WO2013081218A2 - Radiothérapie induite par particules à base de pic de bragg - Google Patents

Radiothérapie induite par particules à base de pic de bragg Download PDF

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WO2013081218A2
WO2013081218A2 PCT/KR2011/009283 KR2011009283W WO2013081218A2 WO 2013081218 A2 WO2013081218 A2 WO 2013081218A2 KR 2011009283 W KR2011009283 W KR 2011009283W WO 2013081218 A2 WO2013081218 A2 WO 2013081218A2
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particle
tumor
dose
radiation
proton
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PCT/KR2011/009283
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Korean (ko)
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김종기
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Kim Jong Ki
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
    • A61N2005/1085—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy characterised by the type of particles applied to the patient
    • A61N2005/1087—Ions; Protons

Definitions

  • the present invention relates to Bragg peak-based particle-guided radiation therapy, which utilizes metal nanoparticles (MMP) to produce particle induced radiation generated from direct coulomb collisions of outer electrons and protons or heavy ion beams of metal nanoparticles.
  • MMP metal nanoparticles
  • Particle-guided radiation therapy characterized in that the treatment of tumors and inflammatory diseases using the PIR) effect.
  • Proton or heavy ion therapy is a method of necrosis of a lesion at a specific position by using a Bragg peak (Pragg-Peak) phenomenon that when the proton or heavy ion beam is incident on the human body to emit energy only at a specific depth depending on the energy intensity of the beam.
  • a Bragg peak Pragg-Peak
  • protons or heavy ions are safer and more effective because they can concentrate energy that kills cells in the target lesion tissue and cause less damage to surrounding healthy tissue.
  • the Spread Out Bragg Peak (SOBP) method which is a combination of several single Bragg peaks, accumulates the proton beam dose evenly on the tumor site.
  • SOBP Spread Out Bragg Peak
  • the entrance part to which the beam is incident is exposed to a dose close to 50% or more of the Bragg peak dose depending on the tumor size, and thus, the advantage of the entrance dose is lost compared to the existing X-ray radiotherapy. Therefore, it is necessary to use a fractionation method in which beam doses are distributed through scanning in various directions or doses are divided by time intervals.
  • Non-Patent Document 1 Pradhan AK, Nahar SN, Montenegro M., Yu Y., Zhang HL, Sur C., Mrozik M. and Pitzer RM Resonant X-ray Enhancement of the Auger Effect in High- Z Atoms, Molecules, and Nanoparticles: Potential Biomedical Applications. J. Phys. Chem. A 113 , pp. 12356-2363 (2009).
  • Non-Patent Document 2 Use of gold nanoparticles to improve Heinfeld JF, Statkin DN and Smilowtz HM radiotherapy. Phys Med Biol 49 , pp. 309-315 (2004).
  • the present invention activates MNP through multiple coulomb collisions by transmitting or absorbing a single or spread out Braggpeak proton beam in a tumor in which MNP is selectively accumulated to generate PIR doses only at the tumor site.
  • Particle Induced Radiation such as Auger Electron Beam, Ionization Electron, Particle Induced X-ray (PIXE), Gamma Ray, etc. is a BP-based particle-induced radiotherapy that greatly increases the treatment dose and preserves surrounding normal tissue. The purpose is to provide.
  • the present invention uses the metal nanoparticles (MMP) to generate a PIR generated from direct coulomb collision of the outer electrons and proton beams of the metal nanoparticles to treat tumors, and thus, spread-out bragg peak (SOBP) and TPBP ( Transmitting-pristine-Bragg-peak) We provide radiation therapy using proton beam and coulomb nano-radiator effect.
  • MMP metal nanoparticles
  • MMPs metal nanoparticles
  • the metal nanoparticles are activated by high energy proton beams, induced by inner shell ionization and subsequent de-excitation processes, which result in local X-ray, ⁇ -ray, optoelectronic and Auger electrons.
