KR102258762B1 - Bio fiducial marker for in-vivo evaluation for proton therapy - Google Patents

Abstract

The present invention relates to a biomarker for proton therapy, and more particularly, to a biomarker that enables precise radiotherapy evaluation by confirming the irregularity of a proton in the body immediately after proton treatment, and the biomarker according to an aspect of the present invention is , ⁶⁸ Zn; And a polymer as an active ingredient, and the polymer may be a polymer including PCLA or the like.

Description

Bio fiducial marker for in-vivo evaluation for proton therapy}

The present invention relates to a biomarker for proton therapy, and more particularly, to a biomarker that enables precise radiotherapy evaluation by confirming the abnormality of a proton in the body immediately after proton treatment.

Proton therapy is a state-of-the-art therapy that uses the characteristics of Bragg Peak to reduce radiation irradiated to surrounding normal tissues and dangerous organs, and delivers radiation intensively only to tumors to minimize side effects. Is increasing.

In the case of such proton therapy, the degree of agreement between the angle of the radiation beam and the target is important in order to give the dose to the tumor location as accurately as possible. In particular, in the case of lung cancer or liver cancer patients who are greatly affected by breathing, it is difficult to accurately irradiate the tumor due to the movement of organs due to breathing. Therefore, in order to increase the success rate of radiation therapy for moving organs, it is important to establish a treatment plan in consideration of the movement of the tumor by respiration. In actual treatment, a method of increasing the accuracy of radiotherapy is used by tracking the movement of a marker inserted inside the human body in real time to accurately and quickly grasp the movement of the organ.

On the other hand, the proton transfers all energy to the medium at the depth (range) where the Bragg Peak is generated and then disappears, so in proton therapy, the depth of the proton and the tumor must be matched.

However, if the patient's movement, respiration, etc., inaccurately predicts the positional change or undefined position of the tumor, high radiation may be given to surrounding normal tissues or a small dose may be delivered to the tumor. Therefore, accurately knowing the reach of protons in the body is essential in radiation therapy.

However, the accuracy of predicting irregularities in the current proton therapy has an uncertainty of 2 to 5% in the human body, and the position of organs in the body may change several mm for physiological reasons such as respiration, so an uncertainty of 1 cm or more may occur. have.

As a related study, in MD Anderson in the United States, a study was conducted to confirm the asymptosis of protons in clinical practice with a Compton camera in the form of an array using instantaneous gamma rays. Specifically, it is a device that checks the proton misalignment by calculating with a scattering reaction equation. It is a Compton camera system composed of four detection modules and one same-time calculation module. Is to confirm. However, there was a disadvantage in that the signal is detected even after the proton's irregular distance, so that a procedure to confirm the irregularity through an additional signal processing process is required (Polf, JC, Avery, S., Mackin, DS, & Beddar, S. ( 2015).Imaging of prompt gamma rays emitted during delivery of clinical proton beams with a Compton camera: feasibility studies for range verification.Physics in medicine and biology, 60(18), 7085.).

On the other hand, the gold inner marker used in the past provides only the function of confirming the location of the tumor with medical images using X-rays, and BaSO ₄ and polymer are used to improve the disadvantages of image distortion and dose distortion of the gold inner marker. Biodegradable markers developed using biodegradable markers in vivo have been studied, but there is a disadvantage in that they do not have a function to confirm proton amorphism (US 9,662,408 B2).

As described above, studies have been conducted to evaluate the proton ratio by using positron tomography (PET) or a gamma camera or instantaneous gamma measuring equipment for radiation emitted from radioactive elements among human elements immediately after proton treatment. There was a problem with clinical application because of the low spatial resolution or low integration efficiency of radioactive elements before image measurement.

In order to solve these problems and implement high-precision proton therapy, it is necessary to study biomarkers that provide the location of the tumor in the medical image immediately before proton therapy, and at the same time enable the evaluation of radiotherapy by confirming the abnormality of the proton in the body after treatment. It was true.

US 9662408 B2

Polf, J. C., Avery, S., Mackin, D. S., & Beddar, S. (2015). Imaging of prompt gamma rays emitted during delivery of clinical proton beams with a Compton camera: feasibility studies for range verification. Physics in medicine and biology, 60(18), 7085.

The present invention is to provide a biomarker capable of precise evaluation of proton patient treatment by being less susceptible to wash out in the body and enabling precise measurement of protons due to high accuracy of location information and measurement efficiency of gamma rays generated at the same time. .

