Differential cytotoxic and radiosensitizing effects of silver nanoparticles on triple-negative breast cancer and non-triple-negative breast cells
Open accessAbstract
Identification of differential sensitivity of cancer cells as compared to normal cells has the potential to reveal a therapeutic window for the use of silver nanoparticles (AgNPs) as a therapeutic agent for cancer therapy. Exposure to AgNPs is known to cause dose-dependent toxicities, including induction of oxidative stress and DNA damage, which can lead to cell death. Triple-negative breast cancer (TNBC) subtypes are more vulnerable to agents that cause oxidative stress and DNA damage than are other breast cancer subtypes. We hypothesized that TNBC may be susceptible to AgNP cytotoxicity, a potential vulnerability that could be exploited for the development of new therapeutic agents. We show that AgNPs are highly cytotoxic toward TNBC cells at doses that have little effect on nontumorigenic breast cells or cells derived from liver, kidney, and monocyte lineages. AgNPs induced more DNA and oxidative damage in TNBC cells than in other breast cells. In vitro and in vivo studies showed that AgNPs reduce TNBC growth and improve radiation therapy. These studies show that unmodified AgNPs act as a self-therapeutic agent with a combination of selective cytotoxicity and radiation dose-enhancement effects in TNBC at doses that are nontoxic to noncancerous breast and other cells.
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Swanner et al. demonstrated that silver nanoparticles significantly enhanced clonogenic radiosensitivity and improved in vivo tumor growth inhibition following irradiation.
“Among relatively simple high-Z systems, Swanner et al. demonstrated that silver nanoparticles significantly enhanced clonogenic radiosensitivity and improved in vivo tumor growth inhibition following irradiation [30].”
From Nanoparticle-Mediated Radiosensitization in Breast Cancer: A Systematic Review of Preclinical Evidence and Translational Challenges (2026) · cites this paper as [30]
The Results section on clonogenic assays reports that silver nanoparticles enhanced the radiation response of breast cancer cells, particularly triple-negative cells. The xenograft Results section reports the greatest tumor-growth inhibition with nanoparticles plus irradiation, but no statistically significant difference between that group and either treatment alone. Thus, improved in vivo inhibition relative to irradiation alone is not established (page numbers unavailable in our copy). (LLM, conf=0.88)
Experimental — accuracy not yet measuredHigh-Z nanoplatforms based on silver, gadolinium, platinum, gold, and bismuth enhance radiation-induced energy deposition through photoelectric interactions and secondary electron generation.
“High-atomic-number (high-Z) nanoplatforms based on silver (Z = 47), gadolinium (Z = 64), platinum (Z = 78), gold (Z = 79), and bismuth (Z = 83) enhance radiation-induced energy deposition through photoelectric interactions and secondary electron generation [15,20,27,28,30,33,34,36,50,63].”
From Nanoparticle-Mediated Radiosensitization in Breast Cancer: A Systematic Review of Preclinical Evidence and Translational Challenges (2026) · cites this paper as [30]
The Results (page unavailable) report that silver nanoparticles increased radiation-associated DNA damage in breast cancer cells, and the Discussion (page unavailable) describes gold nanoparticles as radiation sensitizers. The paper does not establish the claim for gadolinium, platinum, or bismuth, or attribute the observed effects to photoelectric interactions and secondary electron generation. (LLM, conf=0.87)
Experimental — accuracy not yet measuredIncreased ROS production and DNA damage following irradiation were commonly reported in association with high-Z systems.
“Increased ROS production and DNA damage following irradiation were commonly reported in association with these systems [15,20,27,30,33], as summarized in Table 2.”
From Nanoparticle-Mediated Radiosensitization in Breast Cancer: A Systematic Review of Preclinical Evidence and Translational Challenges (2026) · cites this paper as [30]
The Results section reports increased DNA-damage marker γH2AX after irradiation in silver-nanoparticle-treated breast cells compared with radiation alone. The Discussion says silver nanoparticles increase intracellular ROS, but does not establish increased ROS production following irradiation; it describes ROS findings from nanoparticle exposure without that condition. No page numbers are available in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredNanoparticle-assisted irradiation was consistently associated with increased ROS production, leading to oxidative stress, mitochondrial dysfunction, and increased DNA damage.
“This process was consistently associated with increased ROS production following irradiation, leading to oxidative stress, mitochondrial dysfunction, and increased DNA damage [15,20,27,30,33].”
From Nanoparticle-Mediated Radiosensitization in Breast Cancer: A Systematic Review of Preclinical Evidence and Translational Challenges (2026) · cites this paper as [30]
The Results section reports greater DNA damage after silver nanoparticles plus irradiation than after irradiation alone, and separately reports oxidative protein damage after nanoparticle exposure. The Discussion says prior studies found increased ROS with silver nanoparticles and notes decreased mitochondrial activity at higher nanoparticle doses. It does not establish that irradiation increased ROS or that ROS caused the reported mitochondrial and DNA effects. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThese effects were observed in a wide range of nanoplatforms and experimental models and were frequently accompanied by markers of persistent DNA damage and impaired cellular recovery after irradiation.