  • MMP metal nanoparticles
  • PIXE particle-induced X-ray radiation
  • thermal energy by various physical activation methods such as X-rays, ion beams, RF magnetic fields, and NIR light.
  • the absorbed and transmissive Braggpeak proton beam and Coulomb nano-radiator effect are characterized in that the proton beam energy is 40-250 MeV, and Bragg-peak is placed or completely transmitted 14 mm-28 cm from the point of incidence. To provide a radiation therapy using.
  • the TPBP-based particle-induced radiotherapy of the present invention activates nanometal particles in tumor tissues at a plateau dose of a single Braggpeak proton beam exposed to normal tissues, thereby generating PIR doses locally.
  • the therapeutic effect is induced only in the distribution area. Therefore, in the case of invasive tumors in which tumor cells are infiltrated into normal tissues and metastasis cancers spreading in organs, only metal tumor particles accumulate in tumor cells and induce selective necrosis by PIR induced by TPBP-proton beam.
  • SOBP-based particle-guided radiotherapy of the present invention combines the SOBP dose evenly distributed in the tumor tissue and the particle-induced radiation induced by the activation of the nano-metal particles in the tumor tissue to generate a therapeutic effect, so that the previous proton or There is an advantage in greatly reducing the number of fractional treatment while significantly increasing the heavy ion treatment effect.
  • FIG. 1A shows the radiation of the TPBP proton beam of the present invention.
  • 1B illustrates one embodiment of a proton beam and a Bragg peak of the present invention.
  • Figure 2 shows the radiation of the SOBP proton beam of the present invention.
  • FIG. 3 shows a dose-tissue depth curve of a 40 MeV proton beam.
  • 4A depicts the therapeutic effect of TPBP-PIRT analyzed by tumor volume reduction analysis.
  • 4B depicts the therapeutic effect of SOBP-PIRT analyzed by tumor volume reduction analysis.
  • Figure 6 illustrates the effect of tumor treatment on a group of mice receiving several proton beam incident doses for a given MNP dose.
  • MMPs Metal nanoparticles
  • PIR particle induced radiation effects
  • the use of this phenomenon in radiation therapy for the treatment of tumors regulates the Bragg peaks to be evenly distributed in the tissue where the solid cancer is located in solid cancers, and in protons or in the case of metastatic cancers locally invasive to invasive tumors or surrounding organs.
  • the energy of the heavy ion beam is increased so that the Bragg peak penetrates the whole human body including the tumor tissue and lies outside the human body, thereby inducing particle-induced radiation from the nanometal, thereby increasing the therapeutic dose in each tumor tissue. .
  • Bragg-peak (BP) -based particle guided radiation therapy (PIRT) of the present invention uses metal nanoparticles (MMP) to overcome the PIR effects resulting from direct coulomb collisions of outer electrons and proton or heavy ion beams of metal nanoparticles.
  • MMP metal nanoparticles
  • Tumor treatment is characterized by using the generated ion beam and the Coulomb nano-radiator effect.
  • the coulomb nanoradiator effect is that when the metal element is in the form of nanoparticles, in the case of 13-14 nm, hundreds or thousands of gold or iron elements are clustered to form atomic-molecular clusters, and the incident energy of a high energy ion beam (proton or heavy ion)
  • the release of electrons induced through coulomb collisions and the emission of continuous Auger electrons and specific electron orbital X-rays amplify particle induced radiation caused by successive reactivation of neighboring atoms.
  • MMPs metal nanoparticles
  • the metal nanoparticles are activated with high energy proton beams, resulting in local X-rays, ⁇ -rays, optoelectronics and Auger by particle induced atomic shell ionization and subsequent de-excitation processes. Characterized in that to generate the electrons.
  • the metal nanoparticles may be generated by a variety of physical activation methods, such as X-rays, ion beams, RF magnetic fields and NIR light, to generate Auger electrons, particle-induced X-ray radiation (PIXE) or thermal energy, Proton beam energy of 40 MeV or more, Bragg-peak (Bragg-peak) can be placed at 14mm-30cm in the case of SOBP from the entry point of the human skin or completely penetrate the human tissue in the TPBP beam.
