WO2024051308A1 - 一种靶向α型叶酸受体的培美近红外荧光分子及其制备方法和应用 - Google Patents
一种靶向α型叶酸受体的培美近红外荧光分子及其制备方法和应用 Download PDFInfo
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- WO2024051308A1 WO2024051308A1 PCT/CN2023/103821 CN2023103821W WO2024051308A1 WO 2024051308 A1 WO2024051308 A1 WO 2024051308A1 CN 2023103821 W CN2023103821 W CN 2023103821W WO 2024051308 A1 WO2024051308 A1 WO 2024051308A1
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- infrared fluorescent
- pemetrexed
- preparation
- type folate
- peimei
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- 102000006815 folate receptor Human genes 0.000 title claims abstract description 30
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
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- NYDXNILOWQXUOF-UHFFFAOYSA-L disodium;2-[[4-[2-(2-amino-4-oxo-1,7-dihydropyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]amino]pentanedioate Chemical compound [Na+].[Na+].C=1NC=2NC(N)=NC(=O)C=2C=1CCC1=CC=C(C(=O)NC(CCC([O-])=O)C([O-])=O)C=C1 NYDXNILOWQXUOF-UHFFFAOYSA-L 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
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- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1003—Carbocyclic compounds
- C09K2211/1007—Non-condensed systems
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1018—Heterocyclic compounds
- C09K2211/1025—Heterocyclic compounds characterised by ligands
- C09K2211/1029—Heterocyclic compounds characterised by ligands containing one nitrogen atom as the heteroatom
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1018—Heterocyclic compounds
- C09K2211/1025—Heterocyclic compounds characterised by ligands
- C09K2211/1059—Heterocyclic compounds characterised by ligands containing three nitrogen atoms as heteroatoms
Definitions
- the invention belongs to the field of medical technology, and particularly relates to a near-infrared fluorescent molecule targeting ⁇ -type folate receptors and its preparation and application in preparing drugs for inhibiting the growth of non-small cell lung cancer.
- Non-small cell lung cancer is a malignant tumor with high clinical incidence.
- the screening, diagnosis and treatment of non-small cell lung cancer have always been a research topic of great clinical importance.
- non-small cell lung cancer can be diagnosed. Patients often present with symptoms such as fever and chest tightness, but lack typical symptoms. As the disease progresses to an advanced stage, the mortality rate is high.
- Pemetrexed disodium is currently used clinically to treat advanced non-small cell lung cancer, but the effect of single drug application is limited. It is necessary to develop a more effective structure for inhibiting the growth of non-small cell lung cancer.
- Folate receptors comprise a family of glycosylphosphonylidene nolitol (GPI)-anchored folate (FA) high-affinity receptors that are the products of at least four different genes: FR ⁇ , ⁇ , ⁇ , and ⁇ .
- GPI glycosylphosphonylidene nolitol
- FA folate
- Pemetrexed an antifolate
- Clinically Used Pemetrexed whose cellular uptake is primarily through endocytosis of ubiquitously expressed human folate receptors (FRs) and transported into cells, has been proposed as a means to specifically deliver novel antifolate conjugates to tumor or inflammatory sites. target.
- the glutamic acid group in the tail will form a polymerized form, which increases the residence time in the cell, thus prolonging the inhibitory effect of tumor cells.
- the purpose of the present invention is to provide a near-infrared fluorescent molecule targeting ⁇ -type folate receptor and its preparation method and application.
- a near-infrared fluorescent molecule targeting alpha-type folate receptors its structural formula is:
- a method for preparing Peimei near-infrared fluorescent molecules targeting ⁇ -type folate receptors including the following steps:
- step (1) heat to 120°C for 18 hours in a nitrogen atmosphere.
- step (2) heat to 110°C and react for 48 hours.
- step (3) reflux and heat for 6 hours in a nitrogen atmosphere.
- step (4) react at room temperature for 30 minutes.
- step (7) the temperature of the reaction mixture is raised to 90°C, stirred at 90°C for 45 minutes, and the formation of compound 7 is monitored by TLC. After the formation of compound 7 is completed, the reaction mixture is cooled to room temperature, and The casing was transferred to stirring acetone as a steady stream to obtain a green precipitate. The precipitate was filtered on a sintered funnel under vacuum, washed with acetone, and the green powdery solid was dried under high vacuum for 12 h to obtain compound 7.
- the near-infrared fluorescent molecules targeting ⁇ -type folate receptors provided by the present invention can be used for treatment Non-small cell lung cancer, by comparing the clinically approved non-small cell lung cancer chemotherapy drug pemetrexed and the new pemetrexed near-infrared fluorescent molecule on non-small cell lung cancer.
