780衍生物的合成、鉴定及其用于肿瘤靶向显影与治疗的实验研究

  本文关键词：七甲川花菁类荧光小分子IR-780衍生物的合成、鉴定及其用于肿瘤靶向显影与治疗的实验研究，由笔耕文化传播整理发布。

七甲川花菁类荧光小分子IR-780衍生物的合成、鉴定及其用于肿瘤靶向显影与治疗的实验研究

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摘要

研究背景与目的
     尽管近几十年来人们对肿瘤的发生发展、转移等机制研究获得了重要进展，但由于仍缺乏灵敏的早期诊断、高特异性的靶向治疗以及实时有效的治疗监测，恶性肿瘤依然是目前严重威胁人类健康的重大疾病。肿瘤诊断治疗学(Tumor theranostics)是近些年提出来的一种肿瘤诊治新策略，其核心是将肿瘤治疗与实时显影有效结合，引导医生及时调整治疗方案，提高肿瘤病人的生存率和生活质量，为肿瘤个体化治疗提供一种新途径。由于制备同时具有肿瘤特异显影与靶向治疗作用的诊断治疗剂(Theranosticagents)是同步实现肿瘤诊断与治疗的重要途径，因此近两年就该类多功能抗肿瘤药物的研发已成为继分子靶向药物后的新研究热点。
     目前对于诊断治疗剂的制备主要是通过两种策略：一是通过多步化学连接策略，将肿瘤靶向配体，如叶酸、多肽、抗体、核酸适配体等，分别与造影剂和抗肿瘤药物进行连接，从而同时实现肿瘤靶向显影与治疗作用；另一种是基于纳米材料的特殊性质，如利用尺寸依赖性的肿瘤组织增透与阻滞(EPR)效应，或利用其比表面积大，易于表面修饰各种靶向配体的优点，实现肿瘤药物的被动或主动靶向递送，同时利用纳米材料自身显影特性或进一步偶联显影剂，实现肿瘤的靶向显影与治疗监测。通过上述两种策略，目前已经获得了一些具有潜在应用价值的诊断治疗剂。例如，99mTc标记的阿霉素脂质体已经在进入I期临床试验，用于头颈鳞癌病人的治疗与监测。
     然而，通过多步化学连接策略制备诊断治疗剂，可能会导致肿瘤配体靶向性的降低、显影剂成像能力的减弱，甚至药物抗肿瘤活性的丧失。此外，多步化学反应与分离纯化，还可能增加制备成本。特别是基于多功能纳米材料策略制备的诊断治疗剂，容易在内皮网状系统，例如肝脾等组织器官沉积，存在制备复杂、成本较高、潜在毒性等缺点，其应用也受到了很大限制。因此，优化诊断治疗剂的制备方法，或发展新的制备策略具有重要研究意义。
     七甲川花菁类化合物是一类两端氮杂环中间含有多个次甲基长共轭链的花菁小分子，其具有摩尔吸光系数大、荧光量子产率高、稳定性好等优点，作为近红外荧光探针，已经被广泛应用于蛋白与核酸标记、基因测序、动物活体成像以及临床造影等。其中，代表性分子吲哚菁绿(ICG)，已经在临床上广泛用于心脏、肝脏、眼底血管显影等。最近，我们课题组首次报道七甲川花菁荧光小分子IR-780，不需要化学连接肿瘤靶向配体，即在多种肿瘤细胞及其荷瘤模型上显示出良好的肿瘤靶向近红外荧光显影特性。进一步亚细胞器共定位实验结果表明， IR-780选择性蓄积在肿瘤细胞的线粒体内，其亲脂性离域型阳离子特性可能与其靶向肿瘤细胞线粒体密切相关。
     由于IR-780具有良好的肿瘤选择性和近红外荧光显影特性，其也为肿瘤靶向诊断治疗药物的研究提供了新的思路和途径。基于课题组前期研究基础，本研究设想：（1）IR-780能否作为抗肿瘤药物的新型靶向载体，即通过化学连接策略，将抗肿瘤药物与IR-780进行共价连接，能否获得同时具有肿瘤靶向近红外显影与治疗作用的多功能化合物？（2）能否不经过化学连接抗肿瘤药物策略，直接通过对IR-780分子结构进行修饰，通过类似物的合成与筛选，获得自身同时具有肿瘤靶向显影与治疗作用的新型多功能诊断治疗剂，为肿瘤诊断治疗剂探索新的制备策略，为肿瘤个体化治疗提供新途径。
     研究方法与结果
     为了验证上述假设，获得同时具有肿瘤靶向、近红外荧光显影与治疗作用的多功能七甲川花菁分子，本论文分三个部分开展研究，主要结果如下：
     1. IR-780羧基衍生物IR-808的合成及肿瘤近红外荧光显影特性的鉴定
     1.1首先建立并优化了该类七甲川花菁类荧光小分子的合成方法，分别对合成该类七甲川花菁荧光小分子需要的三步反应，即Vilsmeier-Haack甲酰化、N-烷基化、缩合反应进行了改进。与以往文献中报道的常用合成方法相比，新建立的合成方法具有高效简洁、易大量制备等优点，为大量合成七甲川花菁荧光小分子、进一步化学修饰与药物连接奠定了基础。
