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Cited by 7Radiation Therapy and DosimetryEffects of Radiation ExposureAdvanced Radiotherapy Techniques

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Advancing cancer radiotherapy: Harnessing radiosensitizers and nanotechnology for enhanced tumor control

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Shiridokht, Fatemeh, Kehtari, Parniya, Eskandani, Morteza, Farajollahi, Alireza, Vandghanooni, Somayeh·2025·International Journal of Pharmaceutics: X
DOI 10.1016/j.ijpx.2025.100419PMC PMC12581699
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Abstract

Cancer affects millions of individuals annually, with radiotherapy playing a crucial role in the treatment of over 70% of cases. Nevertheless, the effectiveness of radiotherapy is frequently limited by tumor radioresistance and the associated toxicity to normal tissues. Radiosensitizers enhance tumor sensitivity to ionizing radiation, optimizing doses and reducing damage. This review evaluates diverse radiosensitizers, including natural compounds (curcumin, resveratrol), chemotherapeutics (cisplatin, doxorubicin), and high-Z nanoparticles (gold, hafnium), which amplify DNA damage and ROS production. Advanced nanocarriers-carbon-, lipid-, and polymer-based-improve targeted delivery, specificity, and bioavailability. Various molecular mechanisms involving proteins such as p53, PARP1, miRNAs (miR-21, miR-155), and siRNAs are discussed in relation to their roles in modulating cell cycle progression, apoptosis, and gene expression to overcome resistance. Radioprotectors like antioxidants and amifostine safeguard normal tissues. Ongoing trials with hafnium oxide and cisplatin regimens show promise. Key findings highlight nanotechnology's role in enhancing radiosensitization via dose enhancement factors and synergistic therapies. Implications include personalized treatments tailored to tumor biology, the reduction of radioresistance through precision medicine and data-driven strategies, and ultimately, the improvement of radiotherapy efficacy and patient outcomes.

