WO2023097921A1 - 一种共轭碳碘聚合物及制备与用于制备定位标记物的应用 - Google Patents

一种共轭碳碘聚合物及制备与用于制备定位标记物的应用 Download PDF

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WO2023097921A1
WO2023097921A1 PCT/CN2022/079639 CN2022079639W WO2023097921A1 WO 2023097921 A1 WO2023097921 A1 WO 2023097921A1 CN 2022079639 W CN2022079639 W CN 2022079639W WO 2023097921 A1 WO2023097921 A1 WO 2023097921A1
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formula
polymer
iodine
conjugated carbon
pida
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French (fr)
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罗亮
殷明明
刘小明
孟凡玲
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华中科技大学
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Definitions

  • the invention belongs to the technical field of imaging markers, and more specifically relates to a conjugated carbon-iodide polymer and its preparation and application for preparing positioning markers.
  • Cancer is a leading cause of morbidity and mortality worldwide. There are about 14 million new cancer patients and 8 million deaths from cancer-related diseases every year. Considering the high risk and high mortality rate of cancer, researchers around the world have been working hard to develop more precise and rapid diagnosis and treatment methods to fight cancer. In clinical cancer treatment, most cancer treatment methods (such as chemotherapy, radiotherapy and surgery) are partially successful, but they also have certain limitations, and they often damage the surrounding healthy tissue, which ultimately affects the patient's survival period, tumor Precision therapy is considered to be an important direction for future development. Although there are many reports of targeted drugs in chemotherapy, the problem of systemic toxicity and multidrug resistance in patients is still an unavoidable problem. Therefore, people place their hopes on the precise positioning of tumors during radiotherapy and the precise resection of tumors during surgery. The key to achieving this goal lies in the precise marking and real-time tracking of tumor contours under the precise guidance of medical images.
  • CT images of tumors are one of the most important references in the process of tumor diagnosis and treatment planning.
  • CT image analysis can accurately display the three-dimensional shape and relative position of the tumor in the patient's body.
  • the determination of the tumor position is extremely demanding, and it is difficult to maintain the relationship between the tumor and the patient's surface due to the normal breathing movement of the human body or the influence of the surgical operation process. relatively static.
  • CT markers In order to achieve precise tumor positioning during surgery or radiotherapy, it is necessary to introduce additional CT markers to track the status and relative position of the tumor and surrounding tissues and organs in real time, so as to finally achieve precise tumor treatment.
  • the requirements for CT markers mainly focus on high-quality CT imaging, easy to distinguish with the naked eye, stable properties and relative positions during treatment, good biocompatibility, and can be applied to different tumor treatment scenarios.
  • the invention solves the technical problems of low imaging quality, unstable relative position, and poor biocompatibility in the prior art.
  • the invention provides a polydiacetylene (PDA) main chain, but Conjugated polymers with only iodine atom substituents, and methods of synthesis and use in vivo labeling to guide precision surgical resection and radiation therapy.
  • the marker provided by the present invention has high iodine content and ultra-high X-ray absorption efficiency.
  • the nanofiber itself is easy to self-assemble to form a cluster, which is conducive to maintaining stability and non-diffusion at specific parts, and has good biocompatibility.
  • a conjugated carbon-iodide polymer is provided, the structural formula of the conjugated carbon-iodide polymer includes the structure shown in formula II, and the formula II is:
  • the structural formula of the conjugated carbon-iodine polymer is shown in formula I or formula II:
  • reaction formula is as follows:
  • the synthetic method comprises the following steps:
  • the iodine atom on the iodine-substituted ethylenediyne in formula 3 interacts with the pyridine group nitrogen atom at the end of the ligand in formula 2 through a halogen bond, and topologically polymerizes to obtain a conjugated carbon-iodide polymer with the structure shown in formula I;
  • step a after the iodine-substituted acetylene represented by formula 1 and the ligand represented by formula 2 are added to methanol, ethanol or isopropanol, they are first placed at -30°C to -10°C for 5 days- After 10 days, put it under the condition of 10°C ⁇ 30°C for 5h-12h.
  • the synthetic method comprises the following steps:
  • the iodine-substituted acetylene shown in formula 1 and the ligand shown in formula 2 are added to methanol, ethanol and isopropanol, and the ligand is arranged regularly with the iodine-substituted acetylene to form The intermediate shown in formula 3;
  • the iodine atom on the iodine-substituted ethylenediyne in formula 3 interacts with the pyridine group nitrogen atom at the end of the ligand in formula 2 through a halogen bond, and topologically polymerizes to obtain a conjugated carbon-iodide polymer with the structure shown in formula I;
  • step b The conjugated carbon-iodide polymer with the structure shown in formula I obtained in step b is washed with methanol or dilute hydrochloric acid solution, centrifuged to remove the supernatant, and vacuum-dried to obtain the conjugated carbon-iodide polymer with the structure shown in formula II.
  • a method for preparing an aqueous dispersion containing a conjugated carbon-iodide polymer having the structure shown in formula II wherein the conjugated carbon-iodide polymer having the structure shown in formula II is combined with an amphiphilic polymer
  • the amphiphilic polymer is ultrasonically stripped in water, the hydrophobic end of the amphiphilic polymer is an alkyl chain with a carbon number greater than or equal to 10, and the hydrophilic end is polyethylene glycol, so that the conjugated carbon of the structure shown in the formula II
  • the iodine polymer and the amphiphilic polymer are connected by intermolecular forces to form an aqueous dispersion containing a conjugated carbon-iodide polymer with a structure shown in formula II; the conjugated carbon-iodide polymer with a structure shown in formula II is :
  • the aqueous dispersion containing the conjugated carbon-iodide polymer with the structure shown in formula II prepared by the method is provided.
  • the application of the conjugated carbon-iodine polymer or the aqueous dispersion of the conjugated carbon-iodine polymer containing the structure shown in formula II is provided, specifically for preparing a localization marker.
  • the localization marker is an imaging marker.
  • the imaging marker is an X-ray marker
  • the X-ray marker is a CT imaging marker.
  • the application of the conjugated carbon-iodide polymer is provided, specifically for the preparation of body surface auxiliary labeling sheets.
  • the precise treatment of tumors depends on the guidance of CT images, and appropriate CT markers are often used to assist continuous tracking during the process of precise tumor treatment.
  • the invention discloses a new CT marker based on conjugated carbon-iodine polymer PIDA.
  • the conjugated structure makes PIDA have strong absorption in the visible light region, and the iodine content of PIDA as high as 84.1% corresponds to its super CT imaging ability.
  • PIDA markers can better assist in determining tumor resection margins, thereby achieving precise tumor resection and minimizing damage to surrounding normal tissues.
  • PIDA can replace the clinical gold standard to provide CT marking guidance.
  • the present invention discloses a conjugated polymer containing polydiacetylene (PDA) main chain, but only iodine atom substituents, which can be used for labeling and guiding tumor surgical resection and radiotherapy in vivo.
  • the conjugated polymer in the present invention has high absorption efficiency for visible light and X-rays, good biocompatibility, excellent labeling stability, biodegradability, and wide application range. These properties of PIDA can be used as precise surgery and radiotherapy belts for tumors. A revolutionary breakthrough has come, which has greatly promoted the development of precision tumor treatment.
