Requirements for Designing an Effective Metallic Nanoparticle (NP)-Boosted Radiation Therapy (RT)
Abstract
:Simple Summary
Abstract
1. Introduction
1.1. Most Promising Metallic NPs Proposed for RT
1.1.1. Gold (Au, Z = 79)
1.1.2. Platinum (Pt, Z = 78)
1.1.3. Hafnium (Hf, Z = 72)
1.1.4. Gadolinium (Gd, Z = 64)
1.1.5. Silver (Ag, Z = 47)
1.1.6. Iron (Fe, Z = 26)
2. Effects of Size, Shapes, and Surface Treatments
3. Biological/Biochemical Effects
3.1. Nanotoxicity
3.2. Cell Uptake and Localization
3.3. Oxidative Stress
3.4. Effect on Cell Cycle
3.5. Effect on DNA Damage
3.6. Effect on Apoptosis, Autophagy and Senescence
4. Exp. Procedures to Study the Biological Effects of NPs’ Radiosensitization
- Transmission electron microscopy (TEM): TEM can be used to monitor the cellular uptake of NPs and it can be used to detect DNA damage after IR in the presence and absence of NPs. Sample preparations for TEM analysis consists of several stages. After IR, the basic steps for cell or tissue preparation are the following: fixation in aldehyde buffer solution, embedding in gelatin, post fixation in osmium tetroxide, dehydration in ethanol, and embedding in resin (epoxy or acrylic). The choice of fixative and resin depends on the aim of the study (ultrastructural or Immunocyto-histochemical). The chemicals used for these stages such as the aldehyde solution for fixation are adequate to simultaneously preserve the ultrastructure morphology of cell organelles and the antigenicity. However, all chemical preparation stages, if not applied correctly, may lead to image artifacts. For a more detailed information, the reader can resort to a recent technical note about all the technicalities regarding TEM [162]. There exist several other techniques to study DNA damage, e.g., Immunocytochemistry and Gel Electrophoresis, which are considerably more timesaving, require fewer demanding skills and protocols, and are less expensive. However, for detection of type and location of the DNA damage, TEM is unique since the details of the damage cannot be detected in such magnification and resolution (nm scale) with any other method. One disadvantage with TEM is the difficulty in quantifying the damage. Usually, only 10–50 cells are analyzed each time, so the method provides better quality than other methods but cannot accurately quantify the results. However, the use of TEM was performed for the detection of both single and double staining to detect clustered DNA damage and especially DSBs after IR [163,164]. TEM uses normally the immunogold-labelling technique to characterize the DNA damage. Primary antibodies target specific repair proteins are localized by secondary Au-conjugated antibodies, similar to immunocytochemistry methodology. TEM was not used to study DNA damage induced NP radiosensitization until now, but it was used to monitor cellular uptake and distribution of NPs [77,105,165]. Moreover, recently, the technical use of TEM was thoroughly described as a means of studying NP-induced radiosensitization in vitro [162].
- Flow cytometry (FC): Flow cytometry can be used for DNA damage detection and cell cycle analysis. Propidium iodide is the most commonly used dye to quantitatively assess DNA content, and it is a very useful technique to study different checkpoints throughout the cell cycle [119]. Though flow cytometry is broadly used in radiation experiments, cell cycle analysis related to DNA damage-induced NPs radiosensitization was not performed until now. For instance, G2/M checkpoint prevents cells with damaged DNA from entering Mitosis. Phosphorylation at Ser10 of histone H3 is tightly correlated with chromosome condensation during mitosis [166]. An antibody that specifically recognizes the phosphorylated form of histone H3 (p-histone H3 Ser10) is used to identify mitotic cells. Cells are co-stained with anti-p-histone H3 Ser 10 antibody and propidium iodine to distinguish mitotic cells from G2 cells [167]. Milner et al., used flow cytometry on CHO cells to access DNA damage after irradiation with 60Co γ-source [168]. Nucleotides were extracted from cells, then they were stained with the fluorescent dye ethidium bromide and then exposed to laser light within FC. Flow cytometry can be also used to monitor NP uptake. For example, Shapero et al. [169] used flow cytometry to investigate cellular uptake and final localization of silica NPs of different sizes (50, 100, and 300 nm) inside A549 cells as a function of time. They showed that the uptake rate of silica NPs decreases with size; however, due to fluorescent intensity of NPs they suggested that results might be misleading if are not normalized.
- Immunofluorescence: Immunofluorescence uses primary antibodies, labelled with fluorescent secondary antibodies for visualization, specific to targeted DNA repair enzymes. The most common target for DNA damage detection, such as DSBs, is the phosphorylated histone γ-H2AX (phosphorylation at serine 139). Foci represent the DSBs in a 1:1 manner and are used as a DNA damage biomarker. Other DNA repair markers include RAD51, 53BP1 (p53-binding protein 1), phospho-p53, and PARP1 [170]. However, the specificity whether such DSB markers recognize only DSBs is a controversial issue. γH2AX also appears in SSB sites [171]. Beside repair enzymes, primary antibodies can be used to label the damage itself. In this case, the antibodies bind to specific DNA lesions such as 8-oxo-dG, which is used to detect base lesions [172]. Recently electrophoresis-based DNA fractionation methods were used to quantify DNA damage. Detection and quantification of γ-H2AX and 53BP1 is very often employed to assess metallic NP-induced radiosensitization [77,173].