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Graphical abstract
Graphical abstract CC BY-NC · PubMed Central
Fig. 1 A schematic illustrating the mechanism of ionizing radiation (IR) in radiotherapy. The direct effect involves IR-induced DNA damage, which, if unrepaired, leads to cell death or permanent growth inhibition. Indirect effects involve ROS production through water and oxygen radiolysis, leading to DNA damage. Types of damage include base substitutions, single-strand breaks, double-strand breaks, and protein–DNA or DNA–DNA cross-links. Adapted from (Gong et al., 2018b). Licensed under CC BY 4.0.
Fig. 1 A schematic illustrating the mechanism of ionizing radiation (IR) in radiotherapy. The direct effect involves IR-induced DNA damage, which, if unrepaired, leads to cell death or permanent growth inhibition. Indirect effects involve ROS production through water and oxygen radiolysis, leading to DNA damage. Types of damage include base substitutions, single-strand breaks, double-strand breaks, and protein–DNA or DNA–DNA cross-links. Adapted from (Gong et al., 2018b). Licensed under CC BY 4.0.CC BY-NC · PubMed Central
Fig. 2 Schematic illustration of the preparation of MTiO2(SN-38)-TATRGD NPs and its application for enhanced radiotherapy. Adopted with permission from (Pan et al., 2019).
Fig. 2 Schematic illustration of the preparation of MTiO2(SN-38)-TATRGD NPs and its application for enhanced radiotherapy. Adopted with permission from (Pan et al., 2019).CC BY-NC · PubMed Central
Fig. 3 The preparation and anti-glioblastoma mechanism of the Dbait and DOX co-loaded micellar system. (A) The preparation of ch-K5(s-s)8-An/ (Dbait-DOX) micelles. (B) The application of ch-K5(s-s)8-An/(Dbait-DOX) for chemo-radiotherapy in orthotopic glioblastoma-bearing nude mice. (C) The synergistic mechanism of ch-K5(s-s)8-An/(Dbait-DOX) as chemo-radiosensitizer. Adopted from (Zhang et al., 2022). Licensed under CC BY 4.0.
Fig. 3 The preparation and anti-glioblastoma mechanism of the Dbait and DOX co-loaded micellar system. (A) The preparation of ch-K5(s-s)8-An/ (Dbait-DOX) micelles. (B) The application of ch-K5(s-s)8-An/(Dbait-DOX) for chemo-radiotherapy in orthotopic glioblastoma-bearing nude mice. (C) The synergistic mechanism of ch-K5(s-s)8-An/(Dbait-DOX) as chemo-radiosensitizer. Adopted from (Zhang et al., 2022). Licensed under CC BY 4.0.CC BY-NC · PubMed Central
Fig. 4 The effect of bromelain and different treatments on tumor tissues. (A) In the EST sections, tumor tissue showed rapid cell proliferation, extensive necrosis, and loss of normal architecture. Bromelain significantly decreased cellular density and necrotic areas while partially restoring muscle fibers. Irradiation reduced tumor growth and necrosis but was less effective than BL. The BL + IRR treatment yielded the most pronounced effects, markedly inhibiting tumor progression, reducing necrosis, and promoting tissue regeneration. (B) Quantitative evaluation of tumor volumes revealed that the EST exhibited the highest tumor burden. The Irradiation group (EST + IRR) demonstrated a moderate reduction in tumor size. Treatment EST + BL resulted in a marked decrease in tumor volume compared to the control. Notably, the EST + BL + IRR group showed the most pronounced tumor regression. (C) Administration of gamma-irradiation and/or bromelain led to a noticeable reduction in tumor area relative to total tissue area in mice bearing Ehrlich solid tumors. The combination treatment resulted in the greatest decrease, showing statistically significant differences compared to both the untreated and irradiation-only groups (P < 0.05). EST (Ehrlich solid tumor); EST + IRR (Ehrlich solid tumor + irradiation); EST + BL (Ehrlich solid tumor + bromelain); EST + BL + IRR(Ehrlich solid tumor + bromelain + irradiation). Adopted from (Mekkawy et al., 2020). Licensed under CC BY 4.0.
Fig. 4 The effect of bromelain and different treatments on tumor tissues. (A) In the EST sections, tumor tissue showed rapid cell proliferation, extensive necrosis, and loss of normal architecture. Bromelain significantly decreased cellular density and necrotic areas while partially restoring muscle fibers. Irradiation reduced tumor growth and necrosis but was less effective than BL. The BL + IRR treatment yielded the most pronounced effects, markedly inhibiting tumor progression, reducing necrosis, and promoting tissue regeneration. (B) Quantitative evaluation of tumor volumes revealed that the EST exhibited the highest tumor burden. The Irradiation group (EST + IRR) demonstrated a moderate reduction in tumor size. Treatment EST + BL resulted in a marked decrease in tumor volume compared to the control. Notably, the EST + BL + IRR group showed the most pronounced tumor regression. (C) Administration of gamma-irradiation and/or bromelain led to a noticeable reduction in tumor area relative to total tissue area in mice bearing Ehrlich solid tumors. The combination treatment resulted in the greatest decrease, showing statistically significant differences compared to both the untreated and irradiation-only groups (P < 0.05). EST (Ehrlich solid tumor); EST + IRR (Ehrlich solid tumor + irradiation); EST + BL (Ehrlich solid tumor + bromelain); EST + BL + IRR(Ehrlich solid tumor + bromelain + irradiation). Adopted from (Mekkawy et al., 2020). Licensed under CC BY 4.0.CC BY-NC · PubMed Central
Fig. 5 The figure illustrates both passive and active targeting strategies of nanoparticles (NPs) aimed at enhancing the therapeutic efficacy of anticancer drugs. Adopted from (Tarighi et al., 2025). Licensed under CC BY 4.0. (A) In passive targeting, NPs leverage the EPR effect, while active targeting relies on ligand conjugation to enhance cellular uptake through receptor-mediated endocytosis.
Fig. 5 The figure illustrates both passive and active targeting strategies of nanoparticles (NPs) aimed at enhancing the therapeutic efficacy of anticancer drugs. Adopted from (Tarighi et al., 2025). Licensed under CC BY 4.0. (A) In passive targeting, NPs leverage the EPR effect, while active targeting relies on ligand conjugation to enhance cellular uptake through receptor-mediated endocytosis.CC BY-NC · PubMed Central
Fig. 6 Panels A to C illustrate the delivery process of radiosensitizer nanoparticles carrying antibodies into the brain for targeted glioblastoma therapy. (A) Schematic representation of nanoparticle translocation across the blood–brain barrier (BBB) post-radiation, enhancing permeability and promoting accumulation at the tumor site. (B) In vivo fluorescence imaging of the mouse brain demonstrates selective distribution of nanoparticles within the tumor tissue following systemic administration. (C) Microscopic images of brain sections show effective nanoparticle penetration into glioblastoma cells and their interaction with the tumor microenvironment. Adopted from (Gal et al., 2022). Licensed under CC BY 4.0.
Fig. 6 Panels A to C illustrate the delivery process of radiosensitizer nanoparticles carrying antibodies into the brain for targeted glioblastoma therapy. (A) Schematic representation of nanoparticle translocation across the blood–brain barrier (BBB) post-radiation, enhancing permeability and promoting accumulation at the tumor site. (B) In vivo fluorescence imaging of the mouse brain demonstrates selective distribution of nanoparticles within the tumor tissue following systemic administration. (C) Microscopic images of brain sections show effective nanoparticle penetration into glioblastoma cells and their interaction with the tumor microenvironment. Adopted from (Gal et al., 2022). Licensed under CC BY 4.0.CC BY-NC · PubMed Central
Fig. 7 Multifaceted role of AGuIX nanoparticles as radiosensitizers from cellular to in vivo tumor models, highlighting enhanced DNA damage, targeted accumulation, and improved therapeutic efficacy in combination with radiotherapy. (A) AGuIX enhances the radiosensitivity of tumor cells, leading to increased DNA damage (γ-H2AX foci formation) and reduced clonogenic survival after irradiation. (B) In a mouse glioblastoma model, the combination of AGuIX with radiotherapy significantly improved animal survival, reduced off-target damage, and enhanced tumor tissue destruction, as evidenced by histological analysis. (C) Cellular uptake revealed that AGuIX efficiently internalizes and localizes within intracellular compartments such as lysosomes, indicating an endocytic pathway. (D) Upon systemic injection, AGuIX nanoparticles selectively accumulate in brain tumor tissues, with peak concentration observed around 3.5 hours post-injection. Adopted from (Kotb et al., 2016). Licensed under CC BY 4.0.
Fig. 7 Multifaceted role of AGuIX nanoparticles as radiosensitizers from cellular to in vivo tumor models, highlighting enhanced DNA damage, targeted accumulation, and improved therapeutic efficacy in combination with radiotherapy. (A) AGuIX enhances the radiosensitivity of tumor cells, leading to increased DNA damage (γ-H2AX foci formation) and reduced clonogenic survival after irradiation. (B) In a mouse glioblastoma model, the combination of AGuIX with radiotherapy significantly improved animal survival, reduced off-target damage, and enhanced tumor tissue destruction, as evidenced by histological analysis. (C) Cellular uptake revealed that AGuIX efficiently internalizes and localizes within intracellular compartments such as lysosomes, indicating an endocytic pathway. (D) Upon systemic injection, AGuIX nanoparticles selectively accumulate in brain tumor tissues, with peak concentration observed around 3.5 hours post-injection. Adopted from (Kotb et al., 2016). Licensed under CC BY 4.0.CC BY-NC · PubMed Central
Fig. 8 Synergistic effects of BKM120 and radiation on tumor growth inhibition and apoptosis induction via suppression of the PI3K/Akt/mTOR pathway. (A) Tumor growth curves in xenograft mouse models indicate that the combination of BKM120 and radiotherapy (RT) markedly decreases tumor volume in comparison to each treatment administered independently. (B) Immunohistochemical and Western blot analyses show that combined treatment suppresses phosphorylation of Akt and mTOR while increasing caspase-3 activation and TUNEL-positive cells, indicating effective inhibition of survival signaling and promotion of apoptosis. Adopted from (Liu et al., 2014). Licensed under CC BY 4.0.
Fig. 8 Synergistic effects of BKM120 and radiation on tumor growth inhibition and apoptosis induction via suppression of the PI3K/Akt/mTOR pathway. (A) Tumor growth curves in xenograft mouse models indicate that the combination of BKM120 and radiotherapy (RT) markedly decreases tumor volume in comparison to each treatment administered independently. (B) Immunohistochemical and Western blot analyses show that combined treatment suppresses phosphorylation of Akt and mTOR while increasing caspase-3 activation and TUNEL-positive cells, indicating effective inhibition of survival signaling and promotion of apoptosis. Adopted from (Liu et al., 2014). Licensed under CC BY 4.0.CC BY-NC · PubMed Central

