Gold Nanoparticles as Radiosensitizers in Cancer Radiotherapy

Figures & data

Table 1 In vitro Studies on Radiosensitization of GNPs

Study [Ref]	Particle Size	Surface Modifier	Concentration	Cell Line	Radiation Source	Outcomes/DEF
Chithrani et al^Citation64	50nm	Citrate	1nM	Hela	105kVp	1.66
					220kVp	1.43
					660keV	1.18
					6MVp	1.17
Chang et al^Citation25	13nm	Citrate	10nM	B16F10	6 MeV	Significantly reduced survival fraction
Liu et al^Citation59	14.8nm	Citrate	1.5–15μg/mL	Hela	50kVp	1.14–2.88
Butterworth et al^Citation197	1.9nm	Thiol	100μg/mL	AGO-1552B	160kVp	1.97
				MCF-7		1.09
				MDA-MB-231		1.11
						1.02
				PC-3
						1.91
				T98G
Coulter et al^Citation50	1.9nm	Thiol	12μM	MDA-MB-231	160kVp	1.41
Wang et al^Citation114	16nm	Glucose	20nM	MDA-MB-231	6MV	1.49
	49nm					1.86
Soleymanifard et al^Citation115	16nm	Glucose	100µM	QU-DB MCF-7	100kVp 6MV	Increased inhibition of cell proliferation
Joh et al^Citation54	12nm	PEG	1mM	U251	150kVp	1.3
Zhang et al^Citation16	4.8nm	PEG	0.05mM	Hela	662keV (^137Cs)	1.41
	12.1nm					1.65
	27.3nm					1.58
						1.42
	46.6nm
Khoshgard et al^Citation98	52nm	Folate	50µM	Hela	120–250kVp	1.64

Abbreviations: GNPs, gold nanoparticles; DEF, dose enhancement factor; PEG, polyethylene glycol.

Table 2 In vivo Studies on Radiosensitization of GNPs

Study [Ref]	Particle Size	Surface Modifier	Concentration	Tumor Model	Radiation Source	Effects
Hainfeld et al^Citation51	1.9nm	Thiol	1.35g Au/kg 2.7g Au/kg	EMT-6	250kVp 26Gy	50% long-term survival at 1.35 g Au/kg; 86% long-term survival at 2.7 g Au/kg;
Hainfeld et al^Citation52	1.9nm	Thiol	1.9g Au/kg	SCCVII	68keV, 42Gy 157keV, 50.6Gy	Increased in tumor volume doubling time; increased long-term survival rate;
Hainfeld et al^Citation53	1.9nm	Thiol	4g Au/kg	Tu-2449	100kVp,30Gy	50% long-term tumor-free survival;
Chang et al^Citation25	13nm	Citrate	200nM	B16F10	6MeV e^−	Significant delay in tumor growth;
Duo et al^Citation24	13.2nm	PEG	60nM/kg	Hela	6MeV,6Gy	Significant effects on inhibiting tumor growth;
Joh et al^Citation54	12nm	PEG	1.25g Au/kg	U251	175kVp,20Gy	Median survival time prolonged;
Liu et al^Citation89	8nm 50nm	BSA	4mg Au/kg	H22	6MV,5Gy	Tumor growth is inhibited, DEF is 1.93 and 2.02, respectively;
Koonce et al^Citation214	27nm	TNF-α	250 µg/kg	SCCVII 4T1	150kVp,20Gy or 12Gy x 3	2-fold or 5.3 times delay in tumor growth.

Abbreviations: BSA, bovine serum albumin; GNPs, gold nanoparticles; PEG, polyethylene glycol; TNF-α, tumor necrosis factor-α; DEF, dose enhancement factor.

Figure 1 The application advantages of functionalized GNPs.

Notes: Prolong blood circulation time and increase the uptake of tumor cells; selective targeting sites for drug delivery, reducing toxicity, evading clearance of the RES and inhibiting multi-drug resistance (MDR); offer coupling sites for biomarkers for disease diagnosis and efficacy prediction; provide controlled release sites for drugs, reduce the side effects of drugs.

Abbreviations: GNPs, gold nanoparticles; MDR, multi-drug resistance; RES, reticuloendothelial system.

Figure 2 Passive targeting for GNPs.

