WO2021174868A1 - 一种二氢卟吩纳米光敏剂及其制备方法和应用 - Google Patents

一种二氢卟吩纳米光敏剂及其制备方法和应用 Download PDF

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WO2021174868A1
WO2021174868A1 PCT/CN2020/122323 CN2020122323W WO2021174868A1 WO 2021174868 A1 WO2021174868 A1 WO 2021174868A1 CN 2020122323 W CN2020122323 W CN 2020122323W WO 2021174868 A1 WO2021174868 A1 WO 2021174868A1
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chlorin
photosensitizer
nano
aminomethane
hydroxymethyl
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French (fr)
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郭正清
何慧
王孟雅
史梦柯
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苏州大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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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  • the invention relates to the technical field of photosensitizers, in particular to a chlorin nano photosensitizer and a preparation method and application thereof.
  • Photodynamic therapy as an emerging tumor treatment method, is clinically used to treat many diseases, including tumors, especially superficial tumors (esophageal tumors, bladder tumors, melanomas, etc.), with selectivity High, low side effects, strong selectivity and other advantages.
  • Photosensitizers play an important role in photodynamic therapy.
  • the treatment process is to inject photosensitizers into tumor patients and accumulate them in tumor tissues. After irradiation with near-infrared laser, the excited photosensitive drug reacts with oxygen in the tissue to generate reactive oxygen species such as singlet oxygen, leading to cell apoptosis or necrosis, and ultimately achieving the goal of targeted tumor therapy.
  • HpD hematoporphyrin
  • these HpD products generally have disadvantages such as complex composition, poor tissue selectivity, weak absorption in the red light zone, shallow treatment depth, large doses of medicine or light required during treatment, and obvious skin phototoxicity after treatment.
  • the second-generation photosensitizers represented by chlorin photosensitizers have attracted much attention in recent years. Chlorin-based photosensitizers have a single and clear structure, and the absorption capacity in the red or near-infrared region is significantly enhanced.
  • photosensitizers such as hydrophilicity, hydrophobicity, and charge adjustment, etc.
  • they can be further Improve their accumulation in tumor tissues.
  • Verteporfin, Temoporfin and Talaphorfin have been successfully used clinically.
  • the second-generation photosensitizer has made up for the deficiency of the first-generation photosensitizer to a certain extent, it is still difficult to achieve the desired effect of highly selective accumulation of tumors.
  • photosensitizer molecules continue to develop, they still have certain drawbacks. For example, most photosensitizer molecules are difficult to dissolve in water, and the hydrophobic interaction between molecules causes them to form aggregation in water, which cannot be directly injected intravenously.
  • CN103169968A discloses an albumin-based hydrophobic chlorin photosensitizer nano pharmaceutical preparation.
  • the preparation is composed of albumin and hydrophobic chlorin photosensitizer only, and does not contain other cross-linking agents or auxiliary materials, which can avoid the use of cross-linking agents or auxiliary materials.
  • Adverse clinical reactions caused by the coupling agent; the hydrophobic chlorin photosensitizer used has a simple structure and does not contain hydroxyl, alkoxy, amino and other functional groups that can improve the water solubility of the chlorin photosensitizer. It is easy to synthesize and can be used in the superficial layer. Effectively absorb and utilize therapeutic light sources to deeper tissues.
  • CN102397545A discloses a nano photosensitizer drug delivery system for photodynamic therapy.
  • the drug delivery system is composed of chitosan, chlorin e6 and single-walled carbon nanotubes.
  • the chlorin e6 is loaded by covalent bonding, and the outer layer of the obtained chlorin e6-single-walled carbon nanotube composite is wrapped with chitosan.
  • the photosensitizer nano-delivery system can overcome the disadvantages of the photosensitizers mentioned above, and can also enhance the accumulation of photosensitizers at the tumor site through the EPR effect. But at the same time, there are also disadvantages such as complex preparation process, poor controllability, and fewer photosensitizers to choose from.
  • the technical problem to be solved by the present invention is to provide a preparation method of chlorin nano-photosensitizer.
  • the preparation method is very simple, and the prepared nano-photosensitizer is amphiphilic and can quickly self-assemble in water systems and biological fluids.
  • the formation of uniform and stable nanoparticles is conducive to highly selective tumor enrichment and improves the effect of phototherapy.