  • the conjugated polymer itself in the present invention is a nanofiber structure with an iodine content as high as 84.1%.
  • the ultra-high iodine content endows it with ultrahigh X-ray absorption efficiency, and the nanofiber itself is easy to self-assemble to form a group, which is beneficial to It remains stable and does not spread at a specific site.
  • the iodine atom is directly connected to the highly conjugated carbon chain, which endows it with a strong molar extinction coefficient, making it appear dark blue or even black, which is convenient for naked eye observation.
  • the present invention regulates the PIDA block to form a PIDA nanofiber dispersion by introducing an amphiphilic polymer (such as C18-PMH-PEG), so as to achieve local injection to a specific part of the body through an endoscope, which greatly expands the The scope of application of the mark.
  • an amphiphilic polymer such as C18-PMH-PEG
  • the iodine atom substituent of the conjugated polymer in the present invention is connected on both sides of the carbon-carbon double bond of the conjugated main chain, and such a conjugated structure makes the bond energy of the covalent bond between the carbon and iodine lower, and is subjected to It will be broken and deiodinated by stimuli such as Lewis bases.
  • the present invention discloses a conjugated polymer containing polydiacetylene (PDA) main chain, but only iodine atom substituents, which can be used for labeling and guiding precise tumor surgical resection and radiotherapy in vivo.
  • PDA polydiacetylene
  • PIDA has a simple structure and does not contain any other heavy atoms, and its biocompatibility is good.
  • the conjugated structure of the present invention is beneficial to the gradual degradation process of PIDA under external stimuli.
  • Figure 1 is a diagram of the preparation and characterization of PIDA.
  • Figure 2 is a graph showing the stability of PIDA under ionizing radiation.
  • Fig. 3 is the imaging effect diagram of PIDA in the isolated tissue.
  • Fig. 4 is an imaging effect diagram of PIDA in rat muscle.
  • Fig. 5 is a diagram of PIDA-labeled tumor contour-guided surgical resection in rats.
  • Fig. 6 is a diagram of guided surgical resection of tumors in PIDA-labeled rats.
  • Fig. 7 is the effect diagram of PIDA applied to the phantom to simulate the imaging in the human body.
  • Fig. 8 is a diagram showing the distribution of organs in the body of the mannequin.
  • Fig. 9 is a biosafety characterization diagram of PIDA in rat liver.
  • Figure 10 is an implementation diagram of PIDA applied to Cyberknife tracking.
  • Figure 11 is a real view of PIDA implanted in rats under the guidance of CT images.
  • Fig. 12 is a real picture of PIDA implanted in rats and tracked by Cyberknife.
  • Fig. 13 is a real picture of cyberknife tracking with PIDA implanted in a Beagle dog.
  • Figure 14 is a graph showing the degradation of PIDA in vivo and its effects on various organs.
  • Fig. 15 is a diagram of blood analysis after PIDA was implanted in rats.
  • Figure 16 is a schematic diagram of PIDA-guided surgical treatment and CyberKnife radiotherapy.
  • Example 1 Polymer design and CT imaging performance characterization
  • the present invention cultivates single crystal of PIDA monomer and ligand E3 in methanol, and can realize topological polymerization under room temperature to obtain PIDA-E3 co-crystal (a in Fig. 1 ).
  • the three-dimensional structure between the conjugated polymer PIDA and the small molecule ligand E3 was confirmed by single crystal X-ray diffraction analysis (b in Fig. 1 ).
  • the distance between the iodine atom on the side chain of PIDA and the nitrogen atom of the pyridyl group at the end of the ligand E3 is 2.925 angstroms, and the two interact through a strong halogen bond.
  • the small molecule E3 itself is arranged in an orderly manner through the hydrogen bonds between the oxalic acid amide structures, and the distance between the repeating units on PIDA is the same as that of 4.957 angstroms.
  • the main chain of PIDA is a conjugated structure with alternating carbon-carbon double bonds and carbon-carbon triple bonds.
  • the side chain iodine atom substituent is connected to the end of the carbon-carbon double bond, and the angle between C-C-I is 113°.
  • the combination between the PIDA monomer and the ligand E3 is conducive to the 1,4 polymerization of the carbon-carbon triple bond, resulting in the initial PIDA monomer-ligand E3 being light blue when it first forms a crystal at -20 ° C, and at room temperature It can be rapidly polymerized within a few hours under the same conditions, and the final polymer exhibits a metallic luster due to the high degree of polymerization and the completely planar main chain conformation.
  • the present invention introduces the amphiphilic polymer C18-PMH-PEG, the substituent at one end of the polymer is a hydrophobic long alkyl chain, and the substituent at the other end is a hydrophilic Water-based PEG long chain has a good dispersion effect on carbon nanotubes.
  • the PIDA co-crystal and C18-PEM-PEG were ultrasonically stripped in pure water at a mass ratio of 1:1 to obtain a blue dispersion liquid, and the small molecule ligands dissolved in water were removed by dialysis to obtain the blue color of the PIDA polymer. Color water dispersion (c in Figure 1).
  • the positions of the three main Raman characteristic peaks of PIDA dispersion are 966cm -1 , 1417cm -1 and 2075cm -1 , which are closer to PIDA fiber than PIDA cocrystal (d in Figure 1). This indicates that the small molecule ligands are removed, and the main component of the dispersion is PIDA that maintains the alternate conjugation of carbon-carbon double bonds and carbon-carbon triple bonds.
  • the blue PIDA aqueous dispersion corresponds to an ultraviolet-visible absorption peak at 652nm (e in Figure 1), and TEM shows that its microstructure is a dispersed nanofiber structure with a diameter of about 1-3um and a diameter of about 30nm.
  • DLS determined that the particle size was on the order of hundreds of nanometers, and as the concentration increased, it gradually aggregated into fibrous clusters (f in Figure 1).
  • the particle size gradually increases, and the surface charge gradually approaches electrical neutrality, which is related to the fact that nanofibers are easy to aggregate into clusters at the microscopic level.
  • the elemental composition of PIDA characterized by energy spectrum analysis EDX is C: 15.7%, I: 84.3% (g in Figure 1), which is consistent with the theoretical value of PIDA.
  • the X-ray attenuation number is positively correlated with the atomic number and density.
  • the heavy atom iodine with an atomic number of 53 has a strong X-ray attenuation ability.
  • the clinically used CT contrast agents are all small molecules with triiodobenzene as the core. Effective iodine loading is one of the important development directions of CT contrast agents, yet the iodine content of current clinical CT contrast agents such as iohexol (Iohexol) 46.4%, iopromide (Iopromide) 48.1%, iodixanol (Iodixanol) 49.1% etc. failed to exceed 50%.
  • the 84.1% iodine content of PIDA makes it an excellent CT contrast agent.
  • the CT contrast ability gradually increases with the increase of sample concentration. Even at very low concentrations, the CT intensity maintained a good linear relationship with the PIDA concentration.
  • the iodine content of PIDA is 1.81 times that of iohexol, and its imaging efficiency is also 1.76 times that of iohexol (h in Figure 1).