Notes: The wide fenestrations of tumor vascular endothelial, as well as its poor structural integrity, high permeability and impaired lymphatic drainage, allowing the accumulation or passive targeting of GNPs in or around the tumor tissues, which is known as EPR effect.

Abbreviations: EPR, enhanced permeability and retention; GNPs, gold nanoparticles.

Table 3 Summary of Active Targeting and Targeting Approaches of Surface-Modified GNPs

Surface Modifier	Targeting Receptor	Cell or Tumor Model	Reference
Folate	Folate receptor	Hela C6	Samadian et al^Citation99 Kefayat et al^Citation100
Trastuzumab	HER2	MDA-MB-361 BT474 SK-BR-3	Cai et al^Citation103
Panitumumab	EGFR	MDA-MB-468 MDA-MB-231 MCF-7	Yook et al^Citation104 Yook et al^Citation105
EGF	EGFR	MDA-MB-468 MCF-7	Song et al^Citation109
Glucose	GLUT receptors	THP-1	Hu et al^Citation116
GAL	Asialoglycoprotein receptor	HepG2	Zhu et al^Citation118
RGD	Transmembrane heterodimeric αvβ3 integrin receptor	MDA-MB-231	Yang and Chithrani^Citation125
CPPs	The plasma membrane and membrane-associated proteoglycans	LS 180	Zhang et al^Citation130
NLSs	The NPC	Hela	Yang et al^Citation131
NUAP	Nucleolin	A431 FaDu	Zhang et al^Citation141
pHLIP	Acidic pH of TME	A549	Antosh et al^Citation151
Salmonella typhi Ty21a	Tumor hypoxic regions	CT-26	Kefayat et al^Citation162

Abbreviations: EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; GAL, β-d-galactose; GLUT, glucose transporter; GNPs, gold nanoparticles; HER2, human epidermis growth factor receptor 2; NLSs, nuclear localization sequences; NPC, nuclear pore complex; NUAP, nucleolin aptamer; pHLIP, pH low-insertion peptide; TME, tumor microenvironment.

Figure 3 Active targeting for GNPs.

Notes: Overexpression of antibodies or surface-bound antigens on the surface of tumor cells or tumor blood vessels provides an effective pathway for uptake of nanomedicine, namely receptor-mediated endocytosis. Targeting agent-modified GNPs can specifically bind to certain cancer cells through this effect, is denominated as active targeting of GNPs.

Abbreviation: GNPs, gold nanoparticles.

Figure 4 The potential mechanisms of GNP radiosensitization.

Notes: The potential mechanisms of GNP radiosensitization, which could be summarized as three parts: 1) physical dose enhancement, including the Compton effect and the photoelectric effect; 2) chemical contributions based on the chemical sensitization of DNA to radiation-induced damage as well as the increased generation and catalysis of radicals; 3) biological phase could be divided into ROS production, oxidative stress, mitochondrial dysfunction, cell-cycle effect, DNA repair inhibition and other biological mechanisms (such as autophagy and ER stress).

Abbreviations: ER, endoplasmic reticulum; GNPs, gold nanoparticles; ROS, reactive oxygen species.

Chithrani DB, Jelveh S, Jalali F, et al. Gold nanoparticles as radiation sensitizers in cancer therapy. Radiat Res. 2010;173(6):719–728.20518651

 PubMed Web of Science ®Google Scholar

Chang MY, Shiau AL, Chen YH, Chang CJ, Chen HH, Wu CL. Increased apoptotic potential and dose-enhancing effect of gold nanoparticles in combination with single-dose clinical electron beams on tumor-bearing mice. Cancer Sci. 2008;99(7):1479–1484. doi:10.1111/j.1349-7006.2008.00827.x18410403

 PubMed Web of Science ®Google Scholar

Liu Y, Liu X, Jin X, et al. The dependence of radiation enhancement effect on the concentration of gold nanoparticles exposed to low- and high-LET radiations. Phys Med. 2015;31(3):210–218. doi:10.1016/j.ejmp.2015.01.00625651760

 PubMed Web of Science ®Google Scholar

Butterworth KT, Coulter JA, Jain S, et al. Evaluation of cytotoxicity and radiation enhancement using 1.9 nm gold particles: potential application for cancer therapy. Nanotechnology. 2010;21(29):295101. doi:10.1088/0957-4484/21/29/29510120601762