  • the present invention provides a method for preparing a chlorin nano-photosensitizer, which includes the following steps:
  • the chlorin photosensitizer and tris(hydroxymethyl)aminomethane are mixed in an organic solvent. Under electrostatic interaction, the chlorin photosensitizer and tris(hydroxymethyl)aminomethane self-assemble to form the Chlorin nano-photosensitizer (Trisporfin); wherein, the chlorin photosensitizer includes, but is not limited to, chlorin e6, chlorin e6 copper compound, chlorin e6 zinc compound, and chlorin Phenoe e6 manganese compounds and other carboxyl-containing compounds.
  • the organic solvent includes, but is not limited to, anhydrous methanol, tetrahydrofuran, dichloromethane, and N,N-dimethylformamide.
  • the chlorin photosensitizer is preferably chlorin e6 (Ce6). Due to the three carboxyl groups of the chlorin e6 molecule, theoretically the molar ratio of the photosensitizer chlorin e6 and tris(hydroxymethyl)aminomethane is 1:3. However, since the cost of tris(hydroxymethyl)aminomethane is relatively low and easy to remove, in order to fully combine the chlorin e6 and tris(hydroxymethyl)aminomethane, an excess of tris(hydroxymethyl)aminomethane can be used.
  • Ce6 chlorin e6
  • preparation method is specifically:
  • the ultrasound time is 5 minutes to 1 hour.
  • an evaporation device such as a rotary evaporator, is used to remove the organic solvent at a certain temperature and rotation speed.
  • a dialysis bag with a molecular weight of 100-3000 is used for dialysis for more than 24 hours.
  • Another aspect of the present invention provides a chlorin nano-photosensitizer prepared by the method, and the structural formula of the chlorin nano-photosensitizer is:
  • n and n are both positive integers.
  • the present invention also provides a nanomicelle solution of the chlorin nanophotosensitizer, which is prepared through the following steps:
  • the invention also provides the application of the chlorin nano-photosensitizer in photodynamic therapy.
  • the present invention uses electrostatic interaction to make the carboxyl-containing chlorin photosensitizer and tris(hydroxymethyl)aminomethane self-assemble in an organic solvent, thereby introducing hydrophilicity into the chlorin photosensitizer molecule
  • the tris(hydroxymethyl)aminomethane fragment stabilizes the hydrophobic chlorin photosensitizer.
  • the present invention greatly simplifies the preparation process of photosensitizer, and the obtained nano-photosensitizer Trisporfin has uniform and stable size in water system and biological fluid, which is conducive to highly selective tumor enrichment and improves the efficiency of phototherapy. Effect.
  • Figure 1 is the 1 H NMR spectrum of the nano-photosensitizer Triporfin
  • Figure 2 is a diagram showing the state of Chlorin e6 (left) and the nano photosensitizer Trisporfin (right) in water;
  • Figure 3 is a diagram of the nanometer particle size distribution of the nano-photosensitizer Trisporfin measured by a dynamic light scattering instrument
  • Figure 4 is a particle size distribution diagram of the nano-photosensitizer Trisporfin measured by transmission electron microscope
  • Figure 5 is the ultraviolet-visible absorption spectrum of chlorin e6 and nano-photosensitizer Triporfin;
  • Figure 6 is the fluorescence emission spectra of chlorin e6 and nano-photosensitizer Trisporfin;
  • Figure 7 is a dynamic light scattering instrument to test the particle size change of the nano-photosensitizer Trisporfin
  • Figure 8 shows the quenching of DPBF by the nano-photosensitizer Trisporfin under light conditions
  • Figure 9 shows the dark cytotoxicity of chlorin e6 and nano photosensitizer Trisporfin
  • Figure 10 shows the cytotoxicity of chlorin e6 and nano-photosensitizer Trisporfin.
  • Trisporfin (5 mg), add 5 ml of anhydrous methanol, spin dry on a rotary evaporator (30 rpm, 40 degrees Celsius), add ml of deionized water under ultrasonic conditions, continue ultrasonication for 30 minutes, and pass through an aqueous filter membrane (0.22 ( ⁇ m) to remove the free chlorin e6, and finally obtain a clear Trisporfin nanomicelle solution.
  • Trisporfin (5 mg), add 5 ml of anhydrous methanol, spin dry on a rotary evaporator (30 rpm, 40 degrees Celsius), add 5 ml of deionized water under ultrasonic conditions, continue ultrasonication for 30 minutes, and pass through the water filter membrane ( The pore size is 0.45 microns) to remove the free chlorin e6, and finally a clear Trisporfin nanomicelle solution is obtained.