  • the local iodine density increased greatly, and the CT signal intensity directly increased by an order of magnitude from 213HU to 2475HU (i in Figure 1).
  • the CT signal intensity of PIDA in the muscle layer was 17 times that of iohexol (14.5 HU) (Fig. 3).
  • PIDA nanofibers do not diffuse to the surroundings like the small molecule iohexol in a physiological environment, but mainly spontaneously gather locally at the injection site, so as to achieve local CT enhancement under the condition of low iodine concentration. Therefore, the ultra-high iodine content of PIDA endows it with super-strong CT imaging ability, and the aggregation and agglomeration properties of PIDA nanofibers can further improve this ability.
  • the present invention puts PIDA in different states under an X-ray machine for testing.
  • the X-ray machine test condition is 90kV, 4mAs. A total of 50 tests were conducted, and the cumulative radiation dose was 1198.1uGym 2 . Verification of the absorption peak change of PIDA in the PIDA dispersion by UV-Vis absorption, through the introduction of TMB, H 2 O 2 reagents to verify the concentration of iodide ions that may be separated out, both tests show that PIDA remains stable in the test (a, a in Fig. 2 b,c).
  • the present invention has carried out the processing of the cumulative radiation dose of gamma rays of 2Gym to the sample, and the results have also shown the stability of PIDA (d in Fig. 2, e, f). The results demonstrate the stability of PIDA as a benchmark marker in CT diagnosis and radiation therapy.
  • the present invention injects PIDA dispersion liquid and iohexol with the same iodine content locally into the leg muscles of rats respectively under the guidance of CT.
  • the CT signal intensity should be more than 2 times that of the background tissue.
  • the background CT signal of rat muscle tissue is about 50 HU, and the CT marker signal intensity exceeding 100 HU can be regarded as an effective CT marker.
  • the present invention increases the iodine content by 25 times and injects it into the corresponding leg muscles of rats.
  • the results show that the injection site and a large circle around it initially show a strong CT imaging effect, but such enhancement effect rapidly diminishes and continues to the injection point.
  • the surrounding gradually diffused and disappeared completely in less than 6 hours (c in Figure 4).
  • the curve of CT signal intensity versus time shows that 5 mg/ml PIDA dispersion can achieve long-term effective CT labeling, while iohexol with the same iodine content basically has no labeling effect, and the signal intensity attenuates when labeled with ultra-high concentration of iohexol Too fast, the marker position is not fixed (d in Figure 4).
  • the overall experimental results show that, compared with the medical CT contrast agent iohexol, PIDA has high-efficiency CT marking effect and long-term stability at the target position during local injection in vivo, which can better meet the clinical marking needs.
  • the present invention explores the feasibility of using PIDA for tumor marking to guide surgical resection.
  • PIDA is injected around the rat tumor under the guidance of CT.
  • the CT imaging capability of PIDA is used to realize the real-time CT guidance in the process of surgical tumor resection (a in Fig. 5), and on the other hand, the color of PIDA itself is used.
  • the markers mark the tumor outline (b in Figure 5).
  • the present invention directly injects the PIDA dispersion liquid into the tumor under the guidance of CT, and directly performs CT marking and color marking visible to the naked eye on the tumor itself.
  • CT imaging results at different times and the final anatomical observations obtained in the experiment are also in line with the expectations of the present invention.
  • the PIDA inside the tumor always maintains an effective CT marker (a in Figure 6), and it can also be easily distinguished by naked eyes during tumor resection. Dark PIDA locations (c in Fig. 6).
  • the present invention finds that the PIDA dispersion only distributes and gathers inside the tumor contour, even if it is injected at the edge of the tumor, it will not spread to the normal tissue.
  • the change of CT imaging effect of PIDA at different time points inside the tumor is also significantly different from that in normal tissues, and PIDA shows a stronger metabolic process inside the tumor (b in Figure 6).
  • the reason is the unique EPR effect of the tumor, that is, the rich blood supply system and the imperfect lymphatic return lead to the internal retention effect of the tumor. This provides more favorable conditions for PIDA to be used for local marker resection of tumors.
  • the present invention replaces gold markers with PIDA solid fibers, and implants them into the liver of rats under CT guidance for corresponding CT marker-guided follow-up cyberknife treatment (b in FIG. 10 ).
  • the CT imaging results show that while PIDA achieves efficient CT imaging labeling, there is basically no interference from metal artifacts corresponding to gold (b in Figure 7).
  • MRI images after 24 hours verified the local edema induced by the implanted gold marker (c in FIG. 10 ), while there was no significant difference in PIDA (e in FIG. 10 ).
  • the results of dissection (Fig. 9) and the analysis of the blood inflammatory response in the table below further support this conclusion (Fig.
  • the present invention uses the original human CyberKnife treatment mannequin attached to the clinical CyberKnife instrument (Fig. 8).
  • Each movable cylinder in this model corresponds to the CT signal intensity corresponding to real human organs, which can better simulate the CT imaging effect and subsequent radiation dose distribution planning in the human environment.
  • PIDA and gold markers were attached to the surface of cylinders representing different organs of the human body (c in Figure 7). The results showed that PIDA can achieve the effect of local CT marking in the complex human environment, and also exhibit high Quality artifact-free CT imaging (d in Figure 7).
  • the artifact-free CT marking of PIDA is closer to the original real demand, while the artifact of the gold standard has a significant impact on the surrounding dose distribution (Fig. 7 e, f, g).
  • the present invention believes that in addition to the inherent high-efficiency CT imaging of gold markers, PIDA can further reduce its side effects, improve the relative stability of the position and the quality of CT imaging, thereby providing a better therapeutic effect for subsequent CyberKnife. Assure.
  • the International Commission of Radiological Units and Measurements recommends adding markers at the tumor location to compensate for the geometric uncertainty caused by this motion and tumor rotation.
  • Stereotactic body radiation therapy SBRT
  • IGRT image-guided radiation therapy
  • the Cyberknife stereotaxic radiation therapy device (China Nuclear Acre) introduces a fiducial tracking system that requires the use of fiducial markers (radio-opaque markers implanted around or inside the tumor) and synchronized respiration tracking.
  • the CyberKnife can be adjusted in time as the position of the moving target changes. (a in Figure 10)
  • the fiducial tracking system quickly, accurately, and objectively measures the location of trackable fiducials, helping to accurately position and target patients. They can provide the accuracy of benchmark-based IGRTs while maintaining fast, straightforward and objective alignment.
  • the PIDA marker was prepared as a cylinder with a diameter of 1 mm and a length of 3 mm (b in FIG. 10 ).
  • PIDA markers and Au markers were implanted into rat leg muscles (Fig. 11).
  • Fig. 12 We use a human respiratory motion simulation device to assist rats in simulating human respiratory motion (Fig. 12).
  • correlation error we quantify the difference between the target location estimated by the correlation model and the actual location determined by periodic X-ray imaging.
  • the correlation error for the Au label is 0.82 ⁇ 0.36mm, and that for the PIDA label is 0.57 ⁇ 0.19mm.
  • the relevant error value should be kept below 5mm, otherwise the soft stop of the Cyberknife will be triggered.
  • PIDA markers performed well in clinical tracking of Cyberknife in the simulated rat exercise experiment instead of Au markers.
