WO2022156424A1 - 用于肿瘤治疗的双亲性分子自组装纳米药物及制备方法和用途 - Google Patents
用于肿瘤治疗的双亲性分子自组装纳米药物及制备方法和用途 Download PDFInfo
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- WO2022156424A1 WO2022156424A1 PCT/CN2021/137302 CN2021137302W WO2022156424A1 WO 2022156424 A1 WO2022156424 A1 WO 2022156424A1 CN 2021137302 W CN2021137302 W CN 2021137302W WO 2022156424 A1 WO2022156424 A1 WO 2022156424A1
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- A—HUMAN NECESSITIES
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Definitions
- the invention belongs to the field of medicine, and in particular relates to an amphiphilic molecule self-assembled nanomedicine for tumor treatment, a preparation method and application thereof.
- Cancer is a serious threat to human life and health, and overcoming cancer is one of the hottest issues in the world. Although some progress has been made in the treatment and prevention of cancer, the incidence and mortality of cancer are still in a state of rapid increase, and related reports show that the mortality rate of lung cancer patients is as high as 18.4%, followed by colorectal cancer ( 9.2%), gastric and liver cancers both at 8.2%; for incidence, lung cancer ranks first, accounting for 11.6% of cancer cases, breast cancer in women (11.6%), prostate cancer in men (7.1%), and colorectal cancer (6.1%), so it is particularly important to develop new treatments.
- the current clinical treatments for cancer mainly include surgical resection, radiotherapy and chemotherapy.
- Surgical resection involves surgical removal of tumor tissue, but the residual tumor tissue after resection can easily lead to a series of problems such as secondary recurrence of cancer.
- radiotherapy mainly uses X-rays to kill tumor cells, resulting in the death of tumor cells, but at the same time of killing tumors, normal body organs and tissues will also be damaged to varying degrees.
- Chemotherapy is the main method of cancer treatment at present, but the utilization rate of a single chemotherapy method is low, and drug resistance is easy to occur, especially for patients with malignant tumors and advanced cancer. Therefore, in clinical practice, combination therapy is often used to improve the anti-tumor effect through the synergistic effect between drugs.
- the anti-tumor mechanisms of different drugs are inconsistent, and the generation of drug resistance can also be restrained as much as possible.
- the combination therapy does not solve the inherent shortcomings of chemotherapy drugs. For example, most drugs do not have the function of targeting tumor tissues, and they act on normal cells as well as tumor cells, resulting in side effects.
- nanotechnology With the development of nanotechnology, researchers have great potential to apply nanotechnology in tumor treatment, and many nanomaterials with good properties have been produced for the delivery of anticancer drugs.
- the drug system constructed by nanomaterials can be combined with a variety of ligands and drugs to obtain higher targeting and specificity, and overcome the drug resistance mechanism caused by traditional drugs. Or actively targeted, enriched in tumor areas, reducing drug concentrations in normal tissues, thereby reducing systemic toxicity.
- the carrier-free self-assembled nano-drug system does not require nanomaterials as a carrier, and relies on the self-assembly of the drug to form nano-drugs, with a theoretical drug loading rate of 100%, which is simpler and more efficient. Therefore, the present invention provides a self-assembled nanoparticle for tumor treatment and a preparation method, which can improve drug utilization rate, reduce drug waste, and avoid problems such as increased production cost and difficulty in human metabolism caused by introducing nanocarriers in the production process. Reduce the instability and complexity of nanosystems.
- Photothermal therapy is an emerging method of cancer treatment. Most cancer cells are less able to withstand high temperature than normal cells. Using high heat can cause irreversible damage to cancer cells, thereby killing cancer cells. Substances that can heat up by laser irradiation are called photothermal agents. Enriching the photothermal agents in the tumor area can generate high temperature locally, kill cancer cells, and achieve the purpose of treating cancer.
- the invention provides a self-assembled nanomedicine for tumor treatment and a preparation method.
- a first aspect of the present invention provides an amphiphilic compound, which is a conjugate of an organic photothermal agent modified with a hydrazine group and a carbonyl-containing antitumor drug through a hydrazone bond.
- the organic photothermal agent is selected from the organic photothermal agents of heptacyanine, and the organic photothermal agent is selected from IR-780, IR-783, IR-808, IR- 825, IR-1045, IR-1048, IR-1061, IR-26.
