 nm and A at 7.4 MBq/mL. As the 2TiOC increases, the number of TiO2 nanoparticles (

2TiON )

increase and, avgx decreases. The important parameters to consider here are the lengths OAl and

ABl (Eq. 5). An increase in the concentration leads to a decrease in OAl , whereas ABl remains

constant. The smaller the OAl , the less is the energy loss by the β particle before producing

photons in the ABl range. Hence, at higher 2TiOC , high energy β particles produce more photons,

whereas, at lower 2TiOC , low energy β particles produce fewer photons over the same length

range ABl . The photon flux follows a trend similar to that of the number of photons, because of

the constant size of the TiO2 nanoparticles. Overall, both phN and the intN increase with an

increase in concentration [Fig. 5A]. Additionally, more TiO2 nanoparticles are present to absorb

CR, increasing the ROS yield [Fig. 5B]. Mathematically from Eq. 14, ROS concentration is

proportional to the number of TiO2 nanoparticles and the square root of the photon flux; hence,

ROS production rises with 2TiOC .

Effect of TiO2 Nanoparticle Size

Fig. 6A presents the effect of nanoparticle size ( pd ) on phN and intN . 2TiOC and A are

kept constant at 2.5 μg/mL and 7.4 MBq/mL, respectively. As the size increases, 2TiON decreases

and the avgx increases. Therefore, larger the ABl , greater the number of Cerenkov photons. If OAl

is larger, the ABl segment will appear at a larger distance from the origin of the β particle, so the

β particle will have less energy in the ABl range and hence will produce fewer photons. Looking



at Eq. 5, as increases, ABl increases by a larger extent than OAl , hence phN increases, but the

photon flux, intN , decreases due to its inverse relation with pd (Eq. 8).

Interestingly, the effect on ROS concentration is not monotonous [Fig. 6B]: ROS

concentration first increases with pd , peaks out around 800 nm, and then decreases. According

to Eq. 14, ROS concentration is directly proportional to pd , intN , 2TiON , and absorption

efficiency ( ' ). With an increase in pd , intN and 2TiON both decrease as mentioned above, but

they do not play a significant role compare to the size-dependent optical (absorption and

scattering) and electrical properties of the TiO2 nanoparticles. The absorption efficiency of the

nanoparticles increases with the size. Conversely, the separation between e- and h+ is efficient at

smaller sizes, leading to favorable charge-carrier dynamics. Therefore, the optical and electrical

properties of TiO2 (photo-excitation and e--h+ generation) dominate at particle sizes less than 800

nm, resulting in considerable e- and h+ generation and less recombination. However, with

increasing sizes, the properties of TiO2 nanoparticles become similar to the bulk TiO2, i.e., the

charge carrier’s recombination becomes much easier, and the photoactivity thus is dominated by

the available specific surface area of the particles (21).

DISCUSSION

The CR spectrum from the model follows the Frank-Tamm equation (number of photons

α 1/ λ2), and the number of photons generated also matches with the previous report (28). The

model was compared with the two different experimental studies (15,23). The experiments

provide the change in tumor cell viability as a function of 18F-FDG dose, which was then

converted into ROS concentration using a constant scaling factor and compared with the ROS

concentration predicted from the model using the experimental parameters form these studies.



The scaling factor is needed because the studies do not provide the amount of ROS generation;

however, the decrease in the cell viability is directly correlated to the ROS production.

Additionally, scaling factor is different for the two studies due to the use of different type of

TiO2 nanoparticles and cell lines, but is same for all the data points of one particular study. The

model predictions agree well with the experimental data for both the studies and shows similar

trend, thus indicating its robustness. The ROS concentration from the two studies cannot be

cross-compared because of the different type of TiO2 nanoparticle used in these studies and their

distinct optoelectronic properties. Clearly, comparison to additional data would further enhance

the validity of the model, however, due to the novel and innovative nature of this methodology

not many studies report such data.

Having validated the model, we illustrate its capabilities by doing a series of design

simulations to illustrate the potential use in guiding PDT. The effect of radionuclide dose ( A ),

TiO2 concentration (2TiOC ), and size ( pd ) on the amount of ROS generation is studied. phN

generation and ROS concentration rises with A . This feature will help guide the dose of

radionuclides to use and the time interval of injection for continued therapeutic effects. The

2TiOC also directly affect the ROS production. The higher the concentration is, larger is the phN

and intN . Furthermore, more number of TiO2 nanoparticles are present to absorb the photons;

therefore, more ROS is produced at higher TiO2 concentration. The upper limit of the

concentration is ultimately constrained by the distance between the β particles and TiO2, which

tends to zero at very high 2TiOC and the cytotoxicity of TiO2 particles. There has been only one

study (16) on the effect of photocatalyst concentration on the cancer cell viability. The study

reports that cell viability decreases (ROS concentration increase) linearly with the increase in the

photocatalyst concentration, supporting the model predictions.



The effect of pd is not monotonous. Although the intN decreases with an increase in pd ,

amount of ROS increases at smaller sizes, peaks at around 800 nm and then decreases.

Therefore, there is an optimum size of the TiO2 particle to produce the highest ROS

concentration. However, an optimal size of 800 nm observed in the model might not be practical

in deliver the particles to the tumor. Therefore, a balance can be achieved by decreasing the size

and increasing the concentration of the TiO2. Until now, there has been no study on the effect of

the size of TiO2 nanoparticles on the number of Cerenkov photons and cancer cell viability (ROS

production). However, the size of the nanoparticles is an important parameter and affect their

reactivity, as shown in the literature as well (21,38).