A biomarker according to an aspect of the present invention is 68Zn; And a polymer as an active ingredient, wherein the polymer is a biocompatible and biodegradable polymer such as polyglycolic acid (PGA), polylactic acid (PLA), polycaprolactone (PCL), and polycaprolactone (PCL) and a copolymer thereof. (Lactic acid-co-glycolic acid) (PLGA), poly(lactic acid-co-caprolactone) (PCLA), poly(caprolactone-co-glycolic acid) (PCGA) and triple of polyethylene glycol Copolymers polylactic acid-polyethylene glycol-polylactic acid (PLA-PEG-PLA), polycaprolactone-polyethylene glycol-polycaprolactone (PCL-PEG-PCL), poly(lactic acid-co-caprolactone)-polyethylene Glycol-poly(lactic acid-co-caprolactone) (PCLA-PEG-PCLA), poly(lactic acid-co-glycolic acid)-polyethylene glycol-poly(lactic acid-co-glycolic acid) (PLGA -PEG-PLGA) or a mixture thereof may be selected from one or more.

In addition, the polymer is a polymer having an intrinsic viscosity (IV) of 0.7-0.9 dl/g, and may be one or more of the following polymers:

Polyglycolic acid (PGA), polylactic acid (PLA), polycaflolactone (PCL) and their copolymers, poly(lactic acid-co-glycolic acid) (PLGA), poly(caprolactone-co) -Lactic acid) (PCLA), poly(caprolactone-co-glycolic acid) (PCGA) or mixtures thereof.

In addition, the polymer is a polymer having a number average molecular weight of 5,000-20,000 g/mol, and may be one or more of the following polymers:

Polyglycolic acid (PGA), polylactic acid (PLA), polycaprolactone (PCL) and their copolymers, poly(lactic acid-co-glycolic acid) (PLGA), poly(lactic acid-co-) Polylactic acid-polyethylene glycol-polylactic acid (PLA-PEG-PLA), a tripolymer of caprolactone) (PCLA) and polyethylene glycol, polycaprolactone-polyethylene glycol-polycaprolactone (PCL-PEG-PCL), Poly(caprolactone-co-lactic acid)-polyethylene glycol-poly(lactic acid-co-caprolactone)(PCLA-PEG-PCLA), poly(lactic acid-co-glycolic acid)-polyethylene glycol-poly( Lactic acid-co-glycolic acid) (PLGA-PEG-PLGA) can also be used.

In addition, the ⁶⁸ Zn may be included in an amount of 10 to 50% by weight.

In addition, the polymer may be included in an amount of 50 to 90% by weight.

In addition, the biomarker may be a biomarker for internal target labeling that can be used to indicate the location of the affected area in the body during proton therapy.

In addition, the biomarker may be a biomarker for proton aberration that can be used for proton treatment evaluation through proton irregularity confirmation in the body after proton treatment.

In addition, the biomarker may have little effect of wash out of radioactive elements.

In addition, the biomarker ^{may be characterized by comprising 10 to 50% by weight of 68} Zn and 50 to 90% by weight of the polymer.

In the case of using the biomarker for proton therapy according to the present invention, it is less affected by wash out in the body, and the precise location information of the gamma rays generated at the same time and the high efficiency of measurement enable precise measurement of protons, thereby making it possible to evaluate proton patient treatment. It can have the effect of being able to do it precisely.

In addition, it is possible to overcome the shortcomings in which it is difficult to evaluate proton therapy in the patient's body and minimize side effects that may occur during proton therapy, thereby enabling precise proton therapy.

In addition, as an internal target marker, it is possible to provide a biomarker having both a function of confirming a position in an image and a position of an arrival of a proton beam after proton treatment.

1 shows a computational simulation for measuring radioactivity of a marker during proton irradiation,
(a) shows a computational simulation structure in which a marker is placed in a tissue equivalent material and a detector is placed on both sides to irradiate a beam, and (b) is a gamma that confirms that the proton and the marker material react to generate a gamma line. The line (green line) shows the tracking result.
FIG. 2 shows a computational simulation of image verification of gamma ray detection in PET by detecting a gamma ray generated when a marker substance is placed in the center of a circular tissue equivalent substance and irradiating a proton.
3 shows a method of tracking a gamma line obtained from a detector.
4 is a photograph of a marker CT image in the axial direction of a marker positioned on the abdominal-mimicking phantom (position of a marker in a yellow circle).
FIG. 5 is a lateral direction photograph of a marker CT image (position of a yellow circle marker) positioned on an abdominal-mimicking phantom.
6 is a photograph of the marker PET/CT imaging experiment preparation.
7 is a photograph of a proton irradiation experiment in a proton treatment room.
8 shows PET/CT imaging and imaging results.
9 shows a graph of the total cross section of ⁶⁶ Zinc, ⁶⁷ Zinc, and ⁶⁸ Zinc according to the energy of the proton.