- This new pemetrexed near-infrared fluorescent molecule is compared with pemetrexed.
- Metrexed has a three-fold inhibitory effect on the growth of non-small cell lung cancer and is significantly different from pemetrexed in inhibiting tumor tissue growth.
- the design strategy of this molecule is to combine already obtained clinically approved therapeutic agents, which has good druggability and biological safety.
- Figure 1 is a synthetic flow chart for preparing Peimei near-infrared fluorescent molecules
- Figure 2 is the fluorescence performance chart of Peimei near-infrared fluorescent molecules
- Figure 3 is the near-infrared fluorescence molecular hydrogen spectrum of Peimei
- Figure 4 is the near-infrared fluorescence molecular mass spectrum of Peimei
- Figure 5 is a diagram showing the inhibitory effects of Pemet near-infrared fluorescent molecules and pemetrexed on the growth of H1299 cells with high expression of ⁇ -type folate receptors;
- Figure 6 is a diagram showing the inhibitory effects of Pemet near-infrared fluorescent molecules and pemetrexed on the growth of A549 cells with low expression of ⁇ -type folate receptors;
- Figure 7 shows the growth inhibition of H1299 cells by folic acid inhibiting the near-infrared fluorescent molecules of Peimei;
- Figure 8 shows that Peimei near-infrared fluorescent molecules have no inhibitory effect on normal liver cells
- Figure 9 shows the inhibition of tumor growth in nude mice by Peimei near-infrared fluorescent molecules
- Figure 10 shows the detection of cell apoptosis inside the A549 tumor by TUNEL after treatment
- Figure 11 shows the detection of cell apoptosis inside the H1299 tumor by TUNEL after treatment.
- the preparation method of Peimei near-infrared fluorescent molecules targeting ⁇ -type folate receptors includes the following steps:
- Non-small cell lung cancer cell inhibition experiment Select non-small cell lung cancer cells H1299 with high expression of ⁇ -type folate receptors, non-small cell lung cancer cells A549 with low expression of ⁇ -type folate receptors, and macrophages with high expression of ⁇ -type folate receptors.