The model can be used easily employed for any kind of nanoparticle and radionuclide to

determine the Cerenkov-assisted production of ROS. There are four other important points to

consider for future work. First, the refractive index of the medium changes with the addition of

radionuclide and nanoparticles, and there is no direct formula to account for the change. Higher

refractive index decreases the threshold energy for β particles to produce CR, and therefore more

photons are generated. Second, the mechanism of ROS generation is complex. Because this the

first study to show a detailed pathway of cancer cell death caused by radionuclides and

semiconductor nanoparticles, we presented a simple reaction mechanism for ROS generation.

However, other complex reaction and ROS products (H2O2 and singlet oxygen) are reported in

the literature. Third, more experimental investigation is needed to provide data for continued

model validation. Fourth, presence of other mechanisms such as direct excitation and ionization

of nanoparticles by the ionizing radiation may also contribute to the ROS generation as reported

by previous studies (24,39). Direct excitation of nanoparticle was demonstrated by measuring

the radiance output of nanoparticles in the presence of radionuclides, which emit β particles with



energy less than the Cerenkov threshold. The enhancement in the emitted radiance output

compared to the system without nanoparticle implies the direct excitation of nanoparticle with

ionizing radiation. Ionization of nanoparticles by ionizing radiation was determined by

measuring the characteristics X-ray produced during ionization (24) . For a system of 18F-FDG

radionuclides with activity (<30 MBq), which mainly emits β+, and TiO2 nanoparticles

considered in this work, these mechanisms play a slight role. However, they are very significant

when the radioactivity is high, and nanoparticles high atomic number (e.g. Eu2O3, Gd2O3)

element is used. According to our best knowledge, there hasn’t been any study on theoretical

determination of contribution of these mechanistic in ROS generation. It will be of great interest

to determine the share of each individual mechanism to ROS generation and PDT, but is out of

the scope of this article. Having said that, the model presented in this study still quantifies the

contribution of Cerenkov radiation to ROS generation and gives a fair idea about the size and

concentration of TiO2 nanoparticles to be used for effective suppression of cancer cells.

Nonetheless, it is also important to experimentally measure ROS generation in this kind of

system. The consideration of other mechanisms (above described) will affect the scaling factor

used to compare the model prediction of ROS level to the experimental results, and the scaling

factor will change, as the model will then include ROS generated from these mechanisms.

CONCLUSIONS

In summary, we integrated Cerenkov physics, light scattering, and photocatalytic reaction

engineering to understand the detailed mechanism of ROS production (directly attributed to cell

death) in the presence of radionuclides and TiO2 semiconductor nanoparticles. CR is produced

when a β particle (the decay product of a radionuclide) moves at a very high speed in the

medium. The CR, which is dominant in the UV region, is absorbed by the locally present



photoactive TiO2 nanoparticles and results in the generation of e- and h+ pairs. The charge

carriers then react with the medium and produce ROS that result in cell death. Furthermore,

different system parameters (size of TiO2 nanoparticles, concentration of TiO2, and radioactivity

of the nuclide) influence the number of Cerenkov photons and ROS generation. The results

proposed an optimum particle size of the TiO2 for maximum ROS production as a result of

dependency of light absorption, scattering efficiencies and charge-separation on the particle size.

These models can also be used for other types of radionuclide and semiconducting materials and

provide a framework to develop and deploy cancer tumor mitigating strategies.

ACKNOWLEDGMENT

Partial support for this work was provided by NIH Grant U54CA199092, Center for

Multiple Myeloma Nanotherapy (CMMN). Shalinee Kavadiya acknowledges support from the

Solar Energy Research Institute for India and the U.S. (SERIIUS) funded jointly by the

U.S. Department of Energy subcontract DE AC36-08G028308 (Office of Science, Office of

Basic Energy Sciences, and Energy Efficiency and Renewable Energy, Solar Energy Technology

Program, with support from the Office of International Affairs) and the Government of

India subcontract IUSSTF/JCERDC-SERIIUS/2012 dated 22nd Nov. 2012. No potential

conflicts of interest relevant to this article exist.



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FIGURE 1. Schematic of (A) System studied for Cerenkov-assisted PDT (B) Detail mechanism of ROS generation and cancer cell death from CR.



FIGURE 2. Schematic diagram depicting the model (A) β particle (red dot) moves (red arrow) at an angle to the line joining origin of β and TiO2 (hollow blue circle), and the photon moves (blue arrow) at an angle to the β trajectory. (B) part of the β trajectory, showing that the number of photons and photon flux to TiO2 are calculated at each step with . (C) Angular range of interest, shaded in orange.



FIGURE 3. (A) Number of Cerenkov photons generated as a function of wavelength (B) Comparison of the model predictions to the experimental results reported in reference 15 (Kotagiri et al. Nature Nanotechnology, 10, 370, 2015) and reference 23 (Duan et al., Applied Material& Interfaces, 10, 5278, 2018). Parameters ( pd ,

2TiOC , and A ) are taken from references

to determine equivalent ROS concentration from the model.



FIGURE 4. Effect of the decay time (and radioactivity of 18F-FDG) on (A) Nph (solid curve) and Nint (dash curve), (B) the ROS concentration.



FIGURE 5. Effect of TiO2 concentration on (A) Nph (solid curve) and Nint (dash curve), (B) the ROS concentration.



FIGURE 6. Effect of TiO2 nanoparticle size on (A) Nph (solid curve) and Nint (dash curve), (B) the ROS concentration.



Doi: 10.2967/jnumed.118.215608Published online: October 5, 2018.J Nucl Med. Shalinee Kavadiya and Pratim Biswas Oxygen Species Generation for Cancer Treatment

Nanoparticles and Reactive2Design of Cerenkov-assisted Photoactivation of TiO

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