  • physical activation methods such as X-rays, ion beams, RF magnetic fields and NIR light, to generate Auger electrons, particle-induced X-ray radiation (PIXE) or thermal energy, Proton beam energy of 40 MeV or more, Bragg-peak (Bragg-peak) can be placed at 14mm-30cm in the case of SOBP from the entry point of the human skin or completely penetrate the human tissue in the TPBP beam.
  • the Bragg peak is a spread-out Bragg peak (SOBP) for solid cancer having a large size according to the shape of the tumor and the location of the tumor, and for a relatively small solid cancer (less than 2 cm).
  • SOBP spread-out Bragg peak
  • APBP invasive tumors spreading in normal tissues
  • TPBP transmissive single BP
  • PIR particle-induced radiation
  • the proton or medium particle beam energy is 40 MeV or more, the dose is 1 Gy or more at the Bragg-peak position, and the dose rate ranges from low dose rate (30 Gy / hr) and high dose rate (2000 Gy / hr). It is selected according to the characteristics of the treatment patient and characterized by inducing particle-induced radiation by entering a single dose or fractionation.
  • the metallic nanoparticles are metallic elements such as gold (Au), iron (Fe), indium (In), gadolinium (Gd), and platinum (Pt). Nanoparticles consisting of pure metal elements or oxides of 90 nm in size and between 1-100 nm in size, which react with proton beams or heavy ion particles to produce particle induced radiation (PIR). It is done.
  • the proton or medium particle beam is a method in which the beam intensity is modulated by dividing a single Bragg peak or a Spread-out Bragg peak (SOBP) into a single port or several directions.
  • SOBP Spread-out Bragg peak
  • PIR particle induced radiation
  • the metallic nanoparticles are metal nanoparticles to which specific tumor tissues are added with target or pharmacokinetic surface modification formulas and react with proton beams or heavy ion particles (PIR; particle induced radiation). It characterized in that to generate.
  • Auger electrons, particle induced X-rays (PIXE), or thermal energy can be generated from metal nanoparticles (MNP) by various physical activation methods such as X-rays, ion beams, RF magnetic fields, and NIR light. Can be. In view of the much higher energy absorption on the target tissue, all these physically active methods are likely to have therapeutic effects on tumor tissue, but the main advantage of proton or heavy ion beam radiation is compared with high energy X-rays, neutron beams and RF magnetic fields. Therefore, the Bragg Peak effect delivers energy to target tissue sites in the body in a relatively accurate manner and safely.
  • PIR particle induced radiation
  • various secondary radiations including PIXE X-ray emission, optoelectronics, Auger electrons, and gamma rays, react with cabinet electron ionization or nuclear reaction of nanoparticle atoms.
  • Can be generated through It is also characterized by the generation of therapeutically effective particle-induced radiation doses at much lower levels of metal nanoparticles (30-80 ⁇ g / g tissue) than other physical energy activation methods currently under development.
  • the present invention is a new concept of radiation therapy for inducing PIR from MNP by radiation of heavy ion or proton beam, and after delivery of MNP to tumor tissue, PIR is generated in target tumor tissue according to ion beam radiation, thereby causing a therapeutic effect.
  • Roles and effects such as internal emitters are used in therapy.
  • by injecting at 100 Gy single dose on the basis of Bragg peak dose a cure effect by SOBP or TPBP proton beam particle-induced radiation was obtained. Regrowth was observed.
  • low-dose fractional therapy should be performed for the safety of normal tissues.
  • the incident dose per fraction can be selected between 2-50 Gy in SOBP or TPBP beam method depending on the size and location of the tumor.
  • TPBP permeable single Bragg peak
  • TPBP-based particle induced radiation therapy can be applied.