     1.2衍生合成了含有羧基官能团的IR-780衍生物—IR-808。鉴于IR-780缺乏可供直接化学连接抗肿瘤药物的活性反应官能团，需要对其进行结构修饰。本研究以6-溴己酸为原料，在合成IR-780的反应原料中引入羧基活性反应官能团，成功合成了含有两个羧基活性反应官能团的IR-780衍生物IR-808，并经过核磁共振氢谱(1H-NMR)、碳谱(13C-NMR)、高分辨质谱(HRMS)测试确证其结构。
     1.3IR-808肿瘤靶向近红外荧光显影特性的鉴定。经光谱测试发现，IR-808的最大吸收和发射波长均在700-900nm近红外光谱区，具有近红外显影特性和良好的血清稳定性。体内实验表明，IR-808在rTDMCs、HeLa及LCC三种肿瘤细胞动物荷瘤模型中均显示出较好的肿瘤靶向性，提示其用于肿瘤特异性显影与诊断具有潜在应用前景。研究结果表明，IR-808不仅保留了良好的肿瘤靶向近红外荧光显影特性，同时还引入了两个可供化学连接反应的羧基官能团，为进一步化学修饰、药物连接，或放射性核素标记等奠定了基础；为获得同时具有肿瘤靶向显影与治疗作用的多功能分子，或经放射性核素等标记后用于深部组织肿瘤成像与诊断提供了可能性。
     2. IR-808与抗癌药物的化学连接及其肿瘤显影和杀伤活性的实验研究
     2.1成功地将IR-808与临床上常用的三种抗肿瘤药物进行了共价连接。利用IR-808具有羧基活性反应官能团的结构特性，选择临床上常用的分子量小、抗瘤谱广、活性强但选择性差的抗肿瘤药物，包括美法仑(Melphalan)、5-氟尿嘧啶(5-Fu)、阿霉素(DOX)，分别与IR-808进行化学连接，获得与美法仑的连接物IR-808NM，与5-Fu的连接物IR-808-5Fu以及与阿霉素的共价连接物IR-808DOX。前两者获得纯品化合物，其结构经过1H NMR及HRMS测试所确定。后者经HRMS测试证明阿霉素与IR-808连接成功，但经反复优化反应与纯化条件，未获得纯品IR-808DOX。
     2.2对新合成的共价连接产物进行肿瘤显影与杀伤活性的评价。通过上述化学连接策略，将IR-808成功与抗肿瘤药物连接并获得纯品的新共价连接物IR-808NM、IR-808-5Fu分别进行评价。结果表明，IR-808NM保留较好的肿瘤靶向特性，但IR-808-5Fu则失去了肿瘤靶向性。进一步应用MG63骨肉瘤细胞和SW480结肠癌细胞进行IR-808NM的抗肿瘤活性评价。结果显示，IR-808NM对两种细胞的生长抑制活性显著高于对照药美法仑。因此，通过化学连接策略，本研究成功获得了同时具有肿瘤靶向显影与治疗作用的新型多功能荧光小分子IR-808NM，验证了IR-780类似荧光小分子可作为抗肿瘤药物靶向载体的设想。
     3. IR-808酯化衍生物的合成与抗肿瘤活性研究
     鉴于我们的研究和相关文献报道IR-780和某些花菁类分子在较高剂量时可表现出一定的线粒体毒性，本研究提出，通过对IR-808进行酯化衍生化，以提高亲脂性，使其更容易跨过磷脂双层疏水性的线粒体膜，从而增大其在线粒体的浓度及毒性，可望获得不需要化学连接抗肿瘤药物，自身具有肿瘤靶向、近红外荧光显影与抗肿瘤活性的新型多功能小分子。
     3.1IR-808酯化衍生物的高效合成及其近红外荧光显影特性的鉴定。为了提高IR-808亲脂性，显著增强其进入细胞及其线粒体的浓度与毒性，在IR-808的基础上，设计合成四个IR-808亲脂性强的酯化衍生物，包括丁酯(IR-808DB)、己酯(IR-808DH)、环己酯(IR-808DCH)、苯酚酯(IR-808DP)，均为全新结构的化合物，未见文献报道。所建立的合成方法具有高效、易于大量制备等优点。四种IR-808酯类衍生物在甲醇、DMSO、血清中的最大吸收和发射波长均在近红外区域，具有比ICG更高的摩尔吸光系数和荧光量子产率。