Since the present invention can apply various transformations and have various embodiments, specific embodiments are illustrated in the drawings and will be described in detail in the detailed description. However, this is not intended to limit the present invention to a specific embodiment, it should be understood to include all conversions, equivalents, and substitutes included in the spirit and scope of the present invention. In describing the present invention, when it is determined that a detailed description of a related known technology may obscure the subject matter of the present invention, a detailed description thereof will be omitted.

In the present invention, 68Zn; And as a biomarker comprising a polymer as an active ingredient, the polymer provides a biomarker comprising at least one of the following polymers:

As a biocompatible and biodegradable polymer, polyglycolic acid (PGA), polylactic acid (PLA), polycaprolactone (PCL), and a copolymer thereof, poly(lactic acid-co-glycolic acid) ( PLGA), poly(lactic acid-co-caprolactone) (PCLA), polylactic acid-polyethylene glycol-polylactic acid, a tripolymer of poly(caprolactone-co-glycolic acid) (PCGA) and polyethylene glycol (PLA-PEG-PLA), polycaprolactone-polyethylene glycol-polycaprolactone (PCL-PEG-PCL), poly(lactic acid-co-caprolactone)-polyethylene glycol-poly(lactic acid-co-caprolactone) (PCLA-PEG-PCLA), poly(lactic acid-co-glycolic acid)-polyethylene glycol-poly(lactic acid-co-glycolic acid) (PLGA-PEG-PLGA), or a mixture thereof. .

Hereinafter, a biomarker according to a specific embodiment of the present invention will be described in more detail.

Conventionally, attempts have been made to evaluate the proton asymptosis using positron tomography (PET), gamma camera, or instantaneous gamma measuring equipment for radiation emitted from radioactive elements among human elements immediately after proton therapy, but PET image measurement There was a problem with clinical application due to the lack of wash out of all radioactive elements, low spatial resolution, or low integration efficiency of gamma rays.

^{Accordingly, the inventors of the present invention have found that when 68} zinc, which has the highest reaction cross-sectional ratio by energy, is used as a marker, it is possible to obtain a signal with a small dose, less affected by internal washout, and accurate location information of the gamma rays generated at the same time. Through an experiment, it was confirmed through an experiment that it was possible to precisely measure the proton as a result of the high measurement efficiency, so that it is possible to accurately evaluate the proton patient treatment.

A biomarker according to an aspect of the present invention is 68Zn; And a polymer as an active ingredient, and the polymer may be any one or more of the following polymers:

As a biocompatible and biodegradable polymer, polyglycolic acid (PGA), polylactic acid (PLA), polycaprolactone (PCL), and a copolymer thereof, poly(lactic acid-co-glycolic acid) ( PLGA), poly(lactic acid-co-caprolactone) (PCLA), polylactic acid-polyethylene glycol-polylactic acid, a tripolymer of poly(caprolactone-co-glycolic acid) (PCGA) and polyethylene glycol (PLA-PEG-PLA), polycaprolactone-polyethylene glycol-polycaprolactone (PCL-PEG-PCL), poly(lactic acid-co-caprolactone)-polyethylene glycol-poly(lactic acid-co-caprolactone) (PCLA-PEG-PCLA), poly(lactic acid-co-glycolic acid)-polyethylene glycol-poly(lactic acid-co-glycolic acid) (PLGA-PEG-PLGA), or a mixture thereof. .

In addition, among the polymers, polyglycolic acid (PGA), polylactic acid (PLA), polycaflolactone (PCL), and poly(lactic acid-co-glycolic acid) (PLGA), which are copolymers thereof, Poly(caprolactone-co-lactic acid) (PCLA), poly(caprolactone-co-glycolic acid) (PCGA) polymers may be of a pellet type, and these polymers have an intrinsic viscosity (IV) of about 0.7-0.9 dl/g.