  • the PIDA marker was implanted into the liver of the Beagle dog according to the normal operation standard of the cyberknife implanted gold marker patient, and the operation was performed by a professional surgeon.
  • a memory air cushion designed for the posture of the CyberKnife patient was used here.
  • the memory air cushion is soft in its initial state and can be molded into a specific shape according to the body shape lying in it. When the gas inside is exhausted, the memory air cushion becomes a substrate of a specific shape ( Figure 13).
  • PIDA labeling was clearly visible in the CT images of the beagle liver (g in Figure 10), which is consistent with the previous results of the rat model. According to the CT results, the three-dimensional X-ray distribution map of Beagle Cyberknife radiotherapy was designed (h in Figure 10).
  • PIDA markers in the beagle liver were tracked in real time during breathing motion and matched with the constructed 3D model (i in Fig. 10).
  • the beam is modulated during free breathing due to real-time PIDA marker tracking.
  • the regular breathing motion curve of the Beagles was tracked in real time (j in Figure 10).
  • the associated error value (in millimeters) indicating how well a particular model point agrees with the current synchronized model is 1.07 ⁇ 0.55 mm.
  • the reported error value associated with Au labeling in clinical CyberKnife patients was 1.7 ⁇ 1.1 mm (k in Figure 10).
  • the uncertainty (%) parameter gives the detection uncertainty value of the benchmark extraction algorithm, which is the measurement benchmark configuration for the incorrectness of the extraction.
  • the uncertainty of the PIDA marker is 9.10 ⁇ 2.30% (l in Figure 10), according to the CyberKnife manual the default value of the uncertainty (%) threshold parameter is 40%.
  • the experimental results show that PIDA markers meet the clinical needs in tracking the respiratory movement of the beagle dog liver during cyberknife radiotherapy, and PIDA can realize surgical treatment and cyberknife radiotherapy under the dual guidance of image markers and naked eye observation ( Figure 16) .
  • the present invention mixes different concentrations of PIDA dispersions with rat erythrocytes.
  • the negative control PBS group basically did not have hemolysis
  • the positive control Triton group had complete hemolysis, and was set as a 100% hemolysis control
  • the hemolysis rates of different concentrations of PIDA groups were all lower than 5%, indicating that the corresponding PIDA did not cause erythrocytes to rupture and undergo hemolysis ( d) in Figure 14.
  • the present invention co-incubated PIDA dispersions of different concentrations with 4T1 cells (mouse breast cancer cells), NIH 3T3 cells (mouse embryonic fibroblasts) and HEK 293T (human embryonic kidney cells) for 12 hours, and passed MTT verification cell viability.
  • 4T1 cells mouse breast cancer cells
  • NIH 3T3 cells mouse embryonic fibroblasts
  • HEK 293T human embryonic kidney cells

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Abstract