     3.2筛选获得IR-808DB具有显著抗肿瘤活性。应用人肺癌细胞(A549)研究发现，IR-808丁酯衍生物(IR-808DB)具有最显著的抗肿瘤活性(IC50值为0.43μM)。进一步在乳腺癌细胞(MDA231、MCF-7)、肝癌细胞(SMMC-7721, HepG2)、肺癌细胞(NCIH-460)等多种人类肿瘤细胞模型中评价其抗肿瘤活性，结果显示IR-808DB分子对多种肿瘤细胞均具有显著的生长抑制作用(IC50<6μM)。通过荷瘤动物体内研究，发现IR-808DB在rTDMCs、Lewis、HeLa以及A549等四种肿瘤模型上，均显示出较强的抗肿瘤活性。以20mg/kg临床药物环磷酰胺(CTX)为阳性对照，发现5mg/kg IR-808DB可以明显抑制肿瘤的生长。治疗过程中，荷瘤动物的重量和生理状态未见明显异常，主要脏器的组织切片未见明显病理改变。此外，通过荷瘤动物体内研究，比较IR-808DB和新合成的共价连接物IR-808NM的抗肿瘤活性，还发现IR-808DB的抗肿瘤活性显著高于IR-808NM。
     3.3IR-808DB具有良好的肿瘤靶向显影特性。近红外荧光活体成像显示，IR-808DB在大鼠rTDMCs荷瘤模型上显示出肿瘤靶向特性；离体脏器和肿瘤组织的近红外荧光成像进一步证实其在肿瘤组织的选择性蓄积。研究还表明，在荷瘤第4天肉眼未见明显肿瘤包块形成时，荷瘤部位即可显示出近红外荧光显影；当肉眼可见小于0.5cm的肿瘤包块形成时，荷瘤部位即具有显著的近红外荧光显影特性，提示IR-808DB在肿瘤早期识别与诊断中可能具有研究价值。
     结论与创新
     本研究首先建立并优化了IR-780多种衍生物的化学合成方法，制备了含有羧基官能团的IR-808，证明其具有良好的肿瘤靶向近红外荧光显影特性，为连接抗肿瘤药物或放射性核素等显影剂，制备可用于深部组织肿瘤成像和具有肿瘤治疗作用的多功能分子奠定了基础。进而，利用IR-808具有羧基活性反应官能团的结构特性，成功地与三种抗肿瘤药物进行共价连接，筛选获得了同时具有肿瘤靶向显影与杀伤作用的衍生物IR-808NM，验证了IR-780类似荧光小分子可作为抗肿瘤药物靶向载体的设想。最后，通过对IR-808进行酯化修饰，提高其亲脂性，从而增强其线粒体毒性，制备获得了不需要化学连接抗肿瘤药物，自身具有肿瘤靶向、近红外荧光显影与抗肿瘤活性的新型化合物IR-808DB，为进一步研发新型的肿瘤个体化诊断治疗药物提供了新的策略和途径。目前，IR-808DB已获得国家发明专利授权，其抗肿瘤机制与进一步安全性评价等临床前研究正在进行中。
Background and Objectives：
     Despite recent research involving cancer development and metastasis has gainedsignificant progress, malignant tumor still remains one of the most deadly diseases in theworld, due to the inefficient early diagnosis, poor specificity of drugs resulting in severeadverse effects, and lack of sensitive and real-time modalities to monitor therapeuticresponse. Tuomr theranostics, a fusion of therapeutics and diagnostics for optimizingefficacy and safety in cancer treatment, has been considered as a significant alternativenessto overcome these challenges. This integration can monitor therapeutic efficacy followingtreatments which can expedite clinician’s individualized therapeutic decisions. Becausetheranostic agents are of importance to achieve the simultaneous multifunctionality oftumor targeting, imaging and therapy, their preparation has received a great deal of researchinterest in recent years.
