WO2013081218A2 - Bragg peak-based particle-induced radiation therapy - Google Patents

Description

Bragg peak-based particle-guided radiotherapy

BACKGROUND OF THE INVENTION 1. Field of the Invention 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. 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.

Compared to conventional X-rays used for radiotherapy, 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.

However, the above proton or heavy ion treatment necrosis only the lesion tissue at a specific position, so it is effective in treating solid cancer with a definite tumor boundary. There was no.

In addition, a single Bragg peak cannot be effectively treated when the tumor is large. Therefore, 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. Use However, because of this, 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.

[Preceding technical literature]

[Non-Patent Documents]

(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).

In order to solve the above problems, 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.

In addition, the metal nanoparticles (MMPs) are activated by high energy proton beams, induced by inner shell ionization and subsequent de-excitation processes, which result in local X-ray, γ-ray, optoelectronic and Auger electrons. To provide a radiotherapy using the BraggPick proton beam and Coulomb nano-radiator effect, characterized in that to produce a.

In addition, the metal nanoparticles (MMP) generates Auger electrons, particle-induced X-ray radiation (PIXE), or thermal energy by various physical activation methods such as X-rays, ion beams, RF magnetic fields, and NIR light. To provide a radiation therapy using proton or heavy ion beam and Coulomb nano-radiator effect.

In addition, 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. There is a very useful effect that 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.

The following drawings, which are attached in this specification, illustrate exemplary embodiments of the present invention, and together with the detailed description thereof, serve to further understand the technical concept of the present invention. It should not be construed as limited.

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.

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.

5 shows the dependence of the therapeutic effect on the concentration of MNP administered on a given proton beam incident dose.

Figure 6 illustrates the effect of tumor treatment on a group of mice receiving several proton beam incident doses for a given MNP dose.

7 shows pharmacokinetic ICP data.

In the following the present invention will be described in detail with reference to the embodiments shown in the accompanying drawings, but the embodiments presented are exemplary for a clear understanding of the present invention is not limited thereto.

 Hereinafter, the technical configuration of the present invention according to a preferred embodiment in detail.

Metal nanoparticles (MMPs), when activated with high energy proton beams, are localized X-rays, γ-rays, photoelectrons and Augers by particle induced atomic shell ionization and subsequent de-excitation processes. particle induced radiation effects (PIR), such as electrons.

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. .

The potential for the treatment of SOBP-PIRT or TPBP-PIRT has been tested with gold or iron nanoparticles, and intravenously injected with 100-300 mg Kg- ¹ in a CT-26 tumor model generated in the flanks or legs of rats. . Analysis of tumor growth showed that tumors were completely cured by PIR-based nanoradioactive effects compared to mice in the group without MNP ( p <0.001). These TPBP-based PIRTs have been proposed as a new form of radiation therapy to treat invasive metastatic cancers or widespread inflammatory diseases that are uncertain about treatment. It has been suggested as a proton or heavy ion therapy which greatly reduces the number of times.

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. 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.

In addition, the metal nanoparticles (MMPs) are activated with high energy proton beams, resulting in local X-rays, γ-rays, optoelectronics and Auger by particle induced atomic shell ionization and subsequent de-excitation processes. Characterized in that to generate the electrons.

In addition, the metal nanoparticles (MMP) 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.

In addition, 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). BP (APBP), invasive tumors spreading in normal tissues, transmissive single BP (TPBP), etc. are converted into a proton or medium particle beam incident to the tumor tissue and reacted with the received nano-metal particles, particle-induced radiation (PIR; particle induced radiation).

Furthermore, according to any one of claims 1 to 3,

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.

In addition, the metallic nanoparticles (MNP) 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.

In addition, 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. By reacting with the metal nanoparticles by incident on the tumor tissue to generate particle induced radiation (PIR).

In addition, the metallic nanoparticles (MNP) 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. When a high-energy proton beam collides with metal nanoparticles, various secondary radiations called particle induced radiation (PIR), 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 μg / 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. In the embodiment of the present invention, 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. In practice, however, low-dose fractional therapy should be performed for the safety of normal tissues. At this time, 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.