- the carbonyl-containing antitumor drug is selected from the group consisting of doxorubicin, daunorubicin, arubicin, arubicin B, epirubicin, idarubicin, pirarubicin , any one of paclitaxel, docetaxel, formestane, and epothilone.
- the hydrazine group in the organic photothermal agent modified with the hydrazine group and the carboxyl group in the carbonyl-containing antitumor drug are coupled through a dehydration reaction to form a hydrazone bond.
- the hydrazine group modification refers to a Modifications are made where n is 0, 1, 2, 3, 4.
- modification of the hydrazine group refers to It is obtained by reacting with the chlorine group of the organic photothermal agent, with Group-modified organic photothermal agent, wherein n is 0, 1, 2, 3, 4.
- amphiphilic compound has the structural formula shown in the following formula I:
- n 0, 1, 2, 3, 4;
- A is a carbonyl-containing antitumor drug, and the carbon in the carbonyl group is coupled with the nitrogen in the hydrazone bond, and the carbonyl-containing antitumor drug is preferably adriamycin, daunorubicin, arubicin, arubicin Any one of star B, epirubicin, idarubicin, pirarubicin, paclitaxel, docetaxel, formestane, epothilone, the structure of described A is for example
- amphiphilic compound has the structural formula shown in the following formula II
- a second aspect of the present invention provides a nanoparticle obtained by self-assembly of the above-mentioned amphiphilic compound in an aqueous solution.
- the particle size of the nanoparticles is 40-200 nm.
- the nanoparticles do not contain high molecular weight polymers.
- the third aspect of the present invention provides the use of the above-mentioned nanoparticles in the preparation of antitumor drugs.
- the fourth aspect of the present invention provides a dual-action anti-tumor drug, which comprises the above-mentioned nanoparticles.
- the dosage forms of the dual-action antitumor drug are injections, oral preparations, and parenteral preparations.
- the tumor is selected from the group consisting of osteosarcoma, skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, rectal cancer, esophageal cancer , tongue cancer, kidney cancer, cervical cancer, endometrial cancer, testicular cancer, urinary cancer, melanoma, astrocytoma, meningioma, Hodgkin lymphoma, non-Hodgkin lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, adult T-cell leukemia lymphoma, hepatocellular carcinoma, bronchial carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell tumor, seminoma, chondrosarcoma, sarcoma, fibrosarcoma.
- a fifth aspect of the present invention provides a preparation method of the above-mentioned amphiphilic compound, the preparation method comprising the following steps:
- amphiphilic compound is obtained by coupling the modified organic photothermal agent obtained in step 1) and the carboxyl group in the carbonyl-containing antitumor drug to form a hydrazone bond through a dehydration reaction.
- the organic photothermal agent in step 1) is selected from the organic photothermal agent of heptacyanine, and the organic photothermal agent is selected from IR-780, IR-783, IR-805, IR-808, IR-825, IR-1045, IR-1048, IR-1061, IR-26.
- the carbonyl-containing antitumor drug in step 2) is selected from the group consisting of doxorubicin, daunorubicin, arubicin, arubicin B, epirubicin, idarubicin, Any one of pirarubicin, paclitaxel, docetaxel, formestane, and epothilone.
- reaction conditions in step 1) are in an inert atmosphere, the Co-dispersed in organic solvent with organic photothermal agent, and reacted to completion.
- the reaction conditions in step 2) are in an inert atmosphere, the modified organic photothermal agent obtained in step 1) and the carbonyl-containing antitumor drug are co-dispersed in an organic solvent, and a catalyst three is added. Fluoroacetic acid, and react to completion at 50-80 °C.
- step 2) further comprises a purification step.
- the compound in step 1) is to combine hydrazine hydrate and Co-dispersed in an organic solvent, the reaction is complete.
- the sixth aspect of the present invention provides a preparation method of the above-mentioned nanoparticles, and the preparation method comprises the following steps:
- the step b) further comprises the step of mechanically dispersing the aqueous solution.
- the organic solvent in the step b) is a mixed solvent of one or more organic solvents capable of dissolving the amphiphilic compound and miscible with water.