 PubMed Web of Science ®Google Scholar

Coulter JA, Jain S, Butterworth KT, et al. Cell type-dependent uptake, localization, and cytotoxicity of 1.9 nm gold nanoparticles. Int J Nanomed. 2012;7:2673–2685. doi:10.2147/IJN.S31751

 PubMed Web of Science ®Google Scholar

Wang C, Jiang Y, Li X, Hu L. Thioglucose-bound gold nanoparticles increase the radiosensitivity of a triple-negative breast cancer cell line (MDA-MB-231). Breast Cancer. 2015;22(4):413–420. doi:10.1007/s12282-013-0496-924114595

 PubMed Web of Science ®Google Scholar

Soleymanifard S, Rostami A, Aledavood SA, Matin MM, Sazgarnia A. Increased radiotoxicity in two cancerous cell lines irradiated by low and high energy photons in the presence of thio-glucose bound gold nanoparticles. Int J Radiat Biol. 2017;93(4):407–415. doi:10.1080/09553002.2017.126828227921518

 PubMed Web of Science ®Google Scholar

Joh DY, Sun L, Stangl M, et al. Selective targeting of brain tumors with gold nanoparticle-induced radiosensitization. PLoS One. 2013;8(4):e62425. doi:10.1371/journal.pone.006242523638079

 PubMed Web of Science ®Google Scholar

Zhang XD, Wu D, Shen X, et al. Size-dependent radiosensitization of PEG-coated gold nanoparticles for cancer radiation therapy. Biomaterials. 2012;33(27):6408–6419. doi:10.1016/j.biomaterials.2012.05.04722681980

 PubMed Web of Science ®Google Scholar

Khoshgard K, Hashemi B, Arbabi A, Rasaee MJ, Soleimani M. Radiosensitization effect of folate-conjugated gold nanoparticles on HeLa cancer cells under orthovoltage superficial radiotherapy techniques. Phys Med Biol. 2014;59(9):2249–2263. doi:10.1088/0031-9155/59/9/224924733041

 PubMed Web of Science ®Google Scholar

Hainfeld JF, Slatkin DN, Smilowitz HM. The use of gold nanoparticles to enhance radiotherapy in mice. Phys Med Biol. 2004;49(18):N309–N315. doi:10.1088/0031-9155/49/18/N0315509078

 PubMed Web of Science ®Google Scholar

Hainfeld JF, Dilmanian FA, Zhong Z, Slatkin DN, Kalef-Ezra JA, Smilowitz HM. Gold nanoparticles enhance the radiation therapy of a murine squamous cell carcinoma. Phys Med Biol. 2010;55(11):3045–3059.20463371

 PubMed Web of Science ®Google Scholar

Hainfeld JF, Smilowitz HM, O’Connor MJ, Dilmanian FA, Slatkin DN. Gold nanoparticle imaging and radiotherapy of brain tumors in mice. Nanomedicine (Lond). 2013;8(10):1601–1609. doi:10.2217/nnm.12.16523265347

 PubMed Web of Science ®Google Scholar

Dou Y, Guo Y, Li X, et al. Size-tuning ionization to optimize gold nanoparticles for simultaneous enhanced CT imaging and radiotherapy. ACS Nano. 2016;10(2):2536–2548. doi:10.1021/acsnano.5b0747326815933

 PubMed Web of Science ®Google Scholar

Liu S, Piao J, Liu Y, et al. Radiosensitizing effects of different size bovine serum albumin-templated gold nanoparticles on H22 hepatoma-bearing mice. Nanomedicine (Lond). 2018;13(11):1371–1383. doi:10.2217/nnm-2018-005929749804

 PubMed Web of Science ®Google Scholar

Koonce NA, Quick CM, Hardee ME, et al. Combination of gold nanoparticle-conjugated tumor necrosis factor-α and radiation therapy results in a synergistic antitumor response in murine carcinoma models. Int J Radiat Oncol Biol Phys. 2015;93(3):588–596. doi:10.1016/j.ijrobp.2015.07.227526461001

 PubMed Web of Science ®Google Scholar

Samadian H, Hosseini-Nami S, Kamrava SK, Ghaznavi H, Shakeri-Zadeh A. Folate-conjugated gold nanoparticle as a new nanoplatform for targeted cancer therapy. J Cancer Res Clin Oncol. 2016;142(11):2217–2229. doi:10.1007/s00432-016-2179-327209529