When the Bragg-peak energy of the proton beam is large enough, the BP does not occur in the irradiated human body through which the proton beam passes and is completely transmitted without accumulating energy, and energy can be emitted from outside the human body. This is called permeable single Bragg peak (TPBP) for convenience in the present invention. In this case, BraggPeek's tissue permeation depth-dose curves enable MNPs to be activated by coulomb collisions in the tumor cells where nanoparticles accumulate during normal and tumor tissue exposures in the beam path. It just happens. As a novel treatment modality for invasive tumors, locally spreading metastatic cancer, or diffuse inflammatory disease, which has unique therapeutic properties when the PIR dose effect alone has a significant therapeutic effect and is not covered by current radiation therapy, including proton therapy. TPBP-based particle induced radiation therapy (TPBP-PIRT) can be applied.

The BP-based proton beam emission and PIR dose measurement results are described as follows.

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.

<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. When the tumor grew to 4-5 mm in diameter, 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.

In theory, 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. The data summarized in 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.

A 8.5-12.5% reduction was observed when the concentration of nanoparticles ranged from 100 μg Au / g to 2 mg Au / g. This attenuated dose may indicate transmission proton beam loss from scattering or absorption of AuNPs and may contribute in part to the generation of PIR from MNPs in in vivo experiments.

<Table 2>

[Revisions under Rule 91 25.02.2013]

[Revisions under Rule 91 25.02.2013]

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.

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.

The therapeutic effect of SOBP-PIRT by tumor volume reduction analysis is shown in Figure 4b.

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.

In the experimental group receiving the 100 mg / kg MNP dose cure was observed only in the experimental group irradiated with 69 Gy-TPBP. However, cure was observed at the 46 or 69 Gy-TPBP dose in the experimental group receiving 300 mg / kg.

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.

<Table 4>

[Revisions under Rule 91 20.03.2012]

[Revisions under Rule 91 20.03.2012]

Cured rats survived without recurrence during the 9-month to 1-year transition period, whereas both radio- and nanoparticle-untreated controls died within 2-6 weeks without nanoparticle acceptance. The radiation alone treatment group showed 11% long-term survival rate, whereas the experimental group that received gold or iron nanoparticles and radiation showed 64-100% 1-year long-term survival rate.

The tumor absorption of MNP is described as follows.

Quantitative pharmacokinetics of Fe NP and Au NP using ICP showed that the blood concentration of nanoparticles decreased to 50% drop between 2 and 15 minutes, and the remaining 50% decrease slowly between 15 and 48 hours. Showed.

Pharmacokinetic ICP data is shown in FIG. 6.

6, 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.

After 15 minutes of injection with a dose of 300 mg / kg, the tumor concentration of the nanoparticles was 137.4 ± 50.2 μg Au / g tissue and 56.6 ± 18.2 μg Fe / g tissue for gold and iron, respectively, while the concentration in the surrounding normal muscle tissue was 19.5 μg Au / g and 21.1 μg 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. Upon transmission of the beam through tissue, it enables selective activation of MNP in tumor tissue. 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. In quantitative data, 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.

Referring to the size of the synthesized metal nanoparticles are as follows.

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.

Using spread-out Bragg peak (SOBP) technology in Proton Therapy (PT) provides more uniform dose distribution in tumors. However, it also leads to increased introduction doses, so that even though proton therapy results in lower exit doses than X-ray radiation, the main advantage over conventional radiation therapy disappears with the use of SOBP.

In contrast, the main advantage of particle-guided radiation therapy (PIRT) 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. At this time, when 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. When 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. Therefore, 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. When the mean TVGR _10d-15d was positive, the cure rate was distributed from 0 to 50%. When 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 γ-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. Accordingly, 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. Gold L-line X-rays (9-14 keV) and iron element K-line X-rays (7keV) both have short permeation depths that will attenuate less than 1 cm and contribute to tumor treatment dose. Therefore, Auger electrons and PIXE X-rays from AuNP or FeNP are mostly localized inside tumor tissue.

Compared to the X-ray induced Auger electron emission process, 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. Also, in nanoparticles, 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. Since 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. Thus, 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. In addition, 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. For example, to treat target brain tumors with TPBP-PIRT, 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.

While the typical energy of X-rays in photoactivation therapy is less than 100 keV, the proton beam energy in particle guided radiation therapy is more than 100 MeV, resulting in more secondary radiation yields involving Auger electrons by nanoradiator effect under constant therapeutic radiation dose. Is expected.

Referring to the production of metal nanoparticles are as follows.