- mice Animal non-small cell lung cancer tumor growth inhibition experiment: To explore the tumor growth inhibitory effects of pemetrexed and pemetrexed near-infrared fluorescent molecules on H1299 tumor-bearing mice.
- Tumor size was measured every two days and the mean and standard deviation were calculated. Compared with the control group, pemetrexed group *p ⁇ 0.05, and pemetrexed near-infrared fluorescent molecule group compared with the control group **p ⁇ 0.01.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种靶向α型叶酸受体的培美近红外荧光分子及其制备方法和应用，培美近红外荧光分子的结构式为：所述的靶向α型叶酸受体的培美近红外荧光分子能够应用于制备治疗非小细胞肺癌的药物中。通过将临床批准的非小细胞肺癌化疗药物培美曲塞与新型培美近红外荧光分子对非小细胞肺癌药效对比，这种新型培美近红外荧光分子相较于培美曲塞，对非小细胞肺癌的生长抑制效果提升了三倍，以及在抑制肿瘤组织生长方面相较于培美曲塞具有显著性差异。同时该分子的设计策略是将已经获得的临床批准的治疗剂组合在一起，具有较好的成药性与生物安全性。
Description
本发明属于医药技术领域，特别涉及一种靶向α型叶酸受体的培美近红外荧光分子及其制备和用于制备抑制非小细胞肺癌生长药物的应用。
非小细胞肺癌属于临床高发恶性肿瘤，非小细胞肺癌的筛查、诊断及治疗一直是临床高度重视的研究课题。依据组织病理学可经非小细胞肺癌，患者多出现发热、胸闷等症状，缺乏典型症状，随着病情进展发展至晚期，死亡率高。目前临床对晚期非小细胞肺癌采取培美曲塞二钠治疗，但单药应用效果有限，需开发对非小细胞肺癌生长抑制作用更加有效的结构。
叶酸受体(FR)包括一个糖基膦酰亚基诺糖醇(GPI)锚定的叶酸(FA)高亲和力受体家族，是至少四种不同基因的产物：FRα，β，γ和δ。尽管许多研究都将α型叶酸受体(FRα)作为肿瘤治疗和成像的靶点。培美曲塞作为一种抗叶酸剂几十年来已被用于治疗癌症和炎症性疾病。临床使用培美曲塞的细胞摄取主要通过广泛表达的人类叶酸受体(FRs)的内吞作用转运至细胞内部，已被提议作为将新型抗叶酸剂缀合物特异性递送至肿瘤或炎症部位的靶标。据文献报道，培美曲塞分子在进入到细胞内部时，尾部的谷氨酸基团会形成多聚态形式，增加了细胞内的滞留时间，从而延长了肿瘤细胞的抑制作用。基于此，我们对尾部谷氨酸进行修饰，连接近红外荧光基团，对非小细胞肺癌具有较好的生长抑制作用，对术中残余灶的清除具有较好的应用。
发明内容
为解决上述现有技术中存在的问题，本发明的目的是提供一种靶向α型叶酸受体的培美近红外荧光分子及其制备方法和应用。
为实现上述目的，本发明采用如下技术方案：
一种靶向α型叶酸受体的培美近红外荧光分子，其结构式为：
一种靶向α型叶酸受体的培美近红外荧光分子的制备方法，包括以下步骤：
(1)将4-肼苯磺酸、3-甲基-2-丁烷、冰醋酸混合加热反应，在乙酸乙酯中沉淀后，过滤和收集粗产物，将所得产物溶解在甲醇中，溶解液滴加入氢氧化钾和异丙醇的混合溶液中，粗混合物过滤洗涤，得到化合物2；
(2)将化合物2和1,4-丁磺酸内酯在氮气氛加入甲苯溶液中加热反应，得到化合物3；
(3)将化合物3、Vilsmeier-Haack试剂和无水乙酸钠加入无水乙醇中，在氮气气氛下加热反应，反应混合物冷却至室温，然后过滤，用乙醇和甲醇洗涤，得到化合物4；
(4)将培美水解酸溶于N,N-二甲基甲酰胺中，搅拌至溶解，将HATU、O-叔丁基-L-酪氨酸叔丁基酯盐酸盐、DIEA依次加入反应容器中，搅拌至完全溶解，氮气保护，室温反应，将反应后的溶液滴加在HCl中，产生淡黄色沉淀，抽滤真空干燥，得化合物5
(5)将化合物5放入反应容器中，加入TFA和H2O的混合液，搅拌，加入甲基叔丁基醚中，沉淀过滤，真空干燥，得到化合物6；
(6)向S0456的水溶液中，滴加pH 11的Pemetrexed-Tyr三阴离子溶液，加热反应，得到化合物7，即所述靶向α型叶酸受体的培美近红外荧光分子；