- Agarose Gel Electrophoresis (AGE): DNA lesions can be identified through gel electrophoresis. This is a fast method that quantifies the average density of breaks and a variety of DNA lesions in nanogram quantities. AGE can be divided into two main groups: 1) Alkaline Gel Electrophoresis and 2) Glyoxal gel electrophoresis. Agarose gels can separate a mixture of molecules such as DNA fragments between 50 bp (3% agarose) and 500.000 bp (0.1% agarose) in an agarose matrix, with suitable electrophoresis buffers [174]. The gels are stained with ethidium bromide and the image acquisition of the DNA migration is performed with UV light. Alkaline agarose gels are mostly used for single stranded DNA but it is also used for others alkali-labile lesions as well such as 8-oxoguanine base lesions [175]. Glyoxal agarose gel electrophoresis fractionizes DNA the same way, but it also keeps alkali-labile sites intact.
- Pulsed-field gel electrophoresis (PFGE) and Comet Assay (CA): Methods such as the comet assay and pulsed-field gel electrophoresis (PFGE) [176,177] are based on the detection of DNA fragments by electrophoresis. In comet assay, the cells are embedded in agarose gel on a glass slide for microscopy and the DNA fragments are fractionated by electrophoresis. Because of the tail-like images, this method is called comet assay. In PFGE, cells are embedded in agarose gel, called plugs, and then the cells are lysed in these agarose plugs. Only the DNA fragments such as DSBs migrate in the gel, while the undamaged DNA remain. The CA does not need a large number of cells for the analysis, and it is not expensive, but it cannot distinguish the lengths of the DNA fragments. PFGE is there for better to be used for quantitative purposes. Gel electrophoresis was already used in several studies concerning metallic NP (especially AuNPs) radiosensitization [178,179].
- Clonogenic Survival Assay (CSA): One gold standard technique to access cell death and survival rate in radiobiology is CSA. After a stress induced situation, such as IR, survival assay determines the ability of cells to proliferate and form colonies after a few days’ incubation. Cells are seeded into petri dishes, treated with NPs, irradiated and then replated in low seeding densities and left to grow colonies for a few days (depending on the cell line). After these days, the colonies are stained with crystal violet in 80–100% methanol [180]. The individual colonies are counted and then a survival curve can be defined as a relationship between the radiation dose and the fraction of cells that were able to replicate and form colonies. Clonogenic assay is almost always used to compare cell radiosensitization in the presence and absence of metallic NPs [26,179,181].
- TUNEL Assay: TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) staining, also called the TUNEL Assay, detects the DNA breaks formed when DNA fragmentation occurs in the last phase of apoptosis [182]. TdT can label blunt ends of double-stranded DNA breaks as it attaches to deoxynucleotides to the 3′-hydroxyl terminus of DNA breaks. The nucleotides attached by TdT are stained with a fluorescent dye. Tunnel assay is an alternative assay to agarose gel electrophoreses to analyze the formation of DNA fragments during apoptosis. Teraoka et al., used this assay to access apoptotic cells by counting TUNEL-positive cells [156].
- Immunoblotting/Western blotting: Immunoblotting, or western blotting, is used to identify changes in protein expression following treatment. In this assay, protein expression is sampled at different time-points following X-ray irradiation to determine how pretreatment with NPs enhances the radiation sensitivity. This is performed both in the presence and absence of NPs [123]. This assay uses protein expression levels in different time points after radiation. Primary antibodies can be selected according to selected interest such as apoptosis, DNA damage and repair and oxidative stress.
- Immunocyto/histochemistry for Cellular Senescence detection: There is a number of senescence biomarkers. The most common markers are SA-β-Gal, senescence-associated secretory phenotype (SASP) [183], cell cycle inhibitors p16Ink4a and p21Cip1 [184], and lipofuscin [185]. Oxidative stress is one of the possible reasons leading to senescence. Irradiation alone can lead to increased senescent phenotype [186]. Since ROS production can be responsible for NP-induced radiosensitization, it is essential to also study whether or not irradiated cells incubated with NPs lead to increased senescence compared to the irradiated alone. Until now there are only few groups who address senescence [173,187].