- the organic solvent in the step b) is a mixed solvent of chloroform and acetone, preferably the volume ratio of chloroform and acetone is 1:9.
- the seventh aspect of the present invention provides the use of the above-mentioned amphiphilic compound in the preparation of nanoparticles for treating or preventing tumors.
- the carrier-free self-assembled nano-drug system does not require nanomaterials as a carrier, and relies on the self-assembly of the drug to form nano-drugs.
- the theoretical drug loading rate is 100%, which is simpler and more efficient, improves drug utilization, and reduces drug waste.
- Nano-drugs prepared by using photothermal agents and carbonyl-containing anticancer drugs are enriched and dissociated in the tumor area, and have the combined therapeutic function of photothermal therapy and chemotherapy.
- FIG. 1 is a distribution diagram of the hydrodynamic diameter of the nanoparticles prepared in Example 2.
- FIG. 1 is a distribution diagram of the hydrodynamic diameter of the nanoparticles prepared in Example 2.
- FIG. 2 is a transmission electron microscope photograph of the nanoparticles prepared in Example 2.
- FIG. 2 is a transmission electron microscope photograph of the nanoparticles prepared in Example 2.
- Figure 3 shows the dissociation effect of nanoparticles under different pH conditions.
- Figure 4 shows the heating curves of nanoparticles with different concentrations under laser (808 nm) irradiation.
- Figure 5 is a graph of cell viability after treatment with different conditions.
- FIG. 6 is a mass spectrum of compound c obtained in Example 1.
- the structural formula of IR-780 is The structural formula of IR-783 is The structural formula of IR-808 is The structural formula of IR-825 is The structural formula of IR-1045 is The structural formula of IR-1048 is The structural formula of IR-1061 is The structural formula of IR-26 is
- the amphiphilic compound is selected from:
- the chemically modified photothermal agent and the carbonyl-containing anticancer drug are used to prepare the amphiphilic compound coupled with the hydrazone bond, and the photothermal agent IR-780, the drug adriamycin hydrochloride and the coupling agent methyl thioglycolate are used.
- the photothermal agent IR-780, the drug adriamycin hydrochloride and the coupling agent methyl thioglycolate are used.
- Embodiment 4 Photothermal heating ability test
- the nanoparticles of compound c were prepared with aqueous solutions of different concentrations (5 ⁇ g/mL, 10 ⁇ g/mL, 20 ⁇ g/mL, 40 ⁇ g/mL), and the heating curve of the solution as a function of time was measured under the irradiation of 808nm laser (2W/cm 2 ). As shown in Fig. 4, it is proved that the nanoparticles of compound c have good heating ability.
- the nanoparticles of compound c (IR-780-DOX), IR-780, doxorubicin hydrochloride and cell culture medium were prepared into solutions with concentrations of 1 ⁇ g/mL, 2.5 ⁇ g/mL and 5 ⁇ g/mL, respectively, and then mixed with 143B respectively. After the cells (osteosarcoma cells) were co-cultured for 3 hours, a part of the co-culture composition in the IR-780-DOX group and the IR-780 group was irradiated with an 808 nm laser (0.8W/cm 2 ) for 5 minutes, and the other part of the IR-780-DOX group was irradiated for 5 minutes.
- IR-780 is the co-culture of IR-780 and tumor cells without laser irradiation
- IR-780/Lasser 5min group is the co-culture of IR-780 with tumor cells and laser irradiation
- Free IR-780-DOX group The nanoparticles of compound c (IR-780-DOX) were co-cultured with tumor cells without laser irradiation, and the IR-780-DOX/Lasser 5min group was IR-780-DOX co-cultured with tumor cells and subjected to laser irradiation In the Free DOX group, adriamycin and tumor cells were co-cultured without laser irradiation.
- the concentration of the substance is considered, it can be seen that since the molecular weight of IR-780-DOX is much higher than that of doxorubicin, the cell survival rate of doxorubicin under the same concentration of substance is about 5min of IR-780/Lasser twice. It is proved that the nanoparticle of compound c has potential application in the treatment of tumors. It combines two treatment methods to realize the formation of nanoparticle structure without a carrier, release under specific pH conditions, and achieve the purpose of passive targeting. A synergistic effect is achieved.
