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Khosravi H, Doosti-Irani A, Bouraghi H, Nikzad S. Investigation of Gold Nanoparticles Effects in Radiation Therapy of Cancer: A Systematic Review. J Adv Med Biomed Res 2022; 30 (142) :388-396
URL: http://journal.zums.ac.ir/article-1-6609-en.html
Investigation of Gold Nanoparticles Effects in Radiation Therapy of Cancer: A Systematic Review
Hossein Khosravi1 , Amin Doosti-Irani2 , Hamid Bouraghi3 , Safoora Nikzad *4
1- Dept. of Radiology, Faculty of Allied Medical Sciences, Hamadan University of Medical Sciences, Hamadan, Iran
2- Dept. of Epidemiology, Hamadan University of Medical Sciences, Iran
3- Dept. of Health Information Technology, Faculty of Allied Medical Sciences, Hamadan University of Medical Sciences, Hamadan, Iran
4- Dept. of Medical Physics, Faculty of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran , s.nikzad@umsha.ac.ir
Keywords: Gold Nanoparticle, Radiotherapy, Radio sensitization, Cancer
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✅ In recent years, the use of nanoparticles (NPs), especially gold nanoparticles (GNPs) in radiotherapy, has been repeatedly studied by in-vitro, in-vivo experiments, and Monte Carlo simulation. Some studies declare that specific absorption of GNPs (with a higher atomic number) by cancerous cells increases radiations’ lethal effect compared to normal cells. This review article aimed to investigate the radiosensitizing effect of GNPs in cancer radiotherapy.


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Introduction
 

Nanoparticles are particles with a dimension of 1 to 100 nm (1, 2). Medications that can better penetrate the cells have been proposed for diagnosis and targeted treatment of cancer by nanomedicine. The distribution of nanoparticles is affected by various parameters, including their size and ability to inactivate cancer cells (3, 4). In radiation therapy, ionizing radiation such as high-energy photons and particles are widely used to treat cancerous tumors in solid form. Unfortunately, ionizing radiation cannot distinguish cancer cells from healthy cells (5, 6); therefore, normal tissues are damaged by radiation therapy used to eradicate cancer cells. The main purpose of using nanoparticles in cancer treatment is to enhance the outcome of radiotherapy by increasing the lethality of radiation in tumors and reducing it for healthy cells due to the accumulation of nanoparticles in the tumor compared to healthy tissues (7, 8). Among the various nanoparticles, most preclinical studies have been performed on gold nanoparticles with distinctive specifications such as tiny size, desirable biological adaptability and little toxicity (9, 10). These characteristics establish gold nanoparticles for use in various medical applications such as biosensors, drug delivery, chemotherapy, and radiation therapy (11, 12).
Hainfeld et al. (13) investigated the toxicity of GNP on breast cancer cells in mice in experimental training. The first group received GNP before irradiation of 250 kVp photon. The second group received sole radiation, and the last group received merely GNP. Results show that the one-year survival rate was 86%, 20%, and 0% in the first, second and third groups, respectively (13).
In another study by Chithrani et al., the accumulation of GNP in cancer cells and transplanted tumors of mice were studied, and the treatment ratio after 25MeV of 6MeV electron beam was investigated. Results showed that the amount of GNP accumulated in cells significantly affected mortality due to radiation (with a value of P = 0.02). This rate was less than 0.05 in mouse tumors (P<0.05). However, Chang et al. Obtained a more significant effect using GNP with a mean dimensional of 13 nm compared to the former study (14, 15).
Recent progress in synthesizing and creating multifunctional nanoparticle platforms has prepared great opportunities and benefits for targeted gene delivery. Using bioinformatics methods in cancer therapy, such as evaluating the molecular interactions of plant-derived inhibitors in contrast to E6AP, p53, and c-Myc has improved the usage of nanoparticles in cancer treatment (3, 4).
Several studies have been published regarding using gold nanoparticles in radiation therapy. The controversial results concerning GNP radiosensitization could be emanated from the differences in GNP shape, scale, origin and type of cell lines, energy and type of radiation. Therefore, the purpose of this review article was to consider the gold nanoparticles’ radiosensitization in cancer radiation therapy.
 

 

Materials and Methods

A current systematic review was done according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (16). All GNRT studies that investigated the radiosensitization of gold nanoparticles in radiotherapy were included in the article. Moreover, review articles, editorials, and letters to the editor were excluded.