  • the main idea of particle guided radiation therapy is to generate PIR effects resulting from direct Coulomb collisions of the outer electrons of the metal nanoparticles with the proton beam, which has a powerful therapeutic effect. Because the position and shape of the BP can be controlled by the depth of tissue and the relative magnitude of the proton beam energy, the PIR and BP effects can be combined or separated as described in Table 1.
  • 1A is a schematic diagram of the TPBP-PIRT experiment outline, where the proton beam energy after the aluminum window was determined to be 40 MeV in the spectrometer. The sample was 2.06 m away from the beam source. Only the tumor site was exposed to the proton beam; Peripheral normal tissue was shielded using a series of acrylate blocks with variable diameters placed inside the beam spectrometer to match tumor size.
  • FIG. 1B was radiated by a TPBP proton beam generated 14 mm from the point where the Bragg peak enters the tissue in tumor model mice.
  • Proton beam radiation in the animal model was investigated according to experimental equipment as shown in FIG. 1A.
  • the proton beam energy in the spectrometer was determined as 40 MeV.
  • the BP could be placed 14mm from the point of incidence as shown in FIG. 1B.
  • the total tissue including the tumor through which the proton beam passed was less than 7-8 mm, so most of the sample tissue could be exposed to the stagnant dose of the TPBP proton beam. It could occur in vitro through the leg tissue.
  • the location of BP was determined by measuring tissue depth-dose distributions using water phantom and waterproof Markus ion chamber detectors.
  • the charge accumulated on the detector was recorded during the movement of the detector by 1 m and represented as the tissue depth-dose distribution curve of FIG. 2.
  • Dose measurements of the actual sample position and BP are based on two range shifts and GAFCHROMIC It was determined by measuring the radiation exposure dose using an MD-55 radiopigmentation film. If the radiation dose was 100-300 Gy at the BP position, the stagnant dose at the tumor position was typically measured by 23-75 Gy.
  • FIG. 2 is a schematic diagram of the SOBP-PIRT experiment summary, where the proton beam energy after the aluminum window was determined to be 40 MeV in the spectrometer.
  • Animal model samples were 2.06 meters from the beam source. Only the tumor site was exposed to the proton beam; Peripheral normal tissue was shielded using a series of acrylate blocks with variable diameters placed inside the beam spectrometer to match tumor size.
  • the dose shift device (range shift) was used to distribute the dose evenly by placing 10-13 single Bragg peaks in order throughout the tumor tissue, depending on the size of the tumor.
  • the presence of MNP in tissue located in the proton beam path can reduce the radiation dose at the exit of tissue penetration due to its interaction including absorption and scattering.
  • a series of cylindrical tissue phantoms containing various concentrations of MNP was used to measure this effect, and the GAFCHROMIC attached to the bottom of the cylindrical phantom
  • the proton beam transmitted through the MD-55 radiopigment film was measured and the value was read with a micro densitometer.
  • Table 2 showed a proportional decrease in the transmitted dose of the proton beam as the concentration of MNP in the phantom increased relative to the control phantom without MNP.
  • the depth-to-dose distribution for the permeable single Bragg peak (TPBP) of FIG. 3 was measured using a water phantom and a waterproof Markus ion chamber detector.
  • the stagnant dose of TPBP was 7-8 mm with samples placed from the point of incidence, about 23-25% of the peak value.
  • the tumor reduction analysis of the PIRT effect is described as follows.
  • Tumor reduction analysis of FIG. 4A shows that tumor cure groups (AuNP 300 mg-50Gy FeO NP 300mg-75Gy, FeO NP 100mg-75Gy) and partial response groups (RO-25Gy, RO-50Gy) compared to the untreated control group. , RO-75Gy, RO-75Gy, AuNP 100mg-50Gy, FeO NP 100mg-50Gy). Differential tumor size growth rates were observed between the two experimental groups 10-15 days after treatment.