本发明涉及一种共轭碳碘聚合物及制备与用于制备定位标记物的应用，属于成像标记物技术领域。本发明公开的基于共轭碳碘聚合物全新成像标记物，共轭结构使得该聚合物在可见光区域有很强的吸收，高达84.1％的含碘量对应着其超强的成像能力。在肿瘤手术过程中，基于聚合物的影像标记和肉眼观察双重引导，标记可以更好地协助确定肿瘤切缘，从而实现对肿瘤精准切除，尽可能减少对周边正常组织的损伤。在肿瘤射波刀治疗过程中，本发明中的聚合物可以取代临床金标提供射线标记指引，无金属伪影提高了射线成像质量和更精准的放射剂量分布，良好的生物相容性提高了标记的位置相对稳定性，更进一步可以降低放疗副作用。

Description

一种共轭碳碘聚合物及制备与用于制备定位标记物的应用 【技术领域】
本发明属于成像标记物技术领域，更具体地，涉及一种共轭碳碘聚合物及制备与用于制备定位标记物的应用。
【背景技术】
癌症是世界范围内发病率和死亡率的主要原因。每年大约有1400万新增癌症患者，800万人死于癌症相关疾病。考虑到癌症的高风险和高死亡率，世界各地的研究人员一直在努力开发更精准快速的诊疗方法来对抗癌症。在临床癌症治疗中，大多数癌症治疗方法(如化疗、放疗和手术)都是部分成功的，但也有一定的局限性，而且它们往往会损害周围的健康组织，最终影响病人生存期，肿瘤的精准治疗被认为是未来发展的重要方向。虽然在化疗中现在有很多靶向药物报道，然而患者全身毒性和多药耐药性问题依旧是一个无法避免的难题。故而人们寄希望于放疗中对肿瘤的精准定位和手术中对肿瘤的精准切除，实现这样的目标关键在于医学影像精准引导下的对肿瘤轮廓精准标记和实时追踪。
肿瘤的CT影像是肿瘤诊断和治疗规划过程中最重要的参考依据之一。CT影像分析可以精准展现肿瘤在病人体内的三维形态和相对位置，然而实际手术或者放疗过程中，对肿瘤位置的确定要求极高，而人体正常呼吸运动或者手术操作过程影响难以保持肿瘤与病人表观的相对静止。要想实现在手术或者放疗过程中的肿瘤精准定位，就需要额外引入CT标志物用于实时追踪肿瘤及周边组织器官的状态和相对位置，从而最终实现肿瘤的精准治疗。基于临床需要，对CT标志物的要求主要集中于CT成像质量高，易于肉眼分辨，治疗期间性质和相对位置稳定，生物相容性好，可应用于不同肿瘤治疗场景等。
【发明内容】
本发明解决了现有技术中成像标记物的成像质量不高，相对位置不稳定，以及生物相容性不好的技术问题，本发明提供了一种含有聚二乙炔(PDA)主链，但只有碘原子取代基的共轭聚合物，以及合成方法和用于体内标记引导精准手术切除和放射性治疗。本发明提供的标记物含碘量高，具有超高X射线吸收效率纳米纤维本身容易自组装形成团状物，利于在特定部位保持稳定不扩散，且生物相容性好。
根据本发明第一方面，提供了一种共轭碳碘聚合物，所述共轭碳碘聚合物的结构式包括式Ⅱ所示的结构，所述式Ⅱ为：
Figure PCTCN2022079639-appb-000001
优选地，所述共轭碳碘聚合物的结构式如式Ⅰ或式Ⅱ所示：
Figure PCTCN2022079639-appb-000002
根据本发明另一方面，提供了一种具有式Ⅰ所示结构的共轭碳碘聚合 物的合成方法，反应式如下：
Figure PCTCN2022079639-appb-000003
所述合成方法包括以下步骤：
a、将式1所示碘取代的乙二炔和式2所示配体加入到甲醇、乙醇或异丙醇中，所述配体与所述碘取代的乙二炔进行规则排布，形成式3所示的中间体；
b、式3中碘取代乙二炔上的碘原子与式2中配体末端的吡啶基团氮原子通过卤素键作用，拓扑聚合得到式Ⅰ所示结构的共轭碳碘聚合物；
优选地，步骤a中，式1所示碘取代的乙二炔和式2所示配体加入到甲醇、乙醇或异丙醇之后，先置于-30℃～-10℃条件下5天-10天，再置于10℃～30℃条件下5h-12h。
根据本发明另一方面，提供了一种具有式Ⅱ所示结构的共轭碳碘聚合物的合成方法，反应式如下：
Figure PCTCN2022079639-appb-000004
所述合成方法包括以下步骤：
a、将式1所示碘取代的乙二炔和式2所示配体加入到甲醇、乙醇和异丙醇中，所述配体与所述碘取代的乙二炔进行规则排布，形成式3所示的中间体；
b、式3中碘取代乙二炔上的碘原子与式2中配体末端的吡啶基团氮原子通过卤素键作用，拓扑聚合得到式Ⅰ所示结构的共轭碳碘聚合物；
c、将步骤b得到的式Ⅰ所示结构的共轭碳碘聚合物加入甲醇或者稀盐酸溶液洗涤，离心去掉上清液，真空干燥后得到式Ⅱ所示结构的共轭碳碘 聚合物。
根据本发明另一方面，提供了一种含有式Ⅱ所示结构的共轭碳碘聚合物的水分散液的制备方法，将式Ⅱ所示结构的共轭碳碘聚合物与两亲性聚合物在水中超声剥离，所述两亲性聚合物的疏水端为碳原子数大于等于10个的烷基链，亲水端为聚乙二醇，使所述式Ⅱ所示结构的共轭碳碘聚合物与两亲性聚合物通过分子间作用力连接，形成含有式Ⅱ所示结构的共轭碳碘聚合物的水分散液；所述式Ⅱ所示结构的共轭碳碘聚合物为：
Figure PCTCN2022079639-appb-000005
根据本发明另一方面，提供了所述方法制备得到的含有式Ⅱ所示结构的共轭碳碘聚合物的水分散液。
根据本发明另一方面，提供了所述的共轭碳碘聚合物或含有式Ⅱ所示结构的共轭碳碘聚合物的水分散液的应用，具体为用于制备定位标记物。
优选地，所述定位标记物为成像标记物。
优选地，所述成像标记物为X射线标记物；
优选地，所述X射线标记物为CT成像标记物。
根据本发明另一方面，提供了所述的共轭碳碘聚合物的应用，具体为用于制备体表辅助标记帖。
总体而言，通过本发明所构思的以上技术方案与现有技术相比，主要具备以下的技术优点：
(1)肿瘤的精准治疗依赖于CT影像的引导，合适的CT标记物常用 辅助肿瘤精准治疗过程中的持续追踪。本发明公开了一种基于共轭碳碘聚合物PIDA的全新CT标记物，共轭结构使得PIDA在可见光区域有很强的吸收，PIDA高达84.1％的含碘量对应着其超强的CT成像能力。在肿瘤手术过程中，基于PIDA的CT影像标记和肉眼观察双重引导，PIDA标记可以更好地协助确定肿瘤切缘，从而实现对肿瘤精准切除，尽可能减少对周边正常组织的损伤。在肿瘤射波刀治疗过程中，PIDA可以取代临床金标提供CT标记指引，无金属伪影提高了CT成像质量和更精准的放射剂量分布，良好的生物相容性提高了PIDA标记的位置相对稳定性，更进一步可以降低放疗副作用。并且与临床金标使用后永久留在人体内不同，PIDA在治疗期间发挥作用，治疗结束后几个月后会逐渐生物降解。与临床相对应的标记物对比，PIDA在多种肿瘤治疗模式中可以表现出了对应的功能，更可以弥补现有标记的缺陷和不足，更好的满足临床使用需求。
(2)本发明公开了一种含有聚二乙炔(PDA)主链，但只有碘原子取代基的共轭聚合物用于体内标记引导肿瘤精准手术切除和放射性治疗。本发明中的共轭聚合物对可见光和X射线吸收效率高，生物相容性好，标记稳定性优异，生物可降解，可适用范围广，PIDA的这些性质应用为肿瘤的精准手术和放疗带来了革命性的突破，大大推进肿瘤精准治疗的发展。
(3)本发明中的共轭聚合物本身为碘含量高达84.1％的纳米纤维结构，超高碘含量赋予了其超高X射线吸收效率，而纳米纤维本身容易自组装形成团状物，利于在特定部位保持稳定不扩散。碘原子直接连接在高度共轭的碳链上，这赋予了其强摩尔消光系数，使其呈现深蓝色乃至黑色，利于肉眼观察。