Eligibility Criteria
Original peer-reviewed articles published in the English language on the application of GNPs in cancer (as well as in-vitro, cell, cancer, radiation therapy, radiosensitization, and neoplasms) were evaluated. Articles that used NPs without any gold component were omitted. The last finding was assessed in the case of numerous studies derived from the same institution.
Data Origin and Examination
A wide literature search was performed up to December 2019 using Web of Science, PubMed and Scopus databases. The MeSH search terms used were “gold nano*” and “*radiosensitization*” or “*radiation therapy*” or “radiotherapy” and “cancer” and “neoplasms” and “*invitro*”.
Article and Data Assortment Process
In the first step, the title and abstract of chosen articles were independently scanned by two authors (HK, SN). In the case of disagreement between authors in selecting the articles, the problem was resolved using the third author’s judgment (ADI). The next step was considering the chosen articles based on the eligibility criteria. Finally, data such as: (1) the name of the first Authors, (2) date of Publication, (3) Site of Study, (4) Type of Study, (5) used NP Size, (6) NP size in intervention group, (7) NP size in the control group and the (8) Effect of NP Size extracted from the chosen articles by two authors (HK, SN). There was a suitable agreement between the two authors, and minor disagreements were discussed between all authors until a full consensus was reached on the studies included in the study.
Data Items

Microsoft Excel software was used to extract and manage the data of the chosen studies. Other data extracted from the studies: Type of Study, Sample size (Sample size in intervention and control group), type of GNP, shape, average size, Effect size (Radiosensitivity, Dose Enhancement Factor, rate of mortality and percentage of remaining cells).

 
 
Results

OFT results

Initial examines by of the mentioned MeSH terms discovered 706 articles. At first, the titles of the articles were reviewed to reach higher quality and appropriate articles. Duplicate articles and articles whose titles were not related to the dimensions of research effectiveness were removed. After checking the eligibility criteria, 52 articles regarding the radiosensitization of gold nanoparticles in radiotherapy were included in the review (Figure 1).
GNPs used as cancer radiation sensitizers often included a combination of conjugated GNPs with silica, PEG, chitosan and iron core. Although different shapes of NPs have been used, rods and sphere shapes were more common. The identifiable characteristics of GNPs used in articles are presented in Tables 1, 2, and 3.
Table 1 represents the rate of increase in radiation sensitization using gold nanoparticles in recent research. The mean value of rising in radiosensitivity for these studies was SER = 1.59 ± 0.30.
Table 2 shows the rate of increase in the absorption dose factor in the studies conducted using gold nanoparticles in recent years. The mean value of the increase in absorption dose factor for these studies was DEF[1] = 1.45± 0.39.
Table 3 indicates the mortality rate and percentage of cells remaining due to radiation using gold nanoparticles in recent years. The mean mortality for these studies was 42.67±24.78. It should be noted that this table examines the various parameters related to the tumor, but the differences in the results in some studies are very large.

Figure 1. PRISMA Flowchart: Flowchart using syntax appropriate search and identification step to include in the Review 
Figure 1. PRISMA Flowchart: Flowchart using syntax appropriate search and identification step to include in the Review

 
Table 1. The rate of increase in radiosensitivity in research using gold nanoparticles

ID Author Study Shape Average Size (nm) Sample Size Sample size in intervention group Sample size in control group Effect size
1 Zhu, C. D. (17) E Sp 20 3000 cell/well 3000 cell/well 3000 cell/well SER =1.96
2 Zhu, C. (18) E Sp 20 3000 cell/well 3000 cell/well 3000 cell/well SER=2
3 Zheng Q. (19) E Sp 100 4000 cell/well 4000 cell/well 4000 cell/well SER=1.769
4 Zhao, N. (20) E Rod 20 5000 cell/well 5000 cell/well 5000 cell/well SER=1.52
5 Zhang, Y. (21) E Sp 32 mice mice mice SER=1.73
6 Zhang, X. (22) E Sp 4.8-46.6 1000000 cell/well 1000000 cell/well 1000000 cell/well SER=2.07(For GNP: 46.6 nm)
7 Zhang, X. (23) E Sp 6.3 1000000 cell/well 1000000 cell/well 1000000 cell/well SER=1.59
8 Zabihzadeh, M. (24) E Sp 24 1000000 cell/well 1000000 cell/well 1000000 cell/well SER=1.25
9 Wang, C. (25) E Sp 16 & 49 4000 cell/well 4000 cell/well 4000 cell/well SER=1.86  (For GNP: 49nm) SER=1.49 (FOR GNP:16nm)
10 Sung, W. (26) S Sp 2,15,20 & 5 -- SER=1.2(For GNP: 50nm)
11 Shi, M. (27) E Sp 4.8 cell cell cell SER=1.48   (For Dose=1 Gy) SER=1.69 (For Dose=4 Gy)
12 Nicol, J. R. (28) E Sp 13 30000 cell/well 30000 cell/well 30000 cell/well SER=1.25 ( For NPs alone) SER=3.19 ( For NPs+RT)
13 Mehrnia, S.  S. (29) E Sp 10 Cell Cell Cell SER=1.43  AND 1.40
(FOR TWO CELL LINES)
14 McMahon, S. J. (30) S Sp 2 SER = 1.29 and 1.16
(For E=6 MeV and 15 MeV)
15 Ma, N. N. (31) E Sp &
Rod		 20 cell cell cell SER= 1.62, 1.37, and 1.21
(For different shapes of gold nanoparticles)
16 Ma, N. (32) E Sp &
Rod		 50 cell cell cell SER=2.30
17 Ab Rashid, R. (33) E Sp 1.9 2000 cells (HeLa ) 1000 cells per well 1000 cells per well SER=1.78
18 Al Zaki, A. (34) E Sp 1.9 16 mice 8 mice 8 mice SER=1.7
19 Enferadi, M. (35) E Sp 1.8 10000 ALTS1C1, AML12, and RAW cells 5000 5000 SER =1.66
20 Jain, S. (36) E Sp 1.9 150000  MDA-MB-231 breast cancer cells 75000 75000 SER=1.41