所述步骤(1)中，加热到120℃在氮气氛下18h。
所述步骤(2)中，加热到加热110℃，反应48h。
所述步骤(3)中，在氮气气氛下回流加热6h。
所述步骤(4)中，在室温反应30min。
所述步骤(7)中，将反应混合物的温度升至90℃，在90℃下搅拌45分钟，并通过TLC监测化合物7的形成，化合物7形成完成后，将反应混合物冷却至室温，并通过套管作为稳定流转移至搅拌的丙酮中，得到绿色沉淀，沉淀物在抽气机真空下在烧结漏斗上过滤，用丙酮洗涤，将绿色粉末状固体在高真空下干燥12h，得到化合物7。
所述的靶向α型叶酸受体的培美近红外荧光分子在制备治疗非小细胞肺癌的药物中的应用。
有益效果：本发明提供的靶向α型叶酸受体的培美近红外荧光分子能够用于治疗
非小细胞肺癌，通过将临床批准的非小细胞肺癌化疗药物培美曲塞与新型培美近红外荧光分子对非小细胞肺癌药效对比，这种新型培美近红外荧光分子相较于培美曲塞，对非小细胞肺癌的生长抑制效果提升了三倍，以及在抑制肿瘤组织生长方面相较于培美曲塞具有显著性差异。同时该分子的设计策略是将已经获得的临床批准的治疗剂组合在一起，具有较好的成药性与生物安全性。
图1是制备培美近红外荧光分子合成流程图；
图2是培美近红外荧光分子荧光性能图；
图3是培美近红外荧光分子氢谱图；
图4是培美近红外荧光分子质谱图；
图5是培美近红外荧光分子和培美曲塞对α型叶酸受体高表达细胞H1299生长抑制效果图；
图6是培美近红外荧光分子和培美曲塞对α型叶酸受体低表达细胞A549生长抑制效果图；
图7是叶酸抑制培美近红外荧光分子对H1299细胞的生长抑制情况；
图8是培美近红外荧光分子对正常肝细胞无抑制作用；
图9是培美近红外荧光分子对裸鼠肿瘤生长抑制情况；
图10是治疗后通过TUNEL检测A549肿瘤内部细胞凋亡情况；
图11是治疗后通过TUNEL检测H1299肿瘤内部细胞凋亡情况。
下面结合附图对本发明做更进一步的解释。
实施例1
如图1所示，本实施例中，靶向α型叶酸受体的培美近红外荧光分子的制备方法，包括以下步骤：
1、氯代ICG衍生物母体的合成：
(1)4-肼苯磺酸(1.6g,31.9mmol)，3-甲基-2-丁烷(2.10ml,90mmol)冰醋酸(50mL)混合加热到120℃在氮气氛下18h。在乙酸乙酯中沉淀后，以粉红色固体的形式过滤和收集粗产物,所得产物(6.5g,25.4mmol)溶解在甲醇(50mL)中。在温和的条件下，溶解液滴加如以氢氧化钾(1.7g,30mmol)和异丙醇(20mL)的溶液中，粗混合物过滤洗涤，得到棕色固体，产率97％；
(2)将化合物2(2.3g,8.3mmol)和1,4-丁磺酸内酯在氮气氛加入甲苯溶液中
加热110℃，反应48h。将混合料冷却至室温，溶剂析出。在粗混合物中加入甲醇(10mL)搅拌30分钟:粗混合物过滤，收集，在2:1(v/v)水混合物中溶解(10mL)和甲醇(50mL)。用滴液漏斗将混合溶液慢慢加入乙腈(160mL)中。沉淀物被过滤并收集为粉红色固体，产率40％；
(3)将化合物3(1.5g,2.79mmol)、Vilsmeier-Haack试剂(0.5g,1.39mmol)和无水乙酸钠(0.342g,4.17mmol)在20mL的无水乙醇中，在氮气气氛下回流加热6h。反应混合物冷却至室温，然后过滤，用乙醇和甲醇洗涤，收集为棕绿色固体，产率90％；
2、培美靶向药物合成：将培美水解酸(1.05g,3.52mmol)溶于DMF中，搅拌至溶解，将HATU(2.007g,5.28mmol)、O-叔丁基-L-酪氨酸叔丁基酯盐酸盐(1.161g,3.52mmol)、DIEA(1.364g,10.56mmol)依次加入烧瓶中，搅拌至完全溶解，氮气保护，室温反应30min将反应后的溶液滴加在0.1N aq.HCl(1.0L,0.14M)，产生淡黄色沉淀，抽滤真空干燥，得2.04g固体，即化合物5，产率95％。
将化合物5(2.04g,3.34mmol)放入圆底烧瓶中，加入10mLTFA：H2O(体积比95：5)，搅拌两小时，加入甲基叔丁基醚中，沉淀过滤，真空干燥，得1.507g化合物6，产率98％。
3、培美近红外荧光分子的制备：在23℃下向S0456(2.909g，3.276mmol)的水(18mL)溶液中，滴加pH 11的Pemetrexed-Tyr(1.507g，3.276mmol)三阴离子溶液。将反应混合物的温度升至90℃，在90℃下搅拌45分钟，并通过TLC监测化合物7的形成。产物形成完成后，将反应混合物冷却至室温，并通过套管作为稳定流转移至搅拌的丙酮(0.5L)中，得到绿色沉淀，沉淀物在抽气机真空下在烧结漏斗上过滤，用丙酮(3×500mL)洗涤。将绿色粉末状固体在高真空下干燥12h，得到4.34g化合物7，即培美近红外荧光分子；
实施例2