5. Clinicals Trials
5.1. The Use of NPs in Radiotherapy
5.2. Limitations and Challenges in Using Nanoparticles in Clinic
6. Discussion
7. Conclusions
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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Name (Sponsor) | Particle Type/Drug | Application/Indication | Patients | Type of IR/Dose | ClinicalTrials.gov Identifier (Phase) | Status |
---|---|---|---|---|---|---|
AGuIX (University Hospital, Grenoble) | Gadolinium-based nanoparticles | Target tissue: Multiple brain metastases Application: Sequentially rising dose levels of AGuIX NPs were injected in combination with whole brain radiation therapy (Ph I). Based on adapted dose, AGuIX NPs are injected in combination with whole brain radiation therapy (Ph II). | 15 100 | X-rays/30Gy (3Gy/session) | NCT02820454 (Ph I) [68] NCT03818386 (Ph II) | Completed recruiting |
AGuIX (University Hospital, Grenoble) | Gadolinium-based nanoparticles | Target tissue: Pancreatic and lung cancer Application: AGuIX NPs are injected in combination with MR-guided stereotactic body radiation therapy (SBRT) | 100 | X-rays/- | NCT04789486 (Ph I/II) | recruiting |
AGulX (Centre Francois Baclesse) | Polysiloxane and Gadolinium-based nanoparticles | Target tissue: Relapsing tumors of the cephalo-spino-iliosacral axis particularly base of the skull, pharyngeal wall, parapharyngeal, and retropharyngeal lymph nodes, etc. Application: AGuIX NPs are injected in combination with photon therapy | 46 | Photon therapy/- | NCT04784221 (Ph II) | Not yet recruiting |
NBTXR3 PEP503 (Nanobiotix) | Hafnium oxide-based nanoparticles | Target tissue: locally advanced soft-tissue sarcoma of the Extremity and Trunk Wall Application: NPs were stimulated with external radiation to enhance tumor cell death via electron production | 180 | External beam radiotherapy/ 50Gy(2Gy/fraction) | NCT02379845 (Ph II/III) [66] | completed |
NBTXR3 PEP503 (Nanobiotix) | Hafnium oxide-based nanoparticles | Target tissue: locally advanced squamous cell carcinoma of the oral Application: NPs are stimulated with external radiation to enhance tumor cell death via electron production | 48 | Intensity-Modulated Radiation Therapy /70Gy (2Gy/fraction) | NCT01946867 (Ph I) | recruiting |
NBTXR3 PEP503 (Nanobiotix) | Hafnium oxide- based nanoparticles/PD-I inhibitor | Target tissue: advanced cancer types Application: NPs are stimulated with external radiation to enhance tumor cell death via electron production in combination with immunotherapy | 60 | Radiotherapy/- | NCT03589339 (Ph I) | recruiting |
NBTXR3 PEP503 (Nanobiotix) | Hafnium oxide-based nanoparticles | Target tissue: liver cancers Application: NPs are stimulated with external radiation to enhance tumor cell death via electron production NCT02721056 | 23 (initial nu. 200) | Stereotactic Body Radiation Therapy/45Gy (15Gy/fraction) or 50Gy (5Gy/fraction) | NCT02721056 (Ph I), Ph II will be designed independently | terminated |
NBTXR3 PEP503 (Nanobiotix) | Hafnium oxide-based nanoparticles | Target tissue: Prostate Adenocarcinoma Application: NPs are stimulated with external radiation with and without brachytherapy to enhance tumor cell death via electron production. | 5(initial nu. 96) | External Beam Radiation Therapy/45Gy (1.8Gy/ fraction) or Brachytherapy Boost/15Gy + EBRT 45Gy (1.8/fraction) | NCT02805894 (PhI/II) | terminated |
SPION | Iron oxide Nanoparticles/ ferumoxytol | Target tissue: Primary and metastatic hepatic cancers Application: MR-Linac imaging with SPION in combination with radiotherapy to increase detection and efficacy. | 25 | Stereotactic Body Radiotherapy (LINAC)/- | NCT04682847 | recruiting |
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Tremi, I.; Spyratou, E.; Souli, M.; Efstathopoulos, E.P.; Makropoulou, M.; Georgakilas, A.G.; Sihver, L. Requirements for Designing an Effective Metallic Nanoparticle (NP)-Boosted Radiation Therapy (RT). Cancers 2021, 13, 3185. https://doi.org/10.3390/cancers13133185
Tremi I, Spyratou E, Souli M, Efstathopoulos EP, Makropoulou M, Georgakilas AG, Sihver L. Requirements for Designing an Effective Metallic Nanoparticle (NP)-Boosted Radiation Therapy (RT). Cancers. 2021; 13(13):3185. https://doi.org/10.3390/cancers13133185
Chicago/Turabian StyleTremi, Ioanna, Ellas Spyratou, Maria Souli, Efstathios P. Efstathopoulos, Mersini Makropoulou, Alexandros G. Georgakilas, and Lembit Sihver. 2021. "Requirements for Designing an Effective Metallic Nanoparticle (NP)-Boosted Radiation Therapy (RT)" Cancers 13, no. 13: 3185. https://doi.org/10.3390/cancers13133185