     Currently, there are two main strategies explored for the obtainment of suchmultifunctional theranostic agents. One approach is through the multi-step chemicalconjugation of anticancer drugs and contrast agents with various cancer-targeted ligands,such as small molecules, antibodies, peptides, aptamers, etc. With the rapid development onadvanced multifunctional nanomaterials in nanomedicine, the other approach fordevelopment of cancer theranostic agents is based on nanoplatforms. They achievesimultaneous cancer specific detection and therapeutics by specifically delivering a highlypotent cytotoxic agent toward tumors either through the EPR effect of the tumormicrovasculature or through the conjugation of target ligands which can specifically bind tobiomakers highly associated with cancer cells. In many cases, advanced nanomaterialsendowed with imaging capability have been engineered to deliver and release drugsselectively toward tumor tissues. With the two strategies referred abrove, some cancer targeted therapeutic drugs are approved for clinical use or clinical trial. For example,99mTclabeing lipidosomes loaded with DOX has been approved to carry out clinic Phase I trial. Itachieves treatment of head and neck squamous carcinoma by SPECT imaging.
     However, the conjugation may alter the functional activities of tumor-targeted ligands,contrast agents or therapeutic agents. Multi-step chemical conjugation may lead to lowerthe specificity of tumor ligands, weaken the imaging intensity of contrast agents, or lose theantitumor activity of drugs. Meanwhile, additional reaction agents and purificationprocedure in the multi-step conjugation would require higher cost. In particular,nanoplatform-based strategy for the multifunctional nanotheranostic agents has been provenchallenging and is still at an early or proof-of-concept stage due to several fundamentalproblems and technical barriers, such as the lag effect from reticuloendothelial system (RES)and mononuclear phagocytic system, the difficulties in large scale preparation with highreproductivity, and the potential safe concerns for their long-term fate and toxicity. Thus,investigation of new strategy for obtainment of theranostic agents is high necessary.
     Heptamethine cyanine dyes with two terminal indole heterocyclic units linked by apolymethine bridge, characterized with high molar absorption coefficient and fluorescencequantum yield, good photostability, have been applied widely in labeling nucleic acids andproteins, gene sequencing, in vivo imaging animals. Of them, Indocyanine green (ICG)has been used in clinic extensively for visualizing tiny blood vessels of livers and eyes.Recently, our studies have characterized a heptamethine cyanine dye, IR-780with tumortargeting and NIR imaging properties without chemical conjugation of tumor target ligand.The targeting property of IR-780also has been confirmed in a broad spectrum of tumorcells and tumor xenografts, suggesting an attractive diagnostic agent for sensitive andnoninvasive tumor detection. The subcellular localization of IR-780in tumor cells furthershowed that the dye exclusively accumulated in the mitochondria of tumor cells. Theunique property of delocalized lipophilic cation, may give IR-780the ability to target andretain in mitochondria of tumor cells.
     Based on our previous findings on IR-780simultaneously with tumor targeting andNIR imaging properties, we hypothesized:(1) whether IR-780could be used as a carrier tochemically conjugate antitumor drugs for tumor targeted imaging and therapy;(2) whetherthe intrinsically multifunctional heptamethine cyanine dyes could be obtained by rational modification of IR-780without need of chemical conjugation of antitumor durgs. If thesedesigns mentioned above are proved, they would provide a valuable strategy for preparationof theranositc agents applied in cancer personalized therapy.
     Methods and Results：
     In order to verify the hypotheses referred above, and obtain multifunctionalheptamethine cyanine dyes with tumor targeted imaging and therapeutic properties, thisdissertation is divided into three chapters and main results are as follows:
     1. Synthesis and characterization of a carboxyl derivative of IR-780for tumortargeting and NIR imaging
     1.1A modified synthetic method for heptamethine cyanine dyes was established. Dueto low efficiency and small-scale limitation in preparing heptamethine cyanine dyes aspreviously reported in literatures, an improved synthetic method needs to be established.The synthetic routes of heptamethine cyanine dyes including Vilsmeier-Haack formylationreaction, N-alkylation reaction and condensation reaction, were optimized for theconditions of reaction and post-treatment, resulted in the improvement of syntheticefficiency with large-scale available preparation, providing a basis for further drugconjugation.