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Abstract
一种用于肿瘤治疗的双亲性分子自组装纳米药物及制备方法和用途。具体公开了一种两亲性化合物，其为以肼基团修饰的有机光热剂和含羰基的抗肿瘤药物通过腙键进行偶联的偶联物。进一步地，公开了了一种纳米颗粒，所述的纳米颗粒由上述两亲性化合物在水溶液中自组装获得。所述纳米颗粒具有抗肿瘤效果，所述的纳米颗粒能够在肿瘤区域富集并解离，具有光热治疗和化疗的联合治疗协同功能。
Description
本发明属于药物领域，具体涉及一种用于肿瘤治疗的双亲性分子自组装纳米药物及制备方法和用途。
癌症正严重威胁着人类的生命健康安全，攻克癌症是全世界的热点问题之一。虽然现在在癌症的治疗和预防上面有了一定进展，但是癌症的发病率和死亡率仍然处在急速上升状态，相关报告显示肺癌患者死亡率居于高达18.4％，在其后的是结直肠癌(9.2％)，胃癌和肝癌均为8.2％；对于发病率，肺癌排在第一位，占癌症病例的11.6％，女性乳腺癌(11.6％)，男性前列腺癌(7.1％)，以及结直肠癌(6.1％)，因此开发新的治疗手段尤为重要。目前癌症的临床治疗手段主要有手术切除、放射性疗法以及化疗。手术切除顾名思义既以手术的方式切除肿瘤组织，但是切除后残余的肿瘤组织极易引起癌症的二次复发等一系列问题。目前放射性疗法主要以X射线杀伤肿瘤细胞，导致肿瘤细胞死亡，但是在杀伤肿瘤的同时，正常的机体器官和组织也会受到不同程度地损害。化疗是目前癌症治疗的主要手段，但是单一的化疗手段药物的利用率低，极易产生耐药性问题，尤其是恶性肿瘤以及癌症晚期的患者。因此在临床上多采用联合治疗的手段，通过药物之间的协同作用提高抗肿瘤的效果，不同药物的抗肿瘤机制不一致，也可以尽可能的克制耐药性的产生。但是联合治疗没有解决化疗药物的固有缺点，比如大部分药物没有靶向肿瘤组织的功能，作用于肿瘤细胞的同时也会作用于正常细胞，从而产生副作用。
随着纳米技术的发展，研究学者将纳米技术应用在肿瘤治疗方面，具有很大的潜力，已经产生了很多具有良好性能的纳米材料用于抗癌药物的递送。由纳米材料构建的药物体系可以与多种配体、药物相结合，从而获得更高的靶向性和特异性，克服传统药物所引起的耐药机制，更为重要的是纳米体系可以借助被动或主动靶向，富集在肿瘤区域，降低正常组织中的药物浓度，从而减少全身毒性。
无载体自组装纳米药物体系不需要纳米材料作为载体，依靠药物自身自组装形成纳米药物，理论载药率为100％，更加简单，高效。因此，本发明提供一种用于肿瘤治疗的自组装纳米颗粒及制备方法，提高药物利用率，减少药物浪费，避免在制作过程中引入纳米载体而引起的生产成本增加、人体代谢困难等问题，降低纳米体系的不稳定性和复杂性。
光热治疗是新兴的对癌症治疗的方式，大部分癌细胞比正常细胞耐高温的能力弱，利用高热可以引起癌细胞不可逆损伤，从而杀死癌细胞。通过激光照射能升温的物质称为光热剂，将光热剂富集在肿瘤区域则可以在局部产生高温，杀伤癌细胞从而达到治疗癌症的目的。
发明内容
本发明提供一种用于肿瘤治疗的自组装纳米药物及制备方法。
本发明第一个方面提供了一种两亲性化合物，其为以肼基团修饰的有机光热剂和含羰基的抗肿瘤药物通过腙键进行偶联的偶联物。
在本发明的实施方案中，所述的有机光热剂选自七甲川花菁类的有机光热剂，所述有机光热剂选自IR-780、IR-783、IR-808、IR-825、IR-1045、IR-1048、IR-1061、IR-26。