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Citations

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Metadata

Authors
Shiridokht, F., Kehtari, P., Eskandani, M., Farajollahi, A., & Vandghanooni, S.
Affiliations
Tabriz University of Medical Sciences (IR)
Corresponding author
Vandghanooni, Somayeh
ORCID
Venue
International Journal of Pharmaceutics: X
Publisher
Elsevier BV
Published
2025-12
Volume
10
Pages
100419
ISSN
2590-1567 (ISSN-L)
DOI
10.1016/j.ijpx.2025.100419
PMC
PMC12581699
OpenAlex
W4415958691
Cited by
4
References
215
Citations by year
2026: 4
FWCI
0.70
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Pharmaceutics X (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
Tabriz University of Medical Sciences
Topics
  • Physical Sciences › Physics and Astronomy › Radiation › Radiation Therapy and Dosimetry
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
  • Physical Sciences › Physics and Astronomy › Radiation › Advanced Radiotherapy Techniques
Keywords
cancer radiotherapy, radiosensitizers, tumor radioresistance, nanocarriers, high-Z nanoparticles, gold nanoparticles, hafnium oxide nanoparticles, cisplatin, curcumin, resveratrol, reactive oxygen species, DNA damage, p53, PARP1, microRNA, siRNA, radiosensitization, radiotherapy toxicity, antioxidants, amifostine, targeted drug delivery, precision medicine

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