  • Trisporfin (10 mg)
  • Add 10 ml of anhydrous methanol spin dry on a rotary evaporator (30 rpm, 50 degrees Celsius)
  • add 10 ml of deionized water under ultrasonic conditions continue ultrasonication for 30 minutes, and pass through the water filter head ( The pore size is 0.22 microns) to remove the free chlorin e6, and finally a clear Trisporfin nanomicelle solution is obtained.
  • Trisporfin 15 mg
  • Add 10 ml of anhydrous methanol spin dry on a rotary evaporator (60 rpm, 50 degrees Celsius)
  • add 10 ml of deionized water under ultrasonic conditions continue ultrasonication for 30 minutes, and pass through the water filter head ( The pore size is 0.45 microns) to remove the free chlorin e6, and finally a clear Trisporfin nanomicelle solution is obtained.
  • Trisporfin (5 mg) into 5 ml of anhydrous methanol, spin to dry on a rotary evaporator (30 rpm, 60 degrees Celsius), add 5 ml of deionized water under ultrasonic conditions, continue ultrasonication for 30 minutes, and pass through the water filter head ( The pore size is 0.22 microns) to remove the free chlorin e6, and finally a clear Trisporfin nanomicelle solution is obtained.
  • Trisporfin (5 mg), add 5 ml of anhydrous methanol, spin dry on a rotary evaporator (30 rpm, 60 degrees Celsius), add 5 ml of deionized water under ultrasonic conditions, continue ultrasonication for 30 minutes, and pass through the water filter membrane ( The pore size is 0.22 microns) to remove the free chlorin e6, and finally a clear Trisporfin nanomicelle solution is obtained.
  • Trisporfin (5 mg), add 5 ml of anhydrous methanol, spin dry on a rotary evaporator (30 rpm, 60 degrees Celsius), add 5 ml of deionized water under ultrasonic conditions, continue ultrasonication for 30 minutes, and pass through the water filter membrane ( The pore size is 0.22 microns) to remove the free chlorin e6, and finally a clear Trisporfin nanomicelle solution is obtained.
  • Trisporfin (5 mg), add 5 ml of anhydrous methanol, spin dry on a rotary evaporator (30 rpm, 60 degrees Celsius), add 5 ml of deionized water under ultrasonic conditions, continue ultrasonication for 30 minutes, and pass through the water filter membrane ( The pore size is 0.22 microns) to remove the free chlorin e6, and finally a clear Trisporfin nanomicelle solution is obtained.
  • Trisporfin (5 mg), add 5 ml of absolute ethanol, spin dry on a rotary evaporator (30 rpm, 60 degrees Celsius), add 5 ml of deionized water under ultrasonic conditions, continue ultrasonication for 30 minutes, and pass through the water filter membrane ( The pore size is 0.45 microns) to remove the free chlorin e6, and finally a clear Trisporfin nanomicelle solution is obtained.
  • Trisporfin (5 mg), add 5 ml of anhydrous methanol, spin dry on a rotary evaporator (30 rpm, 60 degrees Celsius), add 5 ml of deionized water under ultrasonic conditions, continue ultrasonication for 30 minutes, and pass through the water filter membrane ( The pore size is 0.22 microns) to remove the free chlorin e6, and finally a clear Trisporfin nanomicelle solution is obtained.
  • Trisporfin (5 mg) into 5 ml of anhydrous methanol, spin to dry on a rotary evaporator (30 rpm, 60 degrees Celsius), add 5 ml of deionized water under ultrasonic conditions, continue ultrasonication for 10 minutes, and pass through the water filter membrane ( The pore size is 0.22 microns) to remove the free chlorin e6, and finally a clear Trisporfin nanomicelle solution is obtained.
  • Trisporfin (5 mg), add 5 ml of anhydrous methanol, spin dry on a rotary evaporator (30 rpm, 60 degrees Celsius), add 5 ml of deionized water under ultrasonic conditions, continue ultrasonication for 20 minutes, and pass through the water filter head membrane (The pore size is 0.45 microns) to remove the free chlorin e6, and finally a clear Trisporfin nanomicelle solution is obtained.