And among the polymers according to an aspect of the present invention, polyglycolic acid (PGA), polylactic acid (PLA), polycaprolactone (PCL), and poly(lactic acid-co-glycolic acid) as a copolymer thereof (PLGA), polylactic acid-polyethylene glycol-polylactic acid (PLA-PEG-PLA), polycaprolactone-polyethylene glycol- which is a tripolymer of poly(lactic acid-co-caprolactone) (PCLA) and polyethylene glycol Polycaprolactone (PCL-PEG-PCL), poly(caprolactone-co-lactic acid)-polyethylene glycol-poly(lactic acid-co-caprolactone)(PCLA-PEG-PCLA), poly(lactic acid-co- It is also possible to use glycolic acid)-polyethylene glycol-poly(lactic acid-co-glycolic acid) (PLGA-PEG-PLGA). In addition, it may be of a hydrogel type, and the number average molecular weight of these polymers is about 5,000-20,000 g/mol, where PEG is about 1000-5000 g/mol, and PEG is about 20-30 mol%.

^{If 68} Zinc, which has the highest reaction cross-sectional ratio by energy among the Zn isotopes, is used as a marker, it may be desirable to use ⁶⁸ Zinc because it is possible to obtain a signal with a small dose.

The polymer is polyglycolic acid (PGA), polylactic acid (PLA), polycaflolactone (PCL) and a copolymer thereof, poly(lactic acid-co-glycolic acid) (PLGA), poly(capro). One or more pellet-type polymers of lactone-co-lactic acid) (PCLA), poly(caprolactone-co-glycolic acid) (PCGA), or mixtures thereof; Or polyglycolic acid (PGA), polylactic acid (PLA), polycaprolactone (PCL) and a copolymer thereof, poly(lactic acid-co-glycolic acid) (PLGA), poly(lactic acid-co) -Caprolactone) (PCLA) and polylactic acid-polyethylene glycol-polylactic acid (PLA-PEG-PLA), a tripolymer of polyethylene glycol, polycaprolactone-polyethylene glycol-polycaprolactone (PCL-PEG-PCL) , Poly(caprolactone-co-lactic acid)-polyethylene glycol-poly(lactic acid-co-caprolactone)(PCLA-PEG-PCLA), poly(lactic acid-co-glycolic acid)-polyethylene glycol-poly (Lactic acid-co-glycolic acid) (PLGA-PEG-PLGA) may be used, preferably PCL-PEG-PCL triblock copolymer.

In the biomarker, PCLA polymer is used as a carrier ^{for the 68 Zinc.} The PCLA polymer ^{surrounds 68} Zinc, safely ^{moves 68} Zinc to a target site in vivo, and can form a biomarker at the target site.

The PCLA (Poly (DL-lactide-co- ε -caprolactone)) polymer has a biodegradable property that is degraded in vivo over time after being injected into a living body.

The hydrogel-type biomarker of the present invention maintains a sol or liquid form under room temperature conditions before injection into the body, so it has excellent injectability into the body through injection, etc., and the temperature and pH conditions in the body after injection into the body Under the conditions, a gel or solid form is maintained, thereby satisfying the physical properties required from the marker. In other words, if the target marker remains in a sol or liquid state, it can be safely delivered into the body without clogging of the injection needle, and its mobility in the body is limited due to its change to a gel or solid state in the body, and physical properties as a target marker Is satisfied.

Meanwhile, in the biomarker according to the present invention, ⁶⁸ Zn may be included in an amount of 10 to 50% by weight, and a polymer may be included in an amount of 50 to 90% by weight.

More preferably, the biomarker ^{may be composed of 68} Zn 20% by weight and 80% by weight of the polymer.

In addition, when the biomarker is a hydrogel type, the hydrogel solution is made by adding 15 to 25% by weight of a block copolymer to the buffer solution, and the biomarker is ⁶⁸ Zn 10 to 50% by weight and 50 to 90% by weight of the hydrogel solution. It can be made of.