  • FIG. 4A The therapeutic effect of TPBP-PIRT by tumor volume reduction analysis is shown in FIG. 4A. All of the radiotherapy groups showed delayed tumor growth initially, given retention of 25-75 Gy, followed by regrowth compared to the untreated control, the majority of whom died within 2-4 weeks after treatment. In contrast, tumor cure (CTR) was observed in the MNP-accepted radiotherapy group depending on dose within 13-30 days after treatment.
  • CTR tumor cure
  • FIG. 5 shows cure in the experimental group receiving a higher 300 mg / kg MNP dose compared to the experimental group receiving 100 mg / kg in a constant stagnant dose of TPBP, tumor volume reduction analysis for 46 Gy.
  • the experimental group receiving 300 mg / kg MNP showed cure in contrast to the 100 mg / kg MNP receiving experimental group showing re-growth after partial treatment response.
  • Tumor growth patterns of the experimental groups that receive several radiation doses for a given MNP dose are shown in FIGS. 6A and 6B.
  • Figure 6 shows the tumor volume reduction analysis for a constant MNP dose, 100mg / kg (A) and 300mg / kg (B), the cure was observed in the experimental group receiving the radiation dose of 69Gy and 46Gy.
  • the tumor cure and long-term treatment efficacy of PIRT is described as follows.
  • Rat populations where cure was observed were counted for each experimental group and summarized in Table 4. Cures were observed differently depending on radiation dose and nanoparticle dose. In the radiotherapy group, 80% cure rate was observed at 92 Gy treatment and 100% cure at 115 Gy treatment. In 100 or 300 mg / kg MNP acceptance groups, the cure rate increased with stagnation dose. Gold nanoparticle acceptance test group showed somewhat higher cure rate in the mice treated with Au and Fe NP. Almost 100% cure rate was observed in the 46 Gy stationary dose and 300 mg / kg MNP acceptance group.
  • the tumor absorption of MNP is described as follows.
  • transient tissue concentration of MNP after intravenous injection was measured by ICP-MS method. Fast excretion in blood and special tumor uptake was observed for AuNPs compared to FeO NPs.
  • the tumor concentration of the nanoparticles was 137.4 ⁇ 50.2 ⁇ g Au / g tissue and 56.6 ⁇ 18.2 ⁇ g Fe / g tissue for gold and iron, respectively, while the concentration in the surrounding normal muscle tissue was 19.5 ⁇ g Au / g and 21.1 ⁇ g Fe / g for gold and iron, respectively.
  • Tumor-to-muscle MNP ratios reached 7.0 and 2.7 for gold and iron, respectively, at 15 minutes post injection, and increased to 59.7 and 6.9 for gold and iron, respectively, after 24 hours.
  • Muscle tissue was excreted 24 hours after injection and had almost no gold, whereas iron nanoparticles remained 82% of iron concentration in tissue after 15 minutes.
  • FeNP tumor accumulation increased by 300% as the injection dose increased threefold, and the percentage of tissue nanoparticle concentrations compared to the MNP injection dose was similar at 100 mg / kg and 300 mg / kg doses. Less than 1% of the cells accumulated in the tumor tissue some time after injection.
  • Gold and iron nanoparticles are used in the present invention.
  • Ligand-coated gold nanoparticles (AuL-NP) with an average diameter of 14 nm were used. Average particle size, size distribution and morphology of FeNPs were investigated using transmission electron microscopy (TEM). The Fe-NP particles were spherical with a diameter of 10.6 nm and a standard deviation of 0.8 nm. Fe-NP was measured to have a diameter of 13-15 nm after coating with alginate.
  • SOBP spread-out Bragg peak
  • the main advantage of particle-guided radiation therapy is that the proton beam is radiated to the MNP accumulated in the tumor to generate particle-induced radiation dose (PIR) at the tumor site, activating the MNP in multiple coulomb collisions.
  • the tumor dose is greatly increased while maintaining the tissue dose.