  • Trisporfin (5 mg), add 5 ml of anhydrous methanol, spin dry on a rotary evaporator (30 rpm, 50 degrees Celsius), add 5 ml of deionized water under ultrasonic conditions, continue ultrasonication for 30 minutes, and pass through the water filter membrane ( The pore size is 0.22 microns) to remove the free chlorin e6, and finally a clear Trisporfin nanomicelle solution is obtained.
  • Trisporfin (5 mg) into 5 ml N,N-dimethylformamide, spin-dry on a rotary evaporator (30 rpm, 40 degrees Celsius), add 5 ml deionized water under ultrasonic conditions, and continue ultrasonication for 30 minutes , Pass through an aqueous filter membrane (pore size 0.22 microns) to remove free chlorin e6, and finally obtain a clear Trisporfin nanomicelle solution.
  • Trisporfin (5 mg) and add 5 ml of N,N-dimethylformamide, spin-dry on a rotary evaporator (30 rpm, 70 degrees Celsius), add 5 ml of deionized water under ultrasonic conditions, and continue ultrasonication for 5 minutes , Pass through an aqueous filter membrane (pore size 0.22 microns) to remove free chlorin e6, and finally obtain a clear Trisporfin nanomicelle solution.
  • Trisporfin (5 mg) into 5 ml N,N-dimethylformamide, spin-dry on a rotary evaporator (60 rpm, 60 degrees Celsius), add 5 ml deionized water under ultrasonic conditions, and continue ultrasonication for 5 minutes , Pass through an aqueous filter membrane (pore size 0.22 microns) to remove free chlorin e6, and finally obtain a clear Trisporfin nanomicelle solution.
  • FIG. 2 shows the state of chlorin e6 and nano photosensitizer Trisporfin in water. It can be seen from the figure that the photosensitizer Triporfin obtained by electrostatic interaction has significantly improved water solubility compared to Chlorin e6.
  • the nano-photosensitizer Trisporfin was prepared by the thin film dispersion method, and the nano-photosensitizer Trisporfin was characterized by dynamic light scattering (DLS) and transmission electron microscope. It can be seen from Figure 3 and Figure 4 that the nano-photosensitizer Triporfin has a uniform nanometer size.