     1.2IR-808, a derivative of IR-780with two reactive carboxyl groups was synthesized.In order to obtain multifunctional heptamethine cyanine dyes simultaneously with tumortargeted imaging and antitumor activites, IR-780needs to chemically conjugate with anantitumor drug. However, IR-780is lack of available functional group in its structure forfurther conjugation. IR-808was synthesized by using6-bromo hexanoic acid as the startingmaterial to introduce a carboxyl group in a key raw material which was used to synthesizeIR-780. Its structure was comfirmed with Hydrogen nuclear magnetic resonance (1H-NMR),Carbon-nuclear magnetic resonance (13C-NMR) and High resolution mass spectrum(HRMS).
     1.3IR-808was identified with good tumor targeting and NIR imaging properties.After determining the spectra of IR-808, it was found the peak wavelength of absorbtionand emission was in the NIR region (700-900nm). IR-808exhibited NIR fluorescentimaging ability and pretty good stability in serum. The preferential in vivo tumoraccumulation of IR-808was comfirmed in rTDMCs, HeLa and LLC tumor xenografts, suggesting a prospective potential used for tumor specific imaging and diagnosis. Insummary, our results showed that IR-808with two reactive carboxyl groups exhibited thetumor targeting and NIR imaging properties, providing a basis for further drug conjugation.This finding also provides a possibility in developing a radionuclide-labelled heptamethinecyanine dyes for deep-tumor imaging and diagnosis.
     2. Conjugation of IR-808with antitumor drugs for tumor-targeted imaging andtreatment
     2.1Three clinically available antitumor drugs were covalently conjugated with IR-808.On the basis of the above studies, IR-808was further designed to conjugate with antitumordrugs. We successfully conjugated IR-808with Melphalan,5-Fluoro-2,4(1H,3H)pyrimidinedione (5-Fu), Doxorubicin(DOX), and obtained IR-808NM, IR-808-5Fu andIR-808DOX, respectively. IR-808NM and IR-808-5Fu were afforded with high purity, andtheir structures were comfirmed with1H NMR and HRMS. Successful conjugation of DOXwith IR-808was ensured by the testing report of HRMS. However, IR-808DOX wasafforded with a low pure complex even through continuously optimizing the conditions ofreaction and purification.
     2.2The tumor targeted imaging and antitumor activity of IR-808NM and IR-808-5Fuwere investigated. The two conjugations were injected into the rTDMCs tumor-bearingmice to evaluate their specificity for tumor imaging. In vivo NIR imaging showed thatIR-808NM remained the tumor-targeted NIR imaging ability while IR-808-5Fu failed. Then,the antitumor activity of IR-808NM was evaluated with MG63osteosarcoma cancer cellsand SW480colon cancer cells. It was found that IR-808NM inhibited the growth of cancercells efficiently. Its antitumor activity was significantly higher than that of Melphalan.These results supported that we successfully developed a multifunctional heptamethinecyanine dye with chemical conjugation strategy, and verify the hypothesis that this kind oftumor targeting NIR dyes can be used as a carrier of antitumor drugs for tumor targetedimaging and therapy.
     3. Synthesis of esterified derivatives of IR-808for tumor treatment
     According to our previous work and others, some caynine dyes, including IR-780would exhibit mitochondrial toxicity at higher concentration. Because mitochondria areencircled with two lipophilic membranes, lipophilic agents are more readily transported across bistratal membranes to reach a higher concentration. Basing on these investigations,we hypothesized that esterification of IR-808, would increase its lipophilicity greatly, aswell as its mitochondrial accumulation and potential toxicity. In this case, multifunctionalheptamethine cyanine dyes simultaneously with tumor targeted imaging and antitumoractivity would be obtained without need of chemical conjugation to tumor specific ligands.