  • the proton beam is radiated in SOBP form, the dose is evenly distributed in the tumor, and the PIR is further induced in response to the MNP in the tumor tissue, resulting in a dose increase, thereby increasing the tumor treatment dose.
  • the proton beam is radiated into a single transmission beam, the role of the proton beam activates the MNP mainly without increasing the introduction dose.
  • the specificity of treatment of TPBP-PIRT is determined by the specific site radiation including the proton beam tumor and the tumor selectivity of MNP.
  • Particle-guided radiotherapy cures occurred almost 20-30 days after treatment, with no statistically significant difference between the groups of mice.
  • the cure rate was distributed from 0 to 50%.
  • the negative TVGR was negative, the treated rat group showed a tumor-cure response.
  • PIR mainly consists of PIXE X-rays and ionized electrons, high-LET Auger electrons, and in part consists of incidental ⁇ -ray generation when incident at relatively high proton beam energy (> 100 MeV). Therefore, the therapeutic properties of PIRT are very different from other existing radiation therapies. Collision with high-energy protons results in internal electron ionization through the Coulomb interaction between the incident protons and the orbital electrons providing sufficient energy to ionize the internal electrons. Following ionization of the inner electrons is followed by a deexcitation where the outer electrons transition to a lower energy level to fill the empty energy level.
  • the emission of X-ray radiation or Auger electrons corresponding to the difference between the two outer electron energies is competitively induced from the outer electron orbit.
  • the two empty spaces caused by the outer electron orbit transition can be filled with different electrons, and the Auger electron transition step can be generated continuously.
  • the energy distribution of the Auger electrons emitted from the Auger electron transition step is determined by the cabinet electron transition probability and the energy difference, and is emitted from FeNP or AuNP upon proton exposure and may have an energy range of eV-keV. Therefore, their diffusion distances in aqueous solutions range from several nanometers for low energy electrons ( ⁇ 100 Ev) to several micrometers for high energy electrons (> 10 keV).
  • the energy of X-ray radiation depends on the atomic Z-value of the MNP.
  • the coulomb collision between the high energy positron and the metal nanoparticles can induce the Auger electron emission step more efficiently due to the relatively large impact area.
  • thousands of atoms occupy only 14 nm-diameter space, while thousands of separated atomic samples can be distributed in much larger spaces of 10 6 nm 3 and more at 1 mM concentration.
  • the typical energy of the incident protons is much larger than the electron energy of the K-shell, multiple outer shells of the incident protons are caused by multiple coulomb collisions with atoms within the nanoparticles as well as atoms of the surrounding nanoparticles without losing much kinetic energy. It is anticipated that electron ionization may be induced.
  • nanoparticles can continuously emit Auger electrons, protons, and other secondary electrons while being irradiated with a proton beam. This effect has been experimentally named the nanoradiator effect.
  • MNP injection dose, particle size, Z-value, and pharmacokinetics and target equations can tune the radiation dose treatment efficiency as well as the physicochemical properties of MNP, including biodistribution.
  • the cure rate was observed more frequently with increasing radiation dose or injection dose of MNP.
  • BP energy and BP mode (Table 1) should be selected according to the location of the target tumor in the human body as part of the treatment plan. Stagnant doses of 16-56 Gy of proton beams can damage healthy tissue, so instead of a single dose, radiation doses of TPBP-PIRT are reduced to less than 10 Gy, as with conventional radiation therapy. Can be fractionated.
  • the BP should have at least 150 MeV based on the tissue penetration depth-dose curves of a typical proton beam so that BP completely penetrates the entire brain without interruption. Since the stagnant dose also increases by 40% of the BP when the proton beam reaches 250 MeV, it is necessary to devise BP energy and dose that is appropriate for the target location.
  • Ligand-coated gold nanoparticles were prepared by directly adding an aqueous solution of ligand (L) to a citrate-coated gold nanoparticle solution.
  • Diethylenetriamine- N, N, N, N, N It was prepared directly from the reaction of pentaacetic acid (DTPA) -bis (anhydride) (1.13 g, 3.18 mmol).