为了验证本发明的效果，进行了如下验证实验：
(1)非小细胞肺癌细胞抑制实验：选取α型叶酸受体高表达非小细胞肺癌细胞H1299,和α型叶酸受体低表达非小细胞肺癌细胞A549以及β型叶酸受体高表达巨噬细胞R264.7和正常肝细胞。细胞在37℃下，在5％CO2和95％空气的潮湿空气中，以及含有10％FBS以及1％双抗的RPMI培养基中培养。各种细胞在96孔板中接种，保证每孔细胞数在3-5x105。培养24h后，每孔细胞分别用不同剂量的培美近红外荧光分子(0、10-4、10-3、10-2、0.1、1、
10、100、1000μmol/L)、培美曲塞(0、10-4、10-3、10-2、0.1、1、10、100、1000μmol/L)。孵育24h后加入10μLMTT试剂到每孔中，在37℃的培养箱中避光孵育2h，所有测试孔在450nm处的吸光度值(OD值)使用按照制造商的说明进行酶标仪(Bio-Rad)。简而言之，通过比较实验组与空组的OD值以及两种使用的药物的半数最大抑制浓度(IC50)来计算不同处理的每种细胞系的抑制率和存活率。
(2)动物非小细胞肺癌肿瘤生长抑制实验：为了探究培美曲塞和培美近红外荧光分子对H1299荷瘤鼠的肿瘤生长抑制作用。A.给裸鼠腋下注射细胞(0.2mL细胞悬液)。当植入的肿瘤达到90-100mm3的体积时，小鼠被随机分配到以下实验组之一(每组n＝5)：不治疗，培美曲塞(7mg/kg，尾静脉注射，每周三次)，培美近红外荧光分子(21mg/kg，尾静脉注射，每周三次)。使用公式估算肿瘤体积：体积＝L×W2/2。每两天测量一次肿瘤尺寸并计算平均值与标准差。培美曲塞组与对照组相比*p<0.05，培美近红外荧光分子组与对照组相比**p<0.01。B.在实验结束时，从小鼠身上切除肿瘤组织。显示了来自所有组的代表性肿瘤组织。C.肿瘤切片。通过对比肿瘤切片TUNEL检测结果，绿色荧光代表肿瘤内部细胞凋亡情况，目的是从微观情况验证培美近红外荧光分子对α型叶酸受体高表达肿瘤的生长抑制情况。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (8)
- 一种靶向α型叶酸受体的培美近红外荧光分子，其特征在于：其结构式为：
- 一种权利要求1所述的靶向α型叶酸受体的培美近红外荧光分子的制备方法，其特征在于：包括以下步骤：(1)将4-肼苯磺酸、3-甲基-2-丁烷、冰醋酸混合加热反应，在乙酸乙酯中沉淀后，过滤和收集粗产物，将所得产物溶解在甲醇中，溶解液滴加入氢氧化钾和异丙醇的混合溶液中，粗混合物过滤洗涤，得到化合物2；
(2)将化合物2和1,4-丁磺酸内酯在氮气氛加入甲苯溶液中加热反应，得到化合物3；
(3)将化合物3、Vilsmeier-Haack试剂和无水乙酸钠加入无水乙醇中，在氮气气氛下加 热反应，反应混合物冷却至室温，然后过滤，用乙醇和甲醇洗涤，得到化合物4；
(4)将培美水解酸溶于N,N-二甲基甲酰胺中，搅拌至溶解，将HATU、O-叔丁基-L-酪氨酸叔丁基酯盐酸盐、DIEA依次加入反应容器中，搅拌至完全溶解，氮气保护，室温反应，将反应后的溶液滴加在HCl中，产生淡黄色沉淀，抽滤真空干燥，得化合物5
(5)将化合物5放入反应容器中，加入TFA和H2O的混合液，搅拌，加入甲基叔丁基醚中，沉淀过滤，真空干燥，得到化合物6；
(6)向S0456的水溶液中，滴加pH 11的Pemetrexed-Tyr三阴离子溶液，加热反应，得到化合物7，即所述靶向α型叶酸受体的培美近红外荧光分子；
- 根据权利要求2所述的靶向α型叶酸受体的培美近红外荧光分子的制备方法，其特征在于：所述步骤(1)中，加热到120℃在氮气氛下18h。
- 根据权利要求2所述的靶向α型叶酸受体的培美近红外荧光分子的制备方法，其特征在于：所述步骤(2)中，加热到加热110℃，反应48h。
- 根据权利要求2所述的靶向α型叶酸受体的培美近红外荧光分子的制备方法，其特征在于：所述步骤(3)中，在氮气气氛下回流加热6h。
- 根据权利要求2所述的靶向α型叶酸受体的培美近红外荧光分子的制备方法，其特征在于：所述步骤(4)中，在室温反应30min。
- 根据权利要求2所述的靶向α型叶酸受体的培美近红外荧光分子的制备方法，其特征在于：所述步骤(7)中，将反应混合物的温度升至90℃，在90℃下搅拌45分钟，并通过TLC监测化合物7的形成，化合物7形成完成后，将反应混合物冷却至室温，并通过套管作为稳定流转移至搅拌的丙酮中，得到绿色沉淀，沉淀物在抽气机真空下在烧结漏斗上过滤，用丙酮洗涤，将绿色粉末状固体在高真空下干燥12h，得到化合物7。
- 权利要求1所述的靶向α型叶酸受体的培美近红外荧光分子在制备治疗非小细胞肺癌的药物中的应用。
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