Meanwhile, radiotherapy is a treatment method in which tumor cells are killed by intensively irradiating therapeutic radiation to a tumor based on a diagnostic image for a tumor. During radiation therapy, the surrounding normal tissues excluding the tumor must be protected from the therapeutic radiation to minimize side effects caused by radiation, so the technique of visualizing the location of the tumor in radiation therapy is very important to increase the effectiveness of the treatment. The fiducial marker used in radiation therapy must satisfy the following main conditions. First, it must have excellent discernability in the X-ray area for diagnosis. Second, it is necessary to minimize the distortion of the dose delivered to the tumor by therapeutic radiation. Third, when establishing a treatment plan based on computed tomography (CT), it should be possible to minimize distortion of computed tomography (CT) images. Fourth, it is necessary to minimize the movement of target markers in the human body. Target markers conventionally used to accurately visualize the location of the tumor were metal particles such as gold or titanium, and after inserting the metal particles into the tumor, the location of the affected area was confirmed through diagnostic X-ray images, but these metals were targeted. When used as a marker component, dose distortion and image distortion are greatly increased, which is a problem.

During radiation treatment, the streak and metal artifacts generated by these metal markers make it difficult to distinguish cancer tissues from surrounding normal tissues, and increase uncertainty when setting targets and regions of interest (ROI) for treatment planning. do.

The biomarker according to the present invention may be a biomarker for internal target labeling, which is used to mark the location of the affected area in the body during proton therapy.

In addition, the biomarker according to the present invention may be a biomarker for proton identification, characterized in that it can be used for proton treatment evaluation through proton irregularity confirmation in the body after proton treatment.

Conventionally, attempts have been made to evaluate the proton asymptosis using positron tomography (PET), gamma camera, or instantaneous gamma measuring equipment for radiation emitted from radioactive elements among human elements immediately after proton therapy, but PET image measurement There was a problem with clinical application due to the lack of wash out of all radioactive elements, low spatial resolution, or low integration efficiency of gamma rays.

The present invention is to provide a biomarker capable of precise proton patient treatment evaluation by being less affected by wash out in the body, and high accurate location information and measurement efficiency of gamma rays generated at the same time, enabling precise determination of protons. It is characterized by one.

The biomarker according to the present invention may have very low uncertainty of proton identification.

^{This uses 68} zinc, which has the highest reaction cross-sectional ratio by energy, and by using the polymer according to the present invention, it detects gamma rays generated by the interaction of a proton with a marker carrying ^{68 zinc, thereby minimizing the uncertainty of protons.} Because you can.

In addition, the biomarker according to the present invention is characterized in that the influence of the wash out of the radioactive elements is small.

Compared to the prior art, which has a large effect of wash out of radioactive elements before PET image measurement, it is ⁶⁸ Zinc, and the polymer according to the present invention, in particular, a polymer having an intrinsic viscosity (IV) of 0.7-0.9 dl/g. Glycolic acid (PGA), polylactic acid (PLA), polycaflolactone (PCL) and their copolymers, poly(lactic acid-co-glycolic acid) (PLGA), poly(caprolactone-co-) The use of lactic acid) (PCLA), poly(caprolactone-co-glycolic acid) (PCGA) or a mixture thereof minimizes the effect of wash out of radioactive elements by the hydrophobic interaction between ^{the polymer and 68 Zinc.} Because it becomes.

In addition, it is possible to minimize wash out, as well as to form a homogeneous polymer-zinc mixture, and to prevent agglomeration between zinc powders due to the influence of such hydrophobic interactions.

On the other hand, in order to select a marker substance capable of confirming the proton ascitation, various factors must be considered physically, chemically, biologically, and clinically, and in order to increase the ratio of gamma rays generated even at a small proton dose, the cross section of the substance is high and the substance The half-life of must also satisfy the time range for the video signal to come in.

In addition, it is necessary to chemically maintain a stable form in the body even with changes in pH and temperature, and to select a material candidate that satisfies the conditions that are histologically stable, non-toxic, and clinically easy to inject in the injected organ, and test for the production of markers. , In the present invention, in consideration of these points, gamma rays generated by reacting with protons are quantitatively analyzed by computational simulation for each marker candidate, and a half-life after radiation is applied, and candidate materials are selected with the time and yield available for image signal acquisition. Was completed.

In the case of using the biomarker according to the present invention, more accurate and successful radiation treatment results can be expected because it is possible to evaluate the non-standard distance in the body during radiation treatment within tens of minutes with nuclear medicine imaging equipment outside the patient after proton treatment. In addition, through this, a method in which a limited treatment range can be confirmed with an existing treatment planning system or nuclear medicine imaging equipment may enable treatment evaluation through non-deterministic monitoring of protons in the patient's body. Finally, by using the biomarker according to the present invention, it is possible to implement more precise proton therapy by providing a biomarker having both the function of the internal target marker and the double function of confirming the arrival position of the proton beam after proton treatment. Can be.