(4)本发明通过引入两亲性聚合物(如C18-PMH-PEG)，将PIDA块体调控形成PIDA纳米纤维分散液，从而通过内窥镜实现对体内特定部位的局部注射，这大大拓展了标记应用范围。
(5)本发明中的共轭聚合物碘原子取代基连接在共轭主链的碳碳双键 两侧，这样的共轭结构使得碳碘之间共价键的键能较低，在受到如路易斯碱等刺激时会断裂脱碘。
(6)本发明公开了一种含有聚二乙炔(PDA)主链，但只有碘原子取代基的共轭聚合物用于体内标记引导肿瘤精准手术切除和放射性治疗。PIDA作为纯粹的碳碘非金属有机高分子，结构成分简单，不含有任何其他重原子，其生物相容性良好。本发明的共轭结构有利于PIDA在外界刺激下的逐渐降解过程。
【附图说明】
图1为PIDA的制备与表征图。
图2为PIDA在电离辐射下的稳定性表征图。
图3为PIDA在离体组织中成像效果图。
图4为PIDA在大鼠肌肉中成像效果图。
图5为PIDA标记大鼠肿瘤轮廓引导手术切除图。
图6为PIDA标记大鼠肿瘤内部引导手术切除图。
图7为PIDA应用于人体模体模拟人体内成像效果图。
图8为人体模特体内器官分布图。
图9为PIDA在大鼠肝脏的生物安全性表征图。
图10为PIDA应用于射波刀追踪实施图。
图11为PIDA在CT影像引导下植入大鼠体内实景图。
图12为PIDA种植于大鼠体内应用射波刀追踪实景图。
图13为PIDA种植于比格犬体内应用射波刀追踪实景图。
图14为PIDA在体内降解与对各个器官的影响表征图。
图15为PIDA种植于大鼠体内后血液分析图。
图16为PIDA引导手术治疗和射波刀放疗示意图。
【具体实施方式】
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合附图 及实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅仅用以解释本发明，并不用于限定本发明。此外，下面所描述的本发明各个实施方式中所涉及到的技术特征只要彼此之间未构成冲突就可以相互组合。
实施例1：聚合物设计与CT成像性能表征
Figure PCTCN2022079639-appb-000006
根据配体-受体共晶聚合合成方法，本发明将PIDA单体和配体E3在甲醇中培养单晶，在室温条件下即可实现拓扑聚合得到PIDA-E3共晶(图1中的a)。通过单晶X射线衍射解析，确认共轭聚合物PIDA与小分子配体E3之间的三维结构(图1中的b)。PIDA侧链上的碘原子与配体E3末端的吡啶基团氮原子之间间距为2.925埃米，两者之间通过强烈的卤素键作用。而小分子E3自身通过草酸酰胺结构之间的氢键有序排布，与PIDA上重复单位距离相同均为4.957埃米。PIDA主链为碳碳双键和碳碳三键交替的共轭结构，侧链碘原子取代基连接在碳碳双键端，C-C-I之间夹角为113°。PIDA单体与配体E3之间的结合有利于碳碳三键的1，4聚合，导致初始得到的PIDA单体-配体E3在-20℃刚形成结晶时即为浅蓝色，在室温条件下几个小时以内即可快速聚合，由于聚合度高且完全平面主链构象使最终的聚合物展现出金属光泽。
为了对PIDA共晶形态和物理性质进行调节以便于后续应用，本发明引入了两亲性聚合物C18-PMH-PEG，聚合物一端取代基为疏水性长烷基链，另一端取代基为亲水性PEG长链，对碳纳米管有很好的分散效果。将PIDA共晶与C18-PEM-PEG按照1：1质量比在纯水中超声剥离即可得到蓝色的分散液，通过透析除去溶于水中的小分子配体，得到了PIDA聚合物的蓝色 水分散液(图1中的c)。
由于聚(二乙炔)主链的大极化率和高度共轭平面，PIDA共晶具有很强的拉曼散射强度，三个主要的拉曼特征峰967cm -1,1396cm -1和2064cm -1分别对应着C-C，C＝C和C≡C的伸缩振动。而PIDA分散液的三个主要拉曼特征峰位置为966cm -1,1417cm -1和2075cm -1，相比较而言与PIDA fiber而非PIDA cocrystal更为接近(图1中的d)。这表明小分子配体被除去，分散液主要成分为保持碳碳双键和碳碳三键交替共轭的PIDA。
蓝色PIDA水分散液对应的紫外可见吸收峰在652nm(图1中的e)，TEM显示其微观结构为直径约为长1～3um，直径30nm左右的分散纳米纤维结构。DLS测定其粒径为百纳米量级，且随着浓度升高其逐渐聚集为纤维团(图1中的f)。粒径逐渐增大，且表面电荷也逐渐趋近于电中性，这与纳米纤维微观层面上容易聚集成团有关。通过能谱分析EDX表征PIDA其元素组成为C:15.7％,I:84.3％(图1中的g)，与PIDA理论值相符合。
X射线衰减序数与原子序数、密度呈正相关关系，原子序数为53的重原子碘具有很强的X射线衰减能力，目前临床使用的CT造影剂均为以三碘苯为核心的小分子，提高有效的碘负载量是CT造影剂的重要发展方向之一，然而目前临床的CT造影剂的含碘量如碘海醇(Iohexol)46.4％，碘普罗胺(Iopromide)48.1％，碘克沙醇(Iodixanol)49.1％等均未能超过50％。PIDA 84.1％的含碘量使其具有作为优异的CT造影剂潜质。通过对不同浓度的PIDA和目前最常用的医用CT造影剂碘海醇对比，发现随着样品浓度提高CT造影能力也逐渐增强。即使在很低的浓度条件下，CT强度依旧与PIDA浓度保持很好的线性关系。且由于碘的X射线衰减能力与所处分子结构环境无关，PIDA含碘量为碘海醇的1.81倍，测得其成像效率也为碘海醇的1.76倍(图1中的h)。更进一步，PIDA纳米纤维局部浓缩为纤维团的时候，其局部碘密度大大增加，其CT信号强度从213HU直接提升了一个数量级，到达2475HU(图1中的i)。
将PIDA应用于离体组织CT成像，探究PIDA聚集诱导CT增强在离体组织中应用。在PIDA分散液和相同碘含量的碘海醇对猪皮下注射，检测CT增强对比试验中发现，同等碘含量条件下，碘海醇在猪肉脂肪层和肌肉层中注射后均出现明显弥散现象，导致CT成像信号较弱，PIDA注射后在局部形成亮斑，CT信号强。PIDA在肌肉层中CT信号强度(87.8HU)是对应碘海醇CT信号强度(21.7HU)的4倍。而在相对更为致密的肌肉层中，PIDA在肌肉层中CT信号强度(251.7HU)是对应碘海醇的CT信号强度(14.5HU)的17倍(图3)。这是因为在生理环境下PIDA纳米纤维不会像小分子碘海醇那样向四周大量弥散，而是主要在注射部位自发性局部聚集，从而实现低浓度碘含量条件下局部CT增强。因而，PIDA的超高含碘量赋予了其超强的CT成像能力，且PIDA纳米纤维自身的聚集成团性质可以进一步提高此能力。
为了验证PIDA在不同辐射条件下的稳定性，本发明将不同状态的PIDA置于X光机下测试。X光机测试条件为90kV,4mAs。累计测试50次，累计放射剂量为1198.1uGym 2。通过紫外可见吸收验证PIDA分散液中PIDA的吸收峰变化，通过引入TMB,H 2O 2试剂验证可能析出的碘离子浓度，两项测试均表明在测试中PIDA保持稳定(图2中的a,b,c)。同样的为了验证正常放射治疗中γ射线对PIDA的影响，本发明对样品进行了累计2Gym 2的γ射线累计辐射剂量的处理，结果同样表明了PIDA的稳定性(图2中的d,e,f)。结果证明了PIDA作为基准标记物在CT诊断和放射治疗中的稳定性。