  • the spectroscopic properties of the target product were further determined. See Figures 5-7.
  • the maximum absorption wavelength of the nano-photosensitizer Triporfin is at 664nm. Taking zinc phthalocyanine (ZnPc) as a reference, the fluorescence quantum yield of nano-photosensitizer Trisporfin was 0.35.
  • DPBF 1,3-diphenylisobenzofuran
  • ZnPc zinc phthalocyanine
  • Figure 8 DPBF can have an efficient chemical reaction with singlet oxygen, resulting in a significant drop in its 415nm absorption peak. The experiment found that the 415nm absorption peak of Trisporfin solution was obviously quenched with time, and the singlet oxygen quantum yield of Trisporfin was calculated to be 0.38.
  • nano photosensitizer Trisporfin prepared by the present invention has uniform and stable size in water systems and biological fluids, and has good cell killing ability.

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Abstract

一种二氢卟吩纳米光敏剂的制备方法，包括以下步骤：将二氢卟吩光敏剂与三(羟甲基)氨基甲烷于有机溶剂中混合，在静电相互作用下，所述二氢卟吩光敏剂与三(羟甲基)氨基甲烷发生自组装，形成所述二氢卟吩纳米光敏剂；所述二氢卟吩光敏剂选自二氢卟吩e6、二氢卟吩e6铜化合物、二氢卟吩e6锌化合物、二氢卟吩e6锰化合物等。而且，还包括由所述方法制备得到的二氢卟吩纳米光敏剂及其在光动力治疗中的应用。该二氢卟吩纳米光敏剂呈两亲性，在水体系以及生物体液中可快速自组装形成尺寸均一且稳定的纳米粒，有利于高选择性肿瘤富集，提高光治疗效果。

Description

一种二氢卟吩纳米光敏剂及其制备方法和应用 技术领域
本发明涉及光敏剂技术领域，具体涉及一种二氢卟吩纳米光敏剂及其制备方法和应用。
背景技术
光动力治疗(PDT)作为一种新兴的肿瘤治疗方式，在临床上被用于治疗许多疾病，包括肿瘤，特别是浅表性的肿瘤(食道瘤、膀胱瘤和黑色素瘤等)，具有选择性高、副作用小、选择性强等优点。光敏剂在光动力治疗中起着重要作用，其治疗过程是将光敏药物注射于肿瘤患者体内，并蓄积于肿瘤组织内。随后采用近红外激光进行照射，激发态的光敏药物与组织内的氧气反应生成单线态氧等活性氧物质，从而导致细胞的凋亡或坏死，最终实现肿瘤靶向治疗的目标。
在过去的50年里，已开发出以血卟啉(HpD)为代表的第一代光敏供临床使用，如光卟啉(Photofrin)、光灵素(Photogem)和癌光啉(Photocarcinorin)等。然而这些HpD产品普遍存在成分复杂、组织选择性差、红光区吸收弱、治疗深度浅、治疗时所需的药剂量或光剂量大、且治疗后有明显的皮肤光毒性等不足。鉴于此，近年来以二氢卟吩类光敏剂为代表的第二代光敏剂备受关注。二氢卟吩类光敏剂具有结构单一明确，红光区或近红外区吸收能力显著增强，并且通过对这类光敏剂进行改性(如亲水性、疏水性以及电荷的调节等)可进一步提高它们在肿瘤组织中的蓄积。其中，维替泊芬(Verteporfin)、替莫泊芬(Temoporfin)和他拉泊芬(Talaphorfin)已成功用于临床。虽然第二代光敏剂在一定程度上弥补了第一代光敏剂的不足，但仍难以达到对肿瘤高选择性蓄积 的理想效果。虽然光敏剂分子在不断发展，但其自身仍存在一定的弊端，例如大部分光敏剂分子难溶于水，分子间的疏水作用导致其在水中形成聚集，不能直接静脉注射，肿瘤部位的靶向性不高，在皮肤蓄积容易产生光毒性等。近年来研究发现，光敏剂纳米递送系统可以克服上述光敏剂的弊端，而且还能通过高渗透长滞留效应(EPR)效应增强光敏剂在肿瘤部位的蓄积。因此开发高性能纳米光敏剂是目前光治疗领域的重要方向。