“Across the included studies, these effects were observed in a wide range of nanoplatforms and experimental models and were frequently accompanied by markers of persistent DNA damage and impaired cellular recovery after irradiation [15,20,27,30,33,34].”
From Nanoparticle-Mediated Radiosensitization in Breast Cancer: A Systematic Review of Preclinical Evidence and Translational Challenges (2026) · cites this paper as [30]
The Results (page unavailable) report increased γH2AX one hour after irradiation and reduced clonogenic growth in breast-cell lines treated with silver nanoparticles. These findings support DNA damage and impaired colony-forming survival, but a one-hour measurement does not establish persistent DNA damage. This paper tests silver nanoparticles in breast-cell models; it does not itself establish the sentence’s breadth across nanoplatforms or the frequency of these findings across studies. (LLM, conf=0.86)
Experimental — accuracy not yet measured
While ROS amplification and DNA damage remain the most consistently reported foundational processes, nanoplatforms combining physical dose enhancement with biologically active components such as hypoxia-targeting systems, catalytic redox modulators, or immune-related approaches demonstrate more robust and sustained antitumor effects across preclinical models.
“While ROS amplification and DNA damage remain the most consistently reported foundational processes [15,20,30,33,63], nanoplatforms combining physical dose enhancement with biologically active components, such as hypoxia-targeting systems, catalytic redox modulators, or immune-related approaches, demonstrate more robust and sustained antitumor effects across preclinical models [17,19,21,26,39,45,”
From Nanoparticle-Mediated Radiosensitization in Breast Cancer: A Systematic Review of Preclinical Evidence and Translational Challenges (2026) · cites this paper as [30]
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Experimental — accuracy not yet measuredAt the cellular level, enhanced secondary electron generation increases ROS production and radiation-induced DNA damage, particularly double-strand breaks, leading to reduced clonogenic survival and increased apoptosis.
“At the cellular level, enhanced secondary electron generation increases ROS production and radiation-induced DNA damage, particularly double-strand breaks, leading to reduced clonogenic survival and increased apoptosis [15,20,27,30,33].”
From Nanoparticle-Mediated Radiosensitization in Breast Cancer: A Systematic Review of Preclinical Evidence and Translational Challenges (2026) · cites this paper as [30]
The Results (page not provided) report increased γH2AX, a marker associated with DNA double-strand breaks, and reduced clonogenic growth after silver nanoparticles were combined with irradiation. The Discussion (page not provided) reports that other studies found increased ROS after silver-nanoparticle exposure. This paper does not establish that secondary electrons drive the ROS and DNA damage, or that the combined treatment increases apoptosis. (LLM, conf=0.88)
Experimental — accuracy not yet measuredRadiation parameters were inconsistently reported, with considerable variability in total dose, fractionation schedules, beam energy, dose rate, and irradiation modality.
“Radiation parameters were inconsistently reported, with considerable variability in total dose, fractionation schedules, beam energy, dose rate, and irradiation modality [15,20,24,30,52,63,74], while detailed dosimetric characterization was frequently lacking, reducing reproducibility and limiting radiobiological interpretation.”
From Nanoparticle-Mediated Radiosensitization in Breast Cancer: A Systematic Review of Preclinical Evidence and Translational Challenges (2026) · cites this paper as [30]
The Materials and methods passages on in vitro irradiation and the in vivo tumor study specify doses, X-ray source, beam voltage, and dose rate; the in vivo passage also describes when treatment was repeated. This paper supplies an example of radiation parameters, but it does not establish that reporting was inconsistent or that these parameters varied considerably across studies. (LLM, conf=0.85)
Experimental — accuracy not yet measuredDetailed dosimetric characterization was frequently lacking, reducing reproducibility and limiting radiobiological interpretation.
“Radiation parameters were inconsistently reported, with considerable variability in total dose, fractionation schedules, beam energy, dose rate, and irradiation modality [15,20,24,30,52,63,74], while detailed dosimetric characterization was frequently lacking, reducing reproducibility and limiting radiobiological interpretation.”
From Nanoparticle-Mediated Radiosensitization in Breast Cancer: A Systematic Review of Preclinical Evidence and Translational Challenges (2026) · cites this paper as [30]
The Materials and methods sections on in vitro irradiation and in vivo tumor regression report dose, X-ray voltage, current, and dose rate; the in vivo study assumes a flat tumor dose distribution rather than documenting a measured one (page unavailable). This provides an example of limited dosimetric characterization, but the paper does not establish that such characterization was frequently lacking across studies or that this reduced reproducibility and radiobiological interpretation. (LLM, conf=0.74)
Experimental — accuracy not yet measuredClonogenic survival assays demonstrated reduced survival fractions in nanoparticle-treated cells compared to radiotherapy alone.
“Clonogenic survival assays demonstrated reduced survival fractions in nanoparticle-treated cells compared to radiotherapy alone [20,30,33,79].”