E: Experimental – S: Simulation - Sp: Spherical
 
Table 2. The dose enhancement factor in research using gold nanoparticles

ID Author Shape Average Size (nm) Study Sample Size Sample size in intervention group Sample size in control group Effect size
1 Taggart, L.E. (37) Spherical 1.9 nm Experimental 100000 cell/well 100000 cell/well 100000 cell/well DEF=1.52
2 Khosravi,H. (38) Spherical 15, 50, and 100 nm Simulation - DEF=2.66 (For E=50 keV)
DEF=1.10  (For E=6 MeV)
3 Rezaee, Z. (39) Spherical 15 nm Experimental cell cell cell DEF=1.17-2.89 (For various times)
4 Rahman, W. N. (40) Spherical 1.9 nm Experimental 50000cell 50000cell 50000cell DEF=1.14-1.74 (For different energies)
5 Rahman, W. N. (41) Spherical 1.9 nm Experimental 10000 cell/well 10000 cell/well 10000 cell/well DEF=4  (FOR E=6 MeV)
6 Mousavi, M. (42) Spherical  
24.7±3.6 nm		 Experimental Cell Cell Cell DEF=1.22
7 Cui, L. (43) Spherical 5.81 ± 1.53 nm Experimental 2000000 MDA-MB-231 breast cancer cells 1000000 1000000 DEF=1.39
8 Amato, E. (44) Spherical 50 μm Simulation - DEF=1.6- 6.5
9 Cui, L. (45) Spherical 2.7 nm Experimental 2000000 MDA-MB-231 breast cancer cells 1000000 1000000 DEF = 1.39
10 Khosravi,H. (46) Spherical 15 nm Experimental/ Simulation MAGIC-f polymer gel gel+gnp gel DEF=1.12
11 Her, S. (47) Spherical 15 nm Experimental 2000000 Human breast carcinoma cells 1000000 1000000 DEF=1.55
12 Smith, C. L. (48) Spherical 5 nm Experimental cell cell cell DEF= 10%
13 Roeske, J. C. (49) Spherical 1.9  nm Simulation Simulation - DEF=1.01
14 Chithrani, D. B. (50) Spherical 14–74 nm Experimental 2000000 HeLa cells 1000000 1000000 DEF=1.43
15 Geng, F. (51) Spherical 14.37 ± 2.49 nm Experimental 4000 SK-OV-3 cell 2000 2000 DEF=30.48
16 Brivio, D. (52) Spherical 20 nm Simulation - DEF=1.97
17 Gadoue, S. M. (53) Spherical 100 nm Simulation - DEF=%64
18 Ghorbani, M. (54) Spherical 50 nm Simulation - DEF=1.79
19 Koger, B. (55) Spherical 10, 20, and 50 nm Simulation - DEF=34% (FOR GNP:50 nm)

 
Table 3. Mortality rate and percentage of cells remaining due to radiation using gold nanoparticles