Hereinafter, preferred embodiments of the present invention will be described in detail with reference to the accompanying drawings. However, these examples are for illustrative purposes only, and the scope of the present invention will not be construed as being limited by these examples.

Example 1: computational simulation

A computational simulation was performed using the Geant4 toolkit in order to find out the activity of the proton in the human body according to the interaction between the amorphous and the 68Zinc fiducial marker.

The method of confirming the irregularity is to inject a 68Zinc fiducial marker at the irregular distance end of the proton beam, and then obtain the detected image or location information of the 511 keV energy gamma ray generated from the 68Zinc fiducial marker activated by the proton. To determine the location of the patient, it is possible to determine whether the correct treatment has been performed by comparing it with the CT image taken.

Therefore, in the computational simulation, a computational simulation was performed to determine whether a signal can be obtained in vitro using a marker that combines 68Zinc, one of the candidate marker substances, and PCLA polymer (a substance that maintains the shape of the marker).

Computational simulation method (Computational simulation: simulation calculation method that can obtain results similar to actual experiments)

^{As shown in FIG. 1, it is assumed that a 68} Zinc fiducial marker is injected into the body in order to confirm the exact location of the tumor inside the tissue tissue that simulates the human tissue. The material of the tissue was set to A-150 tissue (density: 1.157 g/cm ^{3 ), which is the information provided in the Geant4 material database.}

Fiducial marker

The fiducial marker set in the computational simulation was set ^{as a mixture of 68} zinc isotope and PCLApolymer that maintains the shape of the fiducial marker. At this time, the mixing ratio was set to 68Zinc isotope: polymer = 20 wt%: 80 wt%.

Video signal detection method

^{A method of detecting 511 kev gamma particles from a 68} zinc fiducial marker activated after irradiating a proton beam to a marker located inside the tissue in both directions based on a marker as shown in FIG. 1, and a method using PET as shown in FIG. Computer simulation was conducted in two ways.

How to determine the amorphous position of a proton

As shown in Figure 1, a marker at a certain depth is activated by a proton, and a gamma source with the same time acquired based on the location information of the gamma source acquired from Detector 1 and Detector 2 is drawn in a three-dimensional line. As a result of finding the source closest to the position of the marker assumed to be acquired, as shown in the right figure in FIG. 3, it was confirmed that the actual error was within 2 mm (Table 1).

[Table 1]

Example 2: Confirmation of marker CT image-Confirmation of the possibility of use of markers in respiratory synchronization treatment

Polymer pure Zinc marker

The test was carried out after injecting a marker material mixed with PCLA polymer and pure zinc powder into the human abdominal phantom on the CT image. The size of the tested marker was made into a cylindrical shape with a diameter of 5 mm and a diameter of 2 mm.

Experimental conditions were set to the same tube voltage as 120 kVp and tube current of 177 mA as the actual patient imaging conditions.

As can be seen in FIGS. 4 and 5, the marker is located in the center of the abdomen of the phantom and can be visually distinguished from the CT image. When measured with the Hound field unit (HU), a CT image index, the value compared to the general tissue is about 2800 HU. I was able to confirm this high.

Therefore, it was confirmed that the same role as the existing gold marker injected to determine the location of the tumor for the existing respiratory synchronization treatment was possible.

Example 3: PET image acquisition experiment of a marker irradiated by a proton

Marker candidate

The experiment was conducted with pure zinc powder containing ⁶⁸ zinc, which is a candidate substance, to confirm the asymptosis of protons.

The composition ratio of Isotope of pure zinc powder was ⁶⁴ Zinc: 48.6%, ⁶⁶ Zinc: 27.9%, ⁶⁸ Zinc: 18.8, and ⁶⁸ Zinc contained about 20%.

Pure zinc powder was purchased from Sigma-aldrich, and to make the shape of the marker, as shown in Fig. 6, it was prepared by filling about 3g in a straw having a length of 5.5 cm and a diameter of 0.5 cm, and to assume that it is inside the human body. In order to reduce unnecessary doses to the skin during radiation treatment with PMMA material, Bolus (density: 1.03 g/cm ³ ) similar to the human skin tissue in use was used to fill the area around the marker.