在本发明的实施方案中，含羰基的抗肿瘤药物选自阿霉素、柔红霉素、阿柔比星、阿柔比星B、表阿霉素、伊达比星、吡柔比星、紫杉醇、多西他赛、福美坦、埃博霉素中的任意一种。
在本发明的实施方案中，以肼基团修饰的有机光热剂中的肼基团和含羰基的抗肿瘤药物中的羧基通过脱水反应形成腙键进行偶联。
在本发明的实施方案中，肼基团修饰指以
进行修饰，其中n为0、1、2、3、4。
在本发明的实施方案中，肼基团修饰是指通过将
与有机光热剂的氯基团进行反应获得，具有
基团修饰的有机光热剂，其中n为0、1、2、3、4。
在本发明的实施方案中，所述的两亲性化合物具有如下式I所示的结构式：
其中，n＝0、1、2、3、4；
X为
A为含羰基的抗肿瘤药物，且其中的羰基中的碳与腙键中的氮偶联，优选含羰基的抗肿瘤药物为阿霉素、柔红霉素、阿柔比星、阿柔比星B、表阿霉素、伊达比星、吡柔比星、紫杉醇、多西他赛、福美坦、埃博霉素中的任意一种，所述A的结构例如为
在本发明的一个优选的实施方案中，所述的两亲性化合物具有如下式II所示的结构式
本发明第二个方面提供了一种纳米颗粒，所述的纳米颗粒由上述两亲性化合物在水溶液中自组装获得。
在本发明的实施方案中，所述的纳米颗粒的粒径为40-200nm。
在本发明的实施方案中，所述的纳米颗粒中不包含高分子聚合物。
本发明第三个方面提供了上述纳米颗粒在制备抗肿瘤药物中的用途。
本发明第四个方面提供了一种双效抗肿瘤药物，所述药物中包含上述纳米颗粒。
在本发明的实施方案中，双效抗肿瘤药物的剂型为注射剂、口服制剂、肠道外给药制剂。
在本发明的实施方案中，所述的肿瘤选自骨肉瘤、皮肤癌、膀胱癌、卵巢癌、乳腺癌、胃癌、前列腺癌、结肠癌、肺癌、骨癌、脑癌、直肠癌、食管癌、舌癌、肾癌、宫颈癌、子宫体癌、子宫内膜癌、睾丸癌、泌尿癌、黑素癌、星型细胞癌、脑膜瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、急性淋巴性白血病、慢性淋巴性白血病、急性骨髓性白血病、慢性粒细胞白血病、成人T细胞白血病淋巴瘤、肝细胞癌、支气管癌、小细胞肺癌、、非小细胞肺癌、多发性骨髓瘤、基底细胞瘤、精原细胞瘤、软骨肉瘤、肌肉瘤、纤维肉瘤。
本发明第五个方面提供了上述两亲性化合物的制备方法，所述制备方法包括以下步骤：
1)将
与有机光热剂的氯基团进行反应获得，具有
基团修饰的有机光热剂；
2)将步骤1)所得的修饰后的有机光热剂与含羰基的抗肿瘤药物中的羧基通过脱水反应形成腙键进行偶联得到两亲性化合物。
在本发明的实施方案中，步骤1)中的有机光热剂选自七甲川花菁类的有机光热剂，所述有机光热剂选自IR-780、IR-783、IR-805、IR-808、IR-825、IR-1045、IR-1048、IR-1061、IR-26。
在本发明的实施方案中，步骤2)中含羰基的抗肿瘤药物选自阿霉素、柔红霉素、阿柔比星、阿柔比星B、表阿霉素、伊达比星、吡柔比星、紫杉醇、多西他赛、福美坦、埃博霉素中的任意一种。
在本发明的实施方案中，步骤1)中反应条件为在惰性气氛下，将
与有机光热剂共同分散在有机溶剂中，并反应至完全。
在本发明的实施方案中，步骤2)中反应条件为惰性气氛下，将步骤1)所得的修饰后的有机光热剂与含羰基的抗肿瘤药物共同分散在有机溶剂中，并加入催化剂三氟乙酸，并在50-80℃条件下反应至完全。
在本发明的实施方案中，步骤2)中还包括纯化步骤。
在本发明的实施方案中，步骤1)中化合物
的制备方法为将水合肼和
共同分散在有机溶剂中，反应至完全即得
本发明第六个方面提供了上述纳米颗粒的制备方法，所述的制备方法包括以下步骤：