Ligand-coated gold nanoparticles (Au NP) were prepared by directly adding an aqueous solution of ligand (L) to a citrate-coated gold nanoparticle solution. The diethylenetriamine pentaacetic acid (DTPA) pair bound to ligand (L), cysteine, had DMF (20 mL and two equivalent L-cysteine methyl esters (1.09 g, 6.37 mmol) at 80 ° C. for 6 hours. Diethylenetriamine-N, N, N, N, NIt 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 HAuCl₄To Prepared in advance by reducing with sodium citrate. Briefly, HAuCl in water (1 L)_4.3 H₂Boil 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. An equal amount of acetone was added thereto and the solution was further stirred for 4 hours, after which gold nanoparticles were collected by centrifugation and washed successively with water, acetone and ether. Particle size and dispersion of gold nanoparticles were measured using light scattering techniques.

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. Alginate was used to coat nanoparticle surfaces to disperse the particles. Briefly, 2 g of magnetite nanoparticles were dispersed in 60 ml of salt and 25 ml of alginic acid solution by heating the solution to 80 ° C. while exposing to a 50 W output for 30 minutes under continuous stirred nitrogen gas. These particles were clarified by washing with saline while exposed to strong neodymium magnets (magnetic density: Br = 11000 gauss). Finally, an autofluid containing 25 mg / ml FeNP was obtained. Average particle size, size dispersion and morphology of FeNPs were examined using transmission electron microscopy (TEM).

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. In SOBP mode particle guided radiation therapy, 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. The 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.

In 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 Reduction Analysis and Statistical Analysis

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. Mean tumor size growth rate (TVGR) for 10-15 days after treatment was calculated for each group using the formula, TVGR = ([tumor size at day 15 of tumor size at 10d] / 5 × 100). 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.

Although one embodiment of the present invention has been described above, the technical idea of the present invention is not limited to the above embodiment, and various treatments and diagnostic methods can be implemented within the scope without departing from the technical idea of the present invention.

Claims (7)

1. Bragg, characterized by the use of metal nanoparticles (MMP) to treat tumors using the Coulomb nanoradiator effect, which generates particle-induced radiation from direct coulomb collisions of electrons and charged particles (protons or heavy particles) beams of metal nanoparticles Peak-Based Particle Induced Radiation Therapy (PIRT).
2. The method of claim 1,

   The metal nanoparticles (MMPs) are activated by high energy protons or heavy particle beams and induced by inner shell ionization and subsequent deexcitation treatment, such as X-rays, γ-rays, optoelectronics and Auger electrons. Charged particle induced radiation therapy characterized by locally generating particle induced radiation (PIR).
3. The method of claim 1,

   The Bragg Peak is SOBP for large sized solid cancers (less than 2 cm) for absorption of solid BCCs (APBP) for large sized solid cancers depending on the shape and location of the tumor. In this case, BP-based particle induction is characterized by converting an incident method of a proton or medium particle beam into a transmissive single BP (TPBP) to enter a tumor tissue and reacting with the received nanometal particles to generate particle guided radiation (PIR). Radiation therapy.
4. The method according to any one of claims 1 to 3,

   Proton or medium particle beam energy of 40 MeV or more, dose of 1 Gy or more at Bragg-peak position, dose rate at low dose rate (30 Gy / hr) and high dose rate (2000 Gy / hr) Particle-induced radiation therapy characterized in that the selected according to the characteristics of the treatment patient and induces particle-induced radiation by entering a single dose or fraction (fractination).
5. The method according to any one of claims 1 to 2,

   The metal nanoparticle (MMP) is a metal element such as gold (Au), iron (Fe), indium (In), gadolinium (Gd), or platinum (Pt), and has a Z value of 26 to 90 pure metal. BP-based particle induced radiation therapy characterized in that the nanoparticles are elemental or their oxides, which are nanoparticles between 1-100 nm in size and react with proton beams or heavy ion particles to produce particle guided radiation (PIR). therapy.
6. The method according to any one of claims 1 to 4.

   The proton or medium particle beam reacts with metal nanoparticles by injecting a single Bragg peak or a spread-out Bragg peak into a tumor port in an intensity modulated manner by dividing a single Bragg peak or a spread-out Bragg peak into a single port or several directions. BP-based particle directed radiation therapy characterized in that it generates radiation (PIR).
7. The method according to any one of claims 1 to 5.

   The metal nanoparticles (MMP) 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 to generate particle induced radiation (PIR). -Based particle guided radiation therapy.

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