     3.1Four esterified derivatives of IR-808were synthesized and characterized with NIRimaging property. In order to improve the lipophilicity of IR-808, and significantly enhancetheir accumulation and toxicity in tumor mitochondria, several esterified derivatives ofIR-808including butyl ester (IR-808DB), hexyl ester (IR-808DH), cyclohexyl ester(IR-808DCH), phenol ester (IR-808DP) were prepared with a highly efficient andlarge-scale available method. All these newly synthesized molecules have not been reportedpreviously. These molecules in methanol, DMSO and serum exhibited the maximumabsorption and emission wavelengths in the NIR region. Compared with ICG, esterderivatives of IR-808exhibited higher molar extinction coefficient and fluorescencequantum yields.
     3.2IR-808DB was characterized with significant antitumor effect. Cytotoxicity ofIR-808and its ester derivatives were performed on A549human lung cancer cells. Studiesshowed that these ester derivatives exhibited diverse anticancer activities on A549carcinoma cells. Of them, IR-808DB displayed most remarkable antitumor activity with anIC50of0.43μM. We further confirmed the antitumor effect of IR-808DB in other humancancer cell lines, including breast cancer cells (MDA231and MCF-7), hepatoma cells(SMMC-7721, HepG2), and non-small-cell lung cancer NCIH-460cells, demonstrating apotent antitumor activity of IR-808DB (IC50<6μM) on a broad spectrum of tumor cells. Invivo tumoricidal activities of IR-808DB were then evaluated in rTDMCs, A549, LLC, andHeLa tumor xenografts. Results revealed that5mg/kg IR-808DB inhibited tumor growthobviously as compared to20mg/kg Cyclophosphamide (CXT) group, a classic antitumordrug which has been widely applied in clinic. Laudable tumoricidal activities of IR-808DBwere observed in rTDMCs, A549, LLC and HeLa tumor xenografts, suggest the potentantitumor activity of IR-808DB in a variety of tumor xenografts. Meanwhile, the bodyweight and physical conditions of mice after treatment were not changed significantly. Inaddition, organs harvested from the mice with IR-808DB treatment were subjected to histopathological analysis and also showed no apparent abnormalities. The tumor growthinhibition of IR-808DB was also compared with IR-808NM, and results revealed thatIR-808DB displayed significantly higher tumor growth inhibition effect than IR-808NMdid.
     3.3IR-808DB was demonstrated with the ability of tumor-targeted imaging. In vivoNIR fluorescence imaging of athymic nude mice bearing with rTDMCs tumor xenograftsshowed IR-80DB with tumor targeting capability. The fluorescent intensity of the dissectedorgans and tumors further confirmed the preferential accumulation of IR-808DB in tumors.To evaluate its potential application in tumor early diagnosis,0.4mg/kg (imaging dosage)of IR-808DB was injected into the rats bearing rTDMCs tumors through tail vein and thefluorescent signals associated with tumor site were clearly detected even the tumor was notvisualized by eyes, indicating a potential used for tumor early identification and diagnosis.
     Conclusion and Innovation:
     In this dissertation, we initially established a modified synthetic method for IR-780and its derivatives, synthesized an analogue of IR-780with reactive carboxyl groups(IR-808) with tumor targeting and NIR imaging properties, providing a basis for furtherdrug conjugation. Next, IR-808was conjugated with three clinically available antitumordrugs respectively, and a multifunctional derivative of IR-808with tumor targeting andantitumor activity (IR-808NM) was successfully obtained. These results supported that wesuccessfully developed a multifunctional heptamethine cyanine dye with chemicalconjugation strategy, and verify the hypothesis that this kind of tumor targeting NIR dyescan be used as a carrier of antitumor drugs for tumor targeted imaging and therapy. Finally,by esterification of IR-808to increase its lipophilicity as well as its mitochondrialaccumulation and toxicity, we eventually obtained a multifunctional heptamethine cyaninedye (IR-808DB) intrinsically with tumor targeted imaging and antitumor effect withoutneed of chemical conjugation to tumor specific ligands. As a potential antitumor drug,IR-808DB has advantages of not only good tumor targeting, potent antitumor effect andfine NIR imaging, but also small molecular weight, low cost and large-scale availablepreparation. This multifunctional small molecule presents a valuable strategy forpreparation of new theranositc agents in cancer personalized therapy.

引文

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  本文关键词：七甲川花菁类荧光小分子IR-780衍生物的合成、鉴定及其用于肿瘤靶向显影与治疗的实验研究，由笔耕文化传播整理发布。