a)将上述两亲性化合物分散在有机溶剂中，配制成有机溶液；
b)将上述有机溶液分散在水溶液中，挥发有机溶剂，得到纳米颗粒水溶液。
在本发明的实施方案中，所述步骤b)中还包括机械力分散水溶液的步骤。
在本发明的实施方案中，所述步骤b)中有机溶剂为能够溶解两亲性化合物且与水互溶的一种或两种以上有机溶剂的混合溶剂。
在本发明的一个具体的实施方案中，所述步骤b)中有机溶剂为氯仿和丙酮的混合溶剂，优选氯仿和丙酮的体积比为1:9。
本发明第七个方面提供了上述两亲性化合物在制备治疗或预防肿瘤的纳米颗粒中的用途。
1.无载体自组装纳米药物体系不需要纳米材料作为载体，依靠药物自身自组装形成纳米药物，理论载药率为100％，更加简单，高效，提高药物利用率，减少药物浪费。
2.使用光热剂和含羰基抗癌药物制备的纳米药物，在肿瘤区域富集并解离，具有光热治疗和化疗的联合治疗功能。实验结果证实在抗肿瘤作用上产生了协同作用。
图1为实施例2制备得到的纳米颗粒的流体力学直径的分布图。
图2为实施例2制备得到的纳米颗粒的透射电镜照片。
图3为纳米颗粒在不同pH条件下解离效果。
图4为不同浓度纳米颗粒在激光(808nm)照射下的升温曲线。
图5为不同条件处理后细胞活力曲线图。
图6为实施例1所得化合物c的质谱图。
为了使本发明的上述目的、特征和优点能够更加明显易懂，下面对本发明的具体实施方式做详细的说明，但不能理解为对本发明的可实施范围的限定。
在本发明中，IR-780的结构式为
IR-783的结构式为
IR-808的结构式为
IR-825的结构式为
IR-1045的结构式为
IR-1048的结构式为
IR-1061的结构式为
IR-26的结构式为
在本发明的一些实施例中，所述的两亲性化合物选自
本发明用经过化学修饰过后的光热剂和含羰基的抗癌药物制备腙键偶联的两亲性化合物，以光热剂IR-780、药物盐酸阿霉素和偶联剂巯基乙酸甲酯为例。
1)化合物a
的合成：氮气环境下，将巯基乙酸甲酯和水合肼分散在甲醇中，室温搅拌，得到的反应液旋干，层析过柱，得无色透明油状液体，即化合物。
2)化合物b
的合成：氮气环境下，将化合物a和IR-780分散在氯仿中，室温搅拌，得到的反应液旋干，加入二氯甲烷溶解，水洗有机相，有机相干燥后蒸干，得到化合物b。
3)化合物c
的合成：氮气环境下，将化合物b和盐酸阿霉素分散在甲醇，滴加催化量的三氟乙酸，在60℃条件下搅拌，得到的反应液旋干，加入二氯甲烷溶解，水洗有机相，有机相干燥后浓缩，层析过柱，得墨绿色固体，即化合物c。
实施例1两亲性化合物的制备
合成流程如下所示：
1)化合物a的合成：氮气环境下，将巯基乙酸甲酯(0.24g,2mmol)和水合肼(0.24g,4.8mmol)分散在5mL甲醇中，室温搅拌12h，得到的反应液旋干，层析过柱，得无色透明油状液体0.15g，即化合物a，产率：62.5％。
2)化合物b的合成：氮气环境下，将化合物a(0.0288g,0.24mmol)和IR-780(0.08g,0.12mmol)分散在20mL氯仿中，室温搅拌12h，得到的反应液旋干，加入二氯甲烷溶解，水洗有机相，有机相干燥后蒸干，得到化合物b。
3)化合物c的合成：氮气环境下，将化合物b(0.04mmol)和盐酸阿霉素(0.0348g,0.06mmol)分散在20mL甲醇，滴加催化量的三氟乙酸，在60℃条件下搅拌48h，得到的反应液旋干，加入二氯甲烷溶解，水洗有机相，有机相干燥后浓缩，层析过柱，得墨绿色固体0.012g，即化合物c，产率：23.5％。质谱检测分子量为1148.56，质谱图见图6。