Proton marker substance investigation experiment

The prepared markers were investigated in the proton treatment room at Samsung Seoul Hospital. The irradiation method proceeded in the same manner as the actual patient treatment conditions, and the marker was positioned perpendicular to the direction of the proton beam as shown in FIG. 7 in accordance with the end of the proton assortment.

A solid water material was placed so that only a certain portion of the marker was activated by the irradiated proton. A 230 MeV 10×10 cm2 square beam was irradiated with 2 Gy, 6 Gy, and 10 Gy to each of the three markers.

PET/CT image acquisition result

The irradiated markers were imaged using PET/CT (Inveon, Siemens Preclinical, Knoxville, TN) for small animals in Samsung Seoul Hospital. In order to proceed, the PET image was taken for 20 minutes and then the CT image was taken for 10 minutes. Each of the captured images was able to confirm the activated part of the marker through registration, and the possibility of confirming the irregular distance of the proton. I did.

The predicted amount of ⁶⁸ Zinc isotope in the activated marker is about 0.7 when calculated as the volume ratio of the marker activated by the proton out of the total 2.75 g, of which ⁶⁸ Zinc isotope is 18.8%, so it corresponds to 0.13 g. It was assumed that the part to be activated was activated.

On the other hand, as shown in the PET / CT image results of FIG. 8, as a result of testing the marker with pure Zinc powder, it was confirmed that the range to which the proton reached was activated by the proton, and the range to which the proton reached can be distinguished by PET image.

However, the reason that the signal comes out from the 6 Gy dose, which is a high dose, was judged to be due to the different reaction rates according to the cross section because various isotope substances (64Zinc, 66Zinc, 68Zinc) are currently composed of pure zinc powder.

^{Particularly, as shown in FIG. 9, if 68} Zinc, which has the highest reaction cross-sectional ratio by energy, was used as a marker, it could be expected that a signal could be obtained even with a small dose.

As can be seen from the above examples, in the present invention, like a conventional metal marker (gold marker), it is possible to distinguish visually from a CT image and to reduce the effect of wash out in the body through a multi-purpose marker material capable of confirming the irregularity of protons. It is possible to provide a biomarker capable of accurately evaluating proton patient treatment by enabling precise measurement of protons due to high accuracy of location information and measurement efficiency of gamma rays generated at the same time.

As described above, specific parts of the present invention have been described in detail, and for those of ordinary skill in the art, it is obvious that this specific technique is only a preferred embodiment, and the scope of the present invention is not limited thereby. something to do. Therefore, it will be said that the practical scope of the present invention is defined by the appended claims and their equivalents.

Claims (9)

⁶⁸ Zn; And as a biomarker comprising a polymer as an active ingredient,
The polymer is one or more of the following polymers, a biomarker:
As a biocompatible and biodegradable polymer, poly(lactic acid-co-caprolactone) (PCLA), poly(lactic acid-co-caprolactone)-polyethylene glycol-poly(lactic acid-co-caprolactone)( PCLA-PEG-PCLA), or mixtures thereof.
The biomarker according to claim 1, wherein the polymer is a polymer having an intrinsic viscosity (IV) of 0.7-0.9 dl/g, and the polymer is poly(caprolactone-co-lactic acid) (PCLA).
The biomarker according to claim 1, wherein the polymer is a polymer having a number average molecular weight of 5,000-20,000 g/mol, and is at least one of the following polymers:
Poly(lactic acid-co-caprolactone) (PCLA), poly(caprolactone-co-lactic acid)-polyethylene glycol-poly(lactic acid-co-caprolactone) (PCLA-PEG-PCLA), or mixtures thereof ,
However, here, PEG is 1000-5000 g/mol, and PEG is 20-30 mol%.
The biomarker of claim 1, wherein the ⁶⁸ Zn is contained in an amount of 10 to 50% by weight.
The biomarker of claim 1, wherein the polymer is contained in an amount of 50 to 90% by weight.
The biomarker according to claim 1, wherein the biomarker is used to mark the location of the affected area in the body during proton therapy.
The biomarker according to claim 1, wherein the biomarker can be used for proton treatment evaluation through proton aberration in the body after proton treatment.
8. The biomarker according to claim 7, wherein the biomarker has little influence on wash out of radioactive elements.
The biomarker according to claim 1, wherein the biomarker comprises ^{10% to 50% by weight of 68} Zn and 50% to 90% by weight of the polymer.

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