ID Author Shape Average Size (nm) Study Sample Size Sample size in intervention group Sample size in control group Effect size
1 Zhang, X. (56) Spherical 15 nm Experimental 3000 cell/well 300 cell/well 300 cell/well Death=45.97%
2 Zhang, A. (57) Spherical 58.14 ± 4 nm Experimental 5000 cell/well 5000 cell/well 5000 cell/well Death in Control=9.9%
Death in Treated =10.85%
3 Hainfeld, J. F. (58) Spherical 1.9 nm Experimental 2000000 EMT-6 mouse 1000000 1000000 Some 86% long-term (>1 year)
cures of EMT-6 mouse mammary
4 Zhang, Z. (59) Spherical 10 nm Experimental 5000 cell/well 5000 cell/well 5000 cell/well Viability=4%
5 Vieira, L. (60) Spherical 18±4 nm Experimental 100000 cell/well 100000 cell/well 100000 cell/well Cell Viability=62%
6 Tentor, F. R. (61) Spherical 20 nm Experimental 250000 cell/well 250000 cell/well 250000 cell/well Viability in Control=94%
Viability in Treated Group=67%
7 Roa, W. (62) Spherical 15 nm Experimental cell cell cell Cell Survival = 36%
8 Movahedi, M. M. (63) Spherical 58 nm Experimental 10000cell/well 10000cell/well 10000cell/well Cell Viability in Control Group =86%
Cell Viability in Treated RT+NP=69%
9 Zavidij,  O. (64) Not mentioned Not mentioned Experimental mice mice mice SF= 30%     In Treated
SF = 0%     In Control
10 Miladi, I. (65) Spherical Not mentioned Experimental mice mice mice Survival in Control Group =28 day
Survival by RT + NPs=117 day
(Improvement: 50%)
11 Atkinson, R. L. (66) nanoshell - Experimental 10 million cells/ml 5 million cells/ml 5 million cells/ml Survival Fraction=1/3
12 Chattopadhyay, N. (67) Spherical 30 nm Experimental 100000 MDA-MB-361 human breast cancer cells 500000 500000 Death=46%
13 Liu, C. J. (68) Spherical 6.1 ± 1.9 Experimental (B16) cell lines 5000 5000 Death≌45%

Discussion

This study investigated the sensitizing effect of gold nanoparticles in cancer radiotherapy around three main axes: the rate of radiation sensitivity, the rate of absorption dose factor, the rate of mortality, and the percentage of remaining cells.
Using gold nanoparticles as a radiation sensitizer in irradiation of cancer cells led to an increase in therapeutic efficiency up to 59% at low photon energies by using orthovoltage sources. The results of using these nanoparticles showed that reducing the prescribed dose by about 60% could have a similar lethal effect in cancer cells. The cause of radiation sensitization of gold nanoparticles is the high atomic number of gold relative to the atomic number of biological elements present in the tissue or cells. Many studies confirm the irradiative sensitivity of gold nanoparticles. As the study conditions vary greatly from study to study, the sensitivities reported in such studies are different (17-36, 69-72).
With the use of gold nanoparticles, the radiation absorption dose was increased by an average of 45%. In general, the difference in the rate of increase in absorbed dose in various studies can be attributed to differences in the concentration of GNPs, the type of coat of GNPs, and the type of investigated cell line or a combination of these factors. It is clear that by increasing the concentration of GNPs, a higher dose coefficient can be achieved. In using larger NPs to increase the dose, a compromise must be made between entering and accumulating more NPs inside the cells (37-55, 69).
The mortality rate and percentage of cancerous cells remaining after radiotherapy using GNPs have been studied in various experimental studies over the past years. The average rate of mortality in these studies was about 42%. Results of studies, which have investigated the toxicity of GNPS, show that these NPs can reduce viability and cancerous cell growth. However, the toxicity of GNPs depends on the concentration, size and shape of NPs, the incubation period, and the investigated cell line type. In addition, comparisons were made between different beams at a given incubation time. Results showed that the X-ray peak at 180 kV could be more effective than the other energies, although this variation was not statistically significant. The theoretical fact can explain this increase in the absorption dose coefficient of 180 kV X-ray that photons with energies about 50 kV have a higher mass-energy absorption coefficient in gold than water or water equivalent (56-69).
Also, recent studies have concluded that gold nanoparticles in combination with chemotherapy medicines such as Bleomycin (70) or immunomodulation (71) can enhance the treatment results and increase the Plasmid DNA damages due to MV radiations (71).

 

Conclusion

The results of all studies in this field confirm the increase in the absorbed dose of the tumor in radiation therapy due to the replacement of gold nanoparticles in the tumor. However, the results of the interaction of photon energy with the magnitude of GNPs are still controversial. Monte Carlo simulation studies have investigated GNPs with 10 to 100 nm dimensions, while biological studies have studied dimensions up to 1.9 nm. Results of simulations show that the most effective parameters of NPs are larger dimensions, high molar concentrations, and low-energy X-ray or gamma photons that allow for higher dose escalation. This article aimed to answer some of the questions in this field. More and more extensive research in this regard is necessary to reach a global consensus and clinical application.

 

Acknowledgements

The authors would like to thank Hamadan University of Medical Sciences research center.

 

Conflicts of Interest

None declared.
 

Funding

This study was supported by the Hamadan University of Medical Sciences contract number of 9710186016 ethical number of IR.UMSHA.REC.1397.648 of Hamadan University of Medical Sciences, Hamadan, Iran.

 

Type of Study: Review Article | Subject: Bionanotechnology
Received: 2021/06/29 | Accepted: 2022/07/7 | Published: 2022/08/8
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