From Nanoparticle-Mediated Radiosensitization in Breast Cancer: A Systematic Review of Preclinical Evidence and Translational Challenges (2026) · cites this paper as [30]
Gold-based nanoparticles were the most frequently investigated class, followed by silver-, platinum-, bismuth-, and gadolinium-based platforms.
“Gold-based nanoparticles were the most frequently investigated class [20,24,27,28,29], followed by silver-, platinum-, bismuth-, and gadolinium-based platforms [15,30,31,32,33,34,35,36].”
From Nanoparticle-Mediated Radiosensitization in Breast Cancer: A Systematic Review of Preclinical Evidence and Translational Challenges (2026) · cites this paper as [30]
Most studies employed both in vitro and in vivo approaches, whereas a smaller subset relied exclusively on a single model type.
“From an experimental standpoint, most studies employed both in vitro and in vivo approaches [17,20,27,39,54], whereas a smaller subset relied exclusively on a single model type [30,57,58].”
From Nanoparticle-Mediated Radiosensitization in Breast Cancer: A Systematic Review of Preclinical Evidence and Translational Challenges (2026) · cites this paper as [30]
The earliest and most extensively investigated approach is conventional radiotherapy enhancement based on high-atomic-number nanomaterials, including gold, silver, platinum, bismuth, gadolinium, and hafnium-containing nanoparticles.
“The earliest and most extensively investigated approach is conventional radiotherapy enhancement based on high-atomic-number (high-Z) nanomaterials, including gold, silver, platinum, bismuth, gadolinium, and hafnium-containing nanoparticles [15,20,27,28,30,33,34,36,50,63].”
From Nanoparticle-Mediated Radiosensitization in Breast Cancer: A Systematic Review of Preclinical Evidence and Translational Challenges (2026) · cites this paper as [30]
Apoptosis was the most commonly described form of cell death.
“Apoptosis was the most commonly described form of cell death [20,27,30,33].”
From Nanoparticle-Mediated Radiosensitization in Breast Cancer: A Systematic Review of Preclinical Evidence and Translational Challenges (2026) · cites this paper as [30]
The Results section on thiol oxidation reports cell death after silver-nanoparticle exposure, and the supplementary cell-death assay describes how dead cells were identified; neither identifies apoptosis as the form of death. Searches for apoptosis and other cell-death mechanisms found no passage assessing which form was most commonly described. Page numbers were not available in our copy. (LLM, conf=0.76)
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Self-citation
- Authors
- Singh, R., Swanner, J., Mims, J., Akman, S., Furdui, C., Torti, S., & Carroll, D.
- Affiliations
- Wake Forest University Health Sciences (US)
- Roper St. Francis Healthcare (US)
- UConn Health (US)
- Wake Forest University (US)
- Corresponding author
- Singh, Ravi
- Venue
- International Journal of Nanomedicine
- Publisher
- Informa UK Limited
- Published
- 2015-06
- Volume
- 10
- Pages
- 3937
- ISSN
- 1176-9114 (ISSN-L)
- 1178-2013
- PMC
- PMC4501353
- OpenAlex
- W1742315769
- Cited by
- 130
- References
- 59
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 7 · 2023: 10 · 2022: 19 · 2021: 14 · 2020: 15 · 2019: 15 · 2018: 15 · 2017: 12 · 2016: 10 · 2015: 2
- FWCI
- 5.28
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- International Journal of Nanomedicine (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Dove Medical Press (Taylor and Francis Group) (submittedVersion, cc-by-nc)
- Funders
- Wake Forest University (P30 CA012197, NCI CCSG P30CA012197)
- National Institutes of Health (5t32ca079448-15, NCI CCSG P30CA012197, CCSG P30CA012197)
- Wake Forest School of Medicine (P30CA012197)
- National Heart, Lung, and Blood Institute (T32HL091797)
- National Cancer Institute (T32-CA079448, R33 CA1777461, R00CA154006, K99CA154006, NCI CCSG P30CA012197, CCSG P30CA012197, R33CA177461, P30CA012197)
- National Institute of General Medical Sciences (T32GM095440)
- National Institute of Environmental Health Sciences (R21ES025645)
- Topics
- Physical Sciences › Materials Science › Materials Chemistry › Nanoparticles: synthesis and applications
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Radiation Therapy and Dosimetry
- Physical Sciences › Materials Science › Electronic, Optical and Magnetic Materials › Gold and Silver Nanoparticles Synthesis and Applications
- Keywords
- silver nanoparticles, triple-negative breast cancer, radiosensitization, selective cytotoxicity, oxidative stress, DNA damage, radiation enhancement, nanoparticle toxicity, therapeutic window, breast cancer cell lines
- MeSH terms
- Antineoplastic Agents, Breast Neoplasms, Cell Survival, Female, Humans, Radiation-Sensitizing Agents, Silver, Cell Line, Tumor, Metal Nanoparticles, Triple Negative Breast Neoplasms
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