实施例2纳米颗粒的制备
将5mg化合物c溶于500μL混合溶剂(50μL氯仿+450μL丙酮)，缓慢滴入剧烈搅拌的5mL去离子水中，待有机溶剂挥发，即得化合物c的纳米颗粒水溶液。本实施例制备的化合物c的纳米颗粒的流体力学直径如图1所示，本实施例制备的化合物c的纳米颗粒的透射电镜照片如图2所示。
实施例3模拟肿瘤微环境的解离实验
通过体外模拟肿瘤微环境，将化合物c的纳米颗粒水溶液置于透析袋中(截流量2000)，分别浸泡在pH＝5.0和7.5的水溶液中，每隔一段时间(12、24、48、60、72、84、96、108、120h)取样，通过测量析出阿霉素的紫外吸光度计算得到纳米颗粒的解离度如图3所示，证 明化合物c的纳米颗粒在酸性条件下存在良好的解离效果。
实施例4光热升温能力测试
将化合物c的纳米颗粒配置不同浓度(5μg/mL、10μg/mL、20μg/mL、40μg/mL)的水溶液，在808nm激光(2W/cm
2)的照射下，测量溶液随时间变化的升温曲线如图4所示，证明化合物c的纳米颗粒具有良好的升温能力。
实施例5抗肿瘤实验结果
分别将化合物c的纳米颗粒(IR-780-DOX)、IR-780、盐酸阿霉素与细胞培养液配置成浓度为1μg/mL、2.5μg/mL、5μg/mL的溶液，然后分别与143B细胞(骨肉瘤细胞)共培养3小时后，IR-780-DOX组和IR-780组中一部分共培养组合物使用808nm激光(0.8W/cm
2)照射5min，另一部分IR-780-DOX组和IR-780组中一部分共培养组合物以及阿霉素组不经过照射，孵育24h后，使用MTT方法进行细胞活性测试如图5所示。其中IR-780为IR-780与肿瘤细胞共培养，且未经过激光照射组，IR-780/Lasser 5min组为IR-780与肿瘤细胞共培养且经过激光照射组，Free IR-780-DOX组为化合物c的纳米颗粒(IR-780-DOX)与肿瘤细胞共培养，且未经过激光照射组，IR-780-DOX/Lasser 5min组为IR-780-DOX与肿瘤细胞共培养且经过激光照射组，Free DOX为阿霉素和肿瘤细胞共培养，且未经过激光照射组。实验结果证实，除IR-780组外，其他四组随着浓度的增加均有不同程度的抑瘤效果。其中阿霉素组以及IR-780-DOX/Lasser 5min组相比于Free IR-780-DOX组和IR-780/Lasser 5min组效果更优。但是如果考虑物质的量浓度条件下对比可知，由于IR-780-DOX的分子量远高于阿霉素，则在相同物质的量浓度条件下阿霉素细胞存活率约为IR-780/Lasser 5min的二倍。证明化合物c的纳米颗粒在治疗肿瘤方面具有潜在应用，其结合两种治疗方式，实现了无需载体就可以形成纳米颗粒结构，在特定pH条件下释放，实现了被动靶向目的，同时两种作用实现了协同效果。
Claims (10)
- 一种两亲性化合物，其特征在于，其为以肼基团修饰的有机光热剂和含羰基的抗肿瘤药物通过腙键进行偶联的偶联物；所述的有机光热剂选自七甲川花菁类的有机光热剂。
- 根据权利要求1所述的两亲性化合物，其特征在于，所述有机光热剂选自IR-780、IR-783、IR-805、IR-808、IR-825、IR-1045、IR-1048、IR-1061、IR-26；含羰基的抗肿瘤药物选自阿霉素、柔红霉素、阿柔比星、阿柔比星B、表阿霉素、伊达比星、吡柔比星、紫杉醇、多西他赛、福美坦、埃博霉素中的任意一种。