  • Gold Nanoparticles with Citrate Coated 12nm Diameter HAuCl 4 To Prepared in advance by reducing with sodium citrate. Briefly, HAuCl in water (1 L) 4.3 H 2 Boil continuously with O (0.33 g, 1 mmol) under vigorous stirring, quickly add sodium citrate (1.14 g, 3.88 mmol) to the stirred solution to change the color of the solution from yellow to purple, and add 10 The solution was stirred for an additional 10 minutes after further boiling to remove the heating lid. Ligand (L; 150 mg) was added to 100 mL solution and the final mixture was stirred for 20 hours.
  • Fe NPs Alginate-coated superferromagnetic nanoparticles (Fe NPs), as reported in previous papers, are synthesized by applying ultrasound to iron containing and iron salt solutions. Briefly, FeCl 2 4H 2 O (1.72 g) and FeCl 3 6H 2 O (4.70 g) (8.65 mmol Fe 2+ /17.30 mmol Fe 3+ ) are dissolved in 80 ml of distilled water, and the black magnetic oxide precipitate is argon. Obtained by heating the solution to 80 ° C. under atmosphere, the pH was increased to 10 by the addition of 28-30% ammonium hydroxide to water and the mixed iron solution exposed to 20kHz ultrasound at an output of 140W for 1 hour.
  • TEM transmission electron microscopy
  • Proton beam irradiation was performed as follows in the animal model by BP mode.
  • Proton beam irradiation in the animal model was irradiated according to the experimental apparatus as shown in FIG. 1.
  • a tumor model was constructed on the side of the rat's leg, and in TPBP mode particle guided radiation therapy, a model was created on the leg of the mouse.
  • the mice were injected with gold or iron nanoparticles at 100-300 mg / kg body weight.
  • Five radiation single treatment groups were prepared as controls. Mice were anesthetized by intraperitoneal injection of 20 mg / kg ketamine and 18.4 mg / kg xylazine.
  • Fifty microliters of MNP saline solution was injected into the tail vein of the animal 24 hours before proton beam irradiation.
  • mice were injected in SOBP or TPBP mode at the LEPT proton beam line of the Korea Cancer Center Hospital (Seoul, Korea), 2.06 m away from the proton beam source, with a BP dose or BP at a dose rate of 0.51 to 0.67 Gy / s for the sample.
  • Coulomb collisions with nanoparticles were induced during delivery of stagnant doses of about 23% of the dose.
  • a single BP dose of 80 Gy in SOBP and three stagnant doses in TPBP (16 Gy, 36 Gy and 55 Gy) were entered into the group of mice receiving nanoparticles, whereas in the SOBP control group, 80 Gy and 16, 36 in the TPBP control group Doses of 55, 74 and 92 Gy were incident. Only the tumor part was exposed to the proton beam and the surrounding normal tissue was shielded using a series of acrylate blocks with varying diameters placed on a beam spectrometer to match the tumor size.
  • TPBP mode the proton beam will penetrate the lesion according to the minimum stagnation dose of the sample's depth-dose curve along the radiation path comprising the tumor and normal tissue. This is, by arranging the two energy conversion range and GAFCHROMIC ⁇ c MD-55 radiation to the sample before and after the dye film was found to be up to BP dosimetry. Stagnant dose of tumor tissue was also measured from each BP dose in the manner described above.
  • Tumor size was measured with a vernier caliper. Tumor shape was estimated to be almost ellipsoid. The magnitude is given by Tumor size after treatment was measured daily, as calculated according to or as part of the tumor growth response analysis following proton beam incidence, until complete cure was observed.
  • the differential distribution of mean TVGR among the individual groups was compared using the Kruskal-Wallis test. For P values less than 0.05 for the control group, different experimental groups were compared with the control for each mode using the Student's t -test. Differences were considered statistically significant at P ⁇ 0.05.
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