 PubMed Web of Science ®Google Scholar

Kefayat A, Ghahremani F, Motaghi H, Amouheidari A. Ultra-small but ultra-effective: folic acid-targeted gold nanoclusters for enhancement of intracranial glioma tumors’ radiation therapy efficacy. Nanomedicine. 2019;16:173–184. doi:10.1016/j.nano.2018.12.00730594659

 PubMed Web of Science ®Google Scholar

Cai Z, Yook S, Lu Y, et al. Local radiation treatment of HER2-positive breast cancer using trastuzumab-modified gold nanoparticles labeled with Lu. Pharm Res. 2017;34(3):579–590. doi:10.1007/s11095-016-2082-227987070

 PubMed Web of Science ®Google Scholar

Yook S, Cai Z, Lu Y, Winnik MA, Pignol JP, Reilly RM. Radiation nanomedicine for EGFR-positive breast cancer: panitumumab-modified gold nanoparticles complexed to the β-particle-emitter, (177)Lu. Mol Pharm. 2015;12(11):3963–3972. doi:10.1021/acs.molpharmaceut.5b0042526402157

 PubMedGoogle Scholar

Yook S, Cai Z, Lu Y, Winnik MA, Pignol JP, Reilly RM. Intratumorally injected 177Lu-labeled gold nanoparticles: gold nanoseed brachytherapy with application for neoadjuvant treatment of locally advanced breast cancer. J Nucl Med. 2016;57(6):936–942. doi:10.2967/jnumed.115.16890626848176

 PubMed Web of Science ®Google Scholar

Song L, Falzone N, Vallis KA. EGF-coated gold nanoparticles provide an efficient nano-scale delivery system for the molecular radiotherapy of EGFR-positive cancer. Int J Radiat Biol. 2016;92(11):716–723. doi:10.3109/09553002.2016.114536026999580

 PubMed Web of Science ®Google Scholar

Hu C, Niestroj M, Yuan D, Chang S, Chen J. Treating cancer stem cells and cancer metastasis using glucose-coated gold nanoparticles. Int J Nanomed. 2015;10:2065–2077.

 PubMed Web of Science ®Google Scholar

Zhu CD, Zheng Q, Wang LX, et al. Synthesis of novel galactose functionalized gold nanoparticles and its radiosensitizing mechanism. J Nanobiotechnol. 2015;13:67. doi:10.1186/s12951-015-0129-x

 PubMed Web of Science ®Google Scholar

Yang CJ, Chithrani DB. Nuclear targeting of gold nanoparticles for improved therapeutics. Curr Top Med Chem. 2016;16(3):271–280. doi:10.2174/156802661566615070111501226126911

 PubMed Web of Science ®Google Scholar

Zhang X, Wang H, Coulter JA, Yang R. Octaarginine-modified gold nanoparticles enhance the radiosensitivity of human colorectal cancer cell line LS180 to megavoltage radiation. Int J Nanomed. 2018;13:3541–3552. doi:10.2147/IJN.S161157

 PubMed Web of Science ®Google Scholar

Yang C, Neshatian M, van Prooijen M. Cancer nanotechnology: enhanced therapeutic response using peptide-modified gold nanoparticles. J Nanosci Nanotechnol. 2014;14(7):4813–4819. doi:10.1166/jnn.2014.928024757948

 PubMed Web of Science ®Google Scholar

Zhang S, Gupta S, Fitzgerald TJ, Bogdanov AA. Dual radiosensitization and anti-STAT3 anti-proliferative strategy based on delivery of gold nanoparticle - oligonucleotide nanoconstructs to head and neck cancer cells. Nanotheranostics. 2018;2(1):1–11. doi:10.7150/ntno.2233529291159

 PubMedGoogle Scholar

Antosh MP, Wijesinghe DD, Shrestha S, et al. Enhancement of radiation effect on cancer cells by gold-pHLIP. Proc Natl Acad Sci U S A. 2015;112(17):5372–5376. doi:10.1073/pnas.150162811225870296

 PubMed Web of Science ®Google Scholar

Kefayat A, Ghahremani F, Motaghi H, Rostami S, Mehrgardi MA. Alive attenuated Salmonella as a cargo shuttle for smart carrying of gold nanoparticles to tumour hypoxic regions. J Drug Target. 2019;27(3):315–324. doi:10.1080/1061186X.2018.152341730207745

 PubMed Web of Science ®Google Scholar