- 根据权利要求1所述的两亲性化合物，其特征在于，以肼基团修饰的有机光热剂中的肼基团和含羰基的抗肿瘤药物中的羧基通过脱水反应形成腙键进行偶联；肼基团修饰是指通过将与有机光热剂的氯基团进行反应获得，具有
基团修饰的有机光热剂。
- 根据权利要求1所述的两亲性化合物，其特征在于，所述的两亲性化合物具有如下式I所示的结构式：
其中，n＝0、1、2、3、4；X为
A为含羰基的抗肿瘤药物，且其中的羰基中的碳与腙键中的氮偶联，优选含羰基的抗肿瘤药物为阿霉素、柔红霉素、阿柔比星、阿柔比星B、表阿霉素、伊达比星、吡柔比星、紫杉醇、多西他赛、福美坦、埃博霉素中的任意一种。 - 一种纳米颗粒，其特征在于，所述的纳米颗粒由权利要求1-4任一项所述的两亲性化合物在水溶液中自组装获得；优选地，所述的纳米颗粒的粒径为40-200nm。
- 根据权利要求5所述的纳米颗粒在制备抗肿瘤药物中的用途；优选地，所述的肿瘤选自骨肉瘤、皮肤癌、膀胱癌、卵巢癌、乳腺癌、胃癌、前列腺癌、结肠癌、肺癌、骨癌、脑癌、直肠癌、食管癌、舌癌、肾癌、宫颈癌、、子宫体癌、子宫内膜癌、睾丸癌、泌尿癌、黑素癌、星型细胞癌、脑膜瘤、霍奇金淋巴瘤、、非霍奇金淋巴瘤、急性淋巴性白血病、慢性淋巴性白血病、急性骨髓性白血病、慢性粒细胞白血病、成人T细胞 白血病淋巴瘤、肝细胞癌、支气管癌、小细胞肺癌、非小细胞肺癌、多发性骨髓瘤、基底细胞瘤、精原细胞瘤、软骨肉瘤、肌肉瘤、纤维肉瘤。
- 一种双效抗肿瘤药物，其特征在于，所述药物中包含权利要求5所述的纳米颗粒；优选地，双效抗肿瘤药物的剂型为注射剂、口服制剂、肠道外给药制剂。
- 根据权利要求1-4任一项所述的两亲性化合物的制备方法，其特征在于，所述制备方法包括以下步骤：1)将具有肼基团的化合物与有机光热剂进行反应，获得具有肼基团修饰的有机光热剂；2)将步骤1)所得的修饰后的有机光热剂与含羰基的抗肿瘤药物中的羧基通过脱水反应形成腙键进行偶联得到两亲性化合物；步骤1)中的有机光热剂选自七甲川花菁类的有机光热剂；优选地，所述有机光热剂选自IR-780、IR-783、IR-805、IR-808、IR-825、IR-1045、IR-1048、IR-1061、IR-26；优选地，步骤2)中含羰基的抗肿瘤药物选自阿霉素、柔红霉素、阿柔比星、阿柔比星B、表阿霉素、伊达比星、吡柔比星、紫杉醇、多西他赛、福美坦、埃博霉素中的任意一种；优选地，步骤1)为将具有肼基团的化合物与有机光热剂的氯基团进行反应获得，具有如
所示的肼基团修饰的有机光热剂，更优选地，所述步骤1)的反应条件为在惰性气氛下，将
与有机光热剂共同分散在有机溶剂中，并反应至完全；
优选地，步骤2)中反应条件为惰性气氛下，将步骤1)所得的修饰后的有机光热剂与含羰基的抗肿瘤药物共同分散在有机溶剂中，并加入催化剂三氟乙酸，并在50-80℃条件下反应至完全。 - 权利要求5所述的纳米颗粒的制备方法，其特征在于，所述的制备方法包括以下步骤：a)将权利要求1-5任一项所述的两亲性化合物分散在有机溶剂中，，配制成有机溶液；b)将上述有机溶液分散在水溶液中，挥发有机溶剂，得到纳米颗粒水溶液；优选地，所述步骤b)中还包括机械力分散水溶液的步骤；优选地，所述步骤b)中有机溶剂为能够溶解两亲性化合物且与水互溶的一种或两种以上有机溶剂的混合溶剂。
- 权利要求1-5任一项所述的两亲性化合物在制备治疗或预防肿瘤的纳米颗粒中的用途；优选地，所述的纳米颗粒的粒径为40-200nm；优先地，所述的纳米颗粒中不包含高分子聚合物。
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