实施例2：动物体内多重局部标记
为了验证PIDA的超强CT成像效果是否可以推向实际应用，本发明在CT引导下将PIDA分散液和同等碘含量的碘海醇分别局部注射到大鼠腿部肌肉中。对于有效的CT标记而言，其CT信号强度应是背景组织的2倍以上。大鼠肌肉组织背景CT信号约为50HU，则CT标记信号强度超过100HU 即可被视为有效CT标记。结果表明PIDA组肌肉注射处即表现出明显的CT增强效果，考虑到临床术前加术中整体操作有效时间，发现6h内PIDA始终保持着强效CT增强效果(图4中的a)。相对应的碘海醇组肌肉注射处则在整个过程中基本未观察到有局部增强(图4中的b)。
为了进一步验证PIDA CT成像的高效性和位置稳定性。本发明将碘含量提高了25倍注入大鼠对应腿部肌肉处，结果表明注射部位及周边很大一圈初始表现出很强的CT成像效果，但是这样的增强效果快速消减且不断向注射点周边逐渐弥散，不到6h即完全消失(图4中的c)。CT信号强度随时间变化曲线表明，5mg/ml的PIDA分散液即可以实现长期有效的CT标记，而同等碘含量的碘海醇基本没有标记效果，超高浓度的碘海醇标记则信号强度衰减过快，标记位置不固定(图4中的d)。整体实验结果表明，相比医用CT造影剂碘海醇，PIDA在活体局部注射过程中具有目标位置高效CT标记效果和长时间稳定性，可以更好的满足临床标记需求。
确定了PIDA在溶液和肌肉组织中均具有良好的CT标记效果之后，本发明探究了PIDA用于肿瘤标记以引导手术切除的可行性。本发明在CT引导下将PIDA注射在大鼠肿瘤周边，一方面利用PIDA的CT成像能力实现对手术肿瘤切除过程中的实时CT引导(图5中的a)，另一方面利用PIDA本身的颜色标记对肿瘤轮廓进行标记(图5中的b)。对注射部位不同时间内的CT信号追踪表明，表明与快速消失无法起到有效CT标记作用的碘海醇相比(图5中的d)，PIDA标记在肿瘤周边，其信号强度和相对位置均表现出很好的时间稳定性，可以一直很好的勾勒肿瘤轮廓(图5中的c,e)。24h后对大鼠进行解剖，透过表皮黏膜也可以很轻易的发现分布在肿瘤四周的PIDA标记(图5中的f)。基于手术切除中的肿瘤轮廓CT影响和肉眼观察双重引导，PIDA更好的协助确定肿瘤切缘，从而实现对肿瘤精准切除，尽可能减少对周边正常组织的损伤。
除了对大块肿瘤的边缘勾勒之外，手术过程中微小肿瘤如淋巴结转移 瘤在体内的相对位置确认也是一个重要的难题，CT影像确认的微小肿瘤在手术过程中难以对应找到其具体位置。针对此种应用场景，本发明在CT引导下将PIDA分散液直接注入到肿瘤内部，直接对肿瘤本身进行CT标记和肉眼可见的颜色标记。实验得到的不同时间CT成像结果和最终的解剖观察也符合本发明的预期，肿瘤内部的PIDA始终保持着有效CT标记(图6中的a)，并且肿瘤切除过程中也可以肉眼很轻易的分辨深色的PIDA位置(图6中的c)。更有意思的是，本发明发现PIDA分散液只分布聚集在肿瘤轮廓内部，即使是注射在肿瘤边缘位置，也不会扩散到正常组织部位。同时PIDA在肿瘤内部的不同时间点CT成像效果变化也与其在正常组织中表现出了明显的差异，PIDA在肿瘤内部表现出更强的代谢过程(图6中的b)。原因是肿瘤独特的EPR效应，即丰富的供血系统，不完善的淋巴回流导致肿瘤的内部滞留效果。这为PIDA用于肿瘤的局部标记切除提供了更有利的条件。
实施例3：PIDA标记用于射波刀治疗
除了肿瘤手术切除之外，放射也是肿瘤治疗中的一个重要手段，目前最前沿的精准放疗方式——射波刀治疗依赖于植入的标记物准确的CT定位(图10中的a)。目前临床常用的金单质标记物虽然可以满足CT定位标记的CT信号强，位置相对稳定的需求，但是其易引发局部水肿，进而导致定位偏移。生物相容性差，体内永久滞留难以降解。CT金属伪影严重(图7中的a)，影响了CT成像质量和后续的放射剂量分布图的规划。这样问题降低了射波刀的治疗疗效，限制了其进一步的推广使用。基于此，本发明将PIDA固体纤维代替金标记物，在CT引导下植入大鼠肝脏部位进行响应的CT标记引导后续射波刀治疗(图10中的b)。CT成像结果表明PIDA在实现高效的CT成像标记的同时，基本没有金对应的金属伪影的干扰(图7中的b)。24小时后MRI成像图验证植入的金标记物引发的局部水肿(图10中的c)，而PIDA则无明显差异(图10中的e)。解剖结果(图9)和下表中的血液炎症反应分析进一步支持了这个结论(图9)，并且金由于生物 相容性不好，与组织之间贴合并不紧密，存在明显的间隙(图10中的d)，这也是临床使用时金标记物出现概率性脱靶的问题。而PIDA则与组织基本融为一体，愈合程度高，难以脱落分离(图10中的f)。
Figure PCTCN2022079639-appb-000007
为了更进一步贴近临床实际应用场景，本发明使用临床射波刀仪器附带的原装人体射波刀治疗模特(图8)。这个模特中每个可活动的圆筒对应着真实的人体器官对应的CT信号强度，可以更好的模拟人体环境下CT成像效果及后续的放射剂量分布规划。将PIDA和金标记物分别附着在代表人体不同器官的圆筒表面(图7中的c)，结果表明PIDA可以很好的在复杂的人体环境中实现局部CT标记的效果，并且同样表现出高质量无伪影的CT成像(图7中的d)。
依据CT成像分布确认后续射波刀治疗的放射剂量分布图时，PIDA的无伪影CT标记更贴近原始真实需求，而金标伪影则对周边剂量分布产生了明显的影响(图7中的e,f,g)。基于此，本发明认为PIDA除了具有金标记物固有的高效CT成像之外，更进一步可以降低其副作用，提高位置相对稳定性和CT成像质量，从而为后续射波刀治疗效果提供了更好的保障。
为了进一步验证PIDA在实际射波刀中表现，我们将PIDA分别植入到大鼠和比格犬体内，使用临床射波刀病人治疗规范对大鼠和比格犬分别进行呼吸运动追踪和后续射波刀治疗。整个过程符合射波刀追踪需求，大鼠最终追踪。
放射治疗的重大挑战之一是补偿由患者呼吸引起的肿瘤运动。国际放射单位和测量委员会(ICRU)建议在肿瘤位置增加标记以补偿由这种运动和肿瘤旋转引起的几何不确定性。基于现状需求，基于图像引导放疗(IGRT)和运动管理技术进步的立体定向放射治疗(SBRT)已被广泛应用。射波刀立体定向放射治疗装置(中核安科锐)引入了需要使用基准标记(植入肿瘤周围或内部的不透射线标记)和同步呼吸跟踪的基准跟踪系统。射波刀可以随着移动目标位置的变化进行时间调整。(图10中的a)
基准跟踪系统可以快速、准确、客观地测量可跟踪基准的位置，有助于准确定位和瞄准患者。它们可以提供基于基准的IGRT的准确性，同时保持快速、直接和客观的对齐。为了验证PIDA标志物在临床射波刀放疗跟踪中的性能，我们根据射波刀手册使用不同的模型动物进行射波刀跟踪放疗。
根据标准Au标记的形状，将PIDA标记制备成直径为1mm、长度为3mm的圆柱体(图10中的b)。在CT图像的引导下，将PIDA标记和Au标记植入大鼠腿部肌肉(图11)。我们使用一种人体呼吸运动模拟装置用于辅助大鼠模拟人体呼吸运动(图12)。对于相关误差，我们量化了相关模型估计的目标位置与由周期性X射线成像确定的实际位置之间的差异。Au标记的相关误差为0.82±0.36mm，PIDA标记的相关误差为0.57±0.19mm。根据射波刀操作手册，相关误差值应保持在5毫米以下，否则将触发射波刀的软停止。PIDA标记在模拟大鼠运动实验中替代Au标记实现射波刀临床跟踪表现良好。
按照射波刀植入金标记患者的正常操作标准，将PIDA标记植入比格犬的肝脏，由专业外科医生进行手术。为保证射波刀治疗过程中术前CT建模与Beagle犬姿势的一致性，这里采用了针对射波刀患者姿势设计的记忆气垫。记忆气垫在初始状态下是柔软的，可以根据躺在里面的体型塑造成特定的形状。当里面的气体排出后，记忆气垫就变成了特定形状的基板(图 13)。在比格犬肝脏的CT图像中PIDA标记清晰可见(图10中的g)，这与之前的大鼠模型的结果一致。根据CT结果确定设计了Beagle射波刀放射治疗的三维X射线分布图(图10中的h)。
在呼吸运动期间实时跟踪比格犬肝脏中的PIDA标记并与构建的3D模型匹配(图10中的i)。由于实时PIDA标记跟踪，光束在自由呼吸期间被调制。实时跟踪比格犬的规律呼吸运动曲线(图10中的j)。指示特定模型点与当前同步模型的一致性程度的相关误差值(以毫米为单位)为1.07±0.55毫米。据报道临床射波刀患者中Au标记的相关误差值为1.7±1.1mm(图10中的k)。不确定性(％)参数给出了基准提取算法的检测不确定性值，是对提取的不正确性的度量基准配置。PIDA标记的不确定性为9.10±2.30％(图10中的l)，根据射波刀手册不确定性(％)阈值参数的默认值为40％。实验结果表明，PIDA标志物在射波刀放疗中跟踪比格犬肝脏呼吸运动过程中满足临床需要，PIDA可以实现影像标记和肉眼观察的双重引导下的手术治疗和射波刀放疗(图16)。
实施例4：PIDA标记物的生物相容性与生物可降解性
在材料应用于生物医学领域时，除了材料特殊的成像/治疗效果之外，最受大家关注的就是材料本身的生物相容性。在细胞层面，本发明通过将不同浓度的PIDA分散液和大鼠的红细胞混合。阴性对照PBS组基本没有出现溶血现象，阳性对照Triton组完全溶血，设置为100％溶血对照，不同浓度PIDA组则溶血率均低于5％，即表明对应的PIDA没有使红细胞破裂发生溶血现象(图14中的d)。此外，本发明将不同浓度的PIDA分散液分别与4T1细胞(小鼠乳腺癌细胞)、NIH 3T3细胞(小鼠胚胎成纤维细胞)和HEK 293T(人胚肾细胞)共同孵育12h，通过MTT验证细胞存活状态。结果表明对应的PIDA均未对细胞表现出明显的杀伤作用(图14中的e)。
在动物层面，将5mg/ml的PIDA分散液注入大鼠腿部肌肉后，大鼠体重正常增长，并且生理状态观察与对照组相比无明显差异。同时，观察到 七天之后PIDA在肌肉和肿瘤中CT信号均最终消失，这表明它在治疗期间可以提高良好的CT成像效果，治疗结束后则会自行降解消失，不会对后续的成像治疗乃至日常生活造成困扰隐患(图14中的a,b,c)。实验观察过程中大鼠状态良好，体重正常增长，与PBS对照组无显著性差异(图14中的f)。主要脏器的组织切片结果显示PIDA在整个过程中均不存在相应的全身毒性(图14中的g)。血常规的相关指标(白细胞，红细胞，血红蛋白，血小板)(图15的a)和肝肾功能检测的相关指标(丙氨酸转氨酶，天冬氨酸转氨酶，碱性磷酸酶，肌酐)(图15的b)的检测对比，PIDA组和PBS对照组的正常大鼠相关指标无显著性差异(图15)，表明对生理状态无影响。在不同时间点将注射点的组织取出测试拉曼，结果表明PIDA的拉曼信号也随着时间变化而逐渐降低最终彻底消失。另外一方面，PIDA固体纤维和金标记物肝脏植入对比，对应种植部位肝脏组织金标记物组出现了明显的细胞坏死，而对应的血液中肝肾功能分析也表明其有明显的炎症反应，而PIDA组未观察到异常。综上而言，PIDA具有良好的生物安全性和生物可降解性。
我们将PIDA通过医用胶带固定在大鼠体表，CT结果表明PIDA在体内清晰可见，并且位置相对体内各种器官较为固定，PIDA在体表随着皮肤运动而伴随运动，可以一定程度上反应大鼠本身的呼吸运动，为相应射波刀治疗提供追踪识别。
本领域的技术人员容易理解，以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 一种共轭碳碘聚合物，其特征在于，所述共轭碳碘聚合物的结构式包括式Ⅱ所示的结构，所述式Ⅱ为：
    Figure PCTCN2022079639-appb-100001
  2. 如权利要求1所述的共轭碳碘聚合物，其特征在于，所述共轭碳碘聚合物的结构式如式Ⅰ或式Ⅱ所示：
    Figure PCTCN2022079639-appb-100002
  3. 一种具有式Ⅰ所示结构的共轭碳碘聚合物的合成方法，其特征在于，反应式如下：
    Figure PCTCN2022079639-appb-100003
    所述合成方法包括以下步骤：
    a、将式1所示碘取代的乙二炔和式2所示配体加入到甲醇、乙醇或异丙醇中，所述配体与所述碘取代的乙二炔进行规则排布，形成式3所示的中间体；
    b、式3中碘取代乙二炔上的碘原子与式2中配体末端的吡啶基团氮原子通过卤素键作用，拓扑聚合得到式Ⅰ所示结构的共轭碳碘聚合物；
    优选地，步骤a中，式1所示碘取代的乙二炔和式2所示配体加入到甲醇、乙醇或异丙醇之后，先置于-30℃～-10℃条件下5天-10天，再置于10℃～30℃条件下5h-12h。
  4. 一种具有式Ⅱ所示结构的共轭碳碘聚合物的合成方法，其特征在于，反应式如下：
    Figure PCTCN2022079639-appb-100004
    所述合成方法包括以下步骤：
    a、将式1所示碘取代的乙二炔和式2所示配体加入到甲醇、乙醇和异丙醇中，所述配体与所述碘取代的乙二炔进行规则排布，形成式3所示的中间体；
    b、式3中碘取代乙二炔上的碘原子与式2中配体末端的吡啶基团氮原子通过卤素键作用，拓扑聚合得到式Ⅰ所示结构的共轭碳碘聚合物；
    c、将步骤b得到的式Ⅰ所示结构的共轭碳碘聚合物加入甲醇或者稀盐酸溶液洗涤，离心去掉上清液，真空干燥后得到式Ⅱ所示结构的共轭碳碘 聚合物。
  5. 一种含有式Ⅱ所示结构的共轭碳碘聚合物的水分散液的制备方法，其特征在于，将式Ⅱ所示结构的共轭碳碘聚合物与两亲性聚合物在水中超声剥离，所述两亲性聚合物的疏水端为碳原子数大于等于10个的烷基链，亲水端为聚乙二醇，使所述式Ⅱ所示结构的共轭碳碘聚合物与两亲性聚合物通过分子间作用力连接，形成含有式Ⅱ所示结构的共轭碳碘聚合物的水分散液；所述式Ⅱ所示结构的共轭碳碘聚合物为：
    Figure PCTCN2022079639-appb-100005
  6. 如权利要求5所述方法制备得到的含有式Ⅱ所示结构的共轭碳碘聚合物的水分散液。
  7. 如权利要求1所述的共轭碳碘聚合物、权利要求2所述的共轭碳碘聚合物或权利要求6所述的含有式Ⅱ所示结构的共轭碳碘聚合物的水分散液的应用，其特征在于，具体为用于制备定位标记物。
  8. 如权利要求7所述的应用，其特征在于，所述定位标记物为成像标记物。
  9. 如权利要求8所述的应用，其特征在于，所述成像标记物为X射线标记物；
    优选地，所述X射线标记物为CT成像标记物。
  10. 如权利要求1或2所述的共轭碳碘聚合物的应用，其特征在于，具体为用于制备体表辅助标记帖。
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