CN103169968A公开了一种基于白蛋白的疏水二氢卟吩光敏剂纳米药物制剂，其制剂仅由白蛋白和疏水性二氢卟吩光敏剂组成，不含有其他交联剂或辅料，可以避免使用交联剂引起的不良临床反应；使用的疏水性二氢卟吩光敏剂结构简单，不含有羟基、烷氧基、氨基等提高二氢卟吩光敏剂水溶性的官能团，合成容易，能够在浅表层至较深组织部位有效地吸收利用治疗性光源。CN102397545A公开了一种用于光动力治疗的纳米光敏剂给药系统，该给药系统由壳聚糖、二氢卟吩e6和单壁碳纳米管构成，所述的单壁碳纳米管通过非共价键结合的方式装载二氢卟吩e6，所得二氢卟吩e6-单壁碳纳米管复合物外层用壳聚糖包裹。目前来看，光敏剂纳米递送系统可以克服上述光敏剂的弊端，而且还能通过EPR效应增强光敏剂在肿瘤部位的蓄积。但同时也存在制备工艺复杂，可控性差等缺陷，并且存在可选择的光敏剂较少等问题。
发明内容
本发明要解决的技术问题是提供一种二氢卟吩纳米光敏剂的制备方法，该制备方法十分简便，且制备的纳米光敏剂具有两亲性，在水体系以及生物体液中可快速自组装形成尺寸均一且稳定的纳米粒，有利于高选择性肿瘤富集，提高光治疗效果。
通过二氢卟吩光敏剂和三(羟甲基)氨基甲烷的化学结构式可以看出，二氢卟吩光敏剂的羧基与三(羟甲基)氨基甲烷的氨基可以通过静电相互作用结合。基于此，本发明提供了二氢卟吩纳米光敏剂的一种制备方法，包括以下步 骤：
将二氢卟吩光敏剂与三(羟甲基)氨基甲烷于有机溶剂中混合，在静电相互作用下，二氢卟吩光敏剂与三(羟甲基)氨基甲烷发生自组装，形成所述二氢卟吩纳米光敏剂(Trisporfin)；其中，所述二氢卟酚光敏剂包括但不限于二氢卟吩e6、二氢卟吩e6铜化合物、二氢卟吩e6锌化合物、二氢卟吩e6锰化合物等含羧基的化合物。
进一步地，所述有机溶剂包括但不限于无水甲醇、四氢呋喃、二氯甲烷、N,N-二甲基甲酰胺。
进一步地，所述二氢卟吩光敏剂优选为二氢卟吩e6(Ce6)。由于二氢卟吩e6分子的三个羧基，理论上光敏剂二氢卟吩e6和三(羟甲基)氨基甲烷的摩尔比例为1:3。但是由于三(羟甲基)氨基甲烷成本较低且易于除去，为了使二氢卟吩e6和三(羟甲基)氨基甲烷充分结合，可以使三(羟甲基)氨基甲烷过量。
进一步地，所述制备方法具体为：
S1.按配比称取二氢卟吩光敏剂和三(羟甲基)氨基甲烷，溶于有机溶剂中并混合，超声，使得二氢卟吩光敏剂和三(羟甲基)氨基甲烷在溶剂中通过静电作用充分结合；
S2.旋干除去溶剂，加入去离子水，继续超声，然后透析除去多余的三(羟甲基)氨基甲烷，冻干后得二氢卟吩纳米光敏剂。
进一步地，所述超声的时间为5分钟至1小时。
进一步地，采用蒸发装置，如旋转蒸发仪，于一定温度和转速下除去有机溶剂。
进一步地，采用分子量为100～3000的透析袋透析24小时以上。
本发明另一方面提供了由所述的方法制备得到的二氢卟吩纳米光敏剂，所述二氢卟吩纳米光敏剂的结构式为：
Figure PCTCN2020122323-appb-000001
其中，m，n均为正整数。
本发明还提供了所述二氢卟吩纳米光敏剂的纳米胶束溶液，其是经如下步骤制备得到的：
将二氢卟吩纳米光敏剂溶于溶剂中，旋干后，在超声条件下加入去离子水，继续超声一段时间，过水系滤膜(孔径为0.22微米或0.45微米)除去游离二氢卟吩光敏剂，得所述二氢卟吩纳米光敏剂的纳米胶束溶液。
本发明还提供了所述的二氢卟吩纳米光敏剂在光动力治疗中的应用。
本发明的有益效果：
本发明利用静电相互作用，使含羧基的二氢卟吩光敏剂与三(羟甲基)氨基甲烷在有机溶剂中发生自组装，从而在二氢卟吩光敏剂分子中引入了亲水性的三(羟甲基)氨基甲烷片段，稳定了疏水性的二氢卟吩光敏剂。与现有技术相比，本发明大幅简化了光敏剂的制备工艺，且得到的纳米光敏剂Trisporfin在水体系以及生物体液中尺寸均一且稳定，有利于高选择性肿瘤富集，提高光治疗的效果。
附图说明
图1是纳米光敏剂Trisporfin的 1H NMR谱；
图2是二氢卟吩e6(左)和纳米光敏剂Trisporfin(右)在水中的状态图；
图3是动态光散射仪测得的纳米光敏剂Trisporfin的纳米粒径分布图；
图4是透射电镜测得的纳米光敏剂Trisporfin的粒径分布图；
图5是二氢卟吩e6和纳米光敏剂Trisporfin的紫外-可见吸收光谱；
图6是二氢卟吩e6和纳米光敏剂Trisporfin的荧光发射光谱；
图7是动态光散射仪测试纳米光敏剂Trisporfin的粒径变化情况；
图8是光照条件下纳米光敏剂Trisporfin对DPBF的淬灭情况；
图9是二氢卟吩e6和纳米光敏剂Trisporfin的细胞暗毒性；
图10是二氢卟吩e6和纳米光敏剂Trisporfin的细胞光毒性。
具体实施方式
下面结合附图和具体实施例对本发明作进一步说明，以使本领域的技术人员可以更好地理解本发明并能予以实施，但所举实施例不作为对本发明的限定。
下述实施例中所使用的实验方法如无特殊说明，均为常规方法，所用的材料、试剂等，如无特殊说明，均可从商业途径得到。
实施例1
称取三(羟甲基)氨基甲烷(5毫克)和二氢卟吩e6(5毫克)于圆底烧瓶中，加入5毫升无水甲醇，超声30分钟使二者通过静电作用充分结合。用旋转蒸发仪(30转/分钟，40摄氏度)旋干除去有机溶剂，超声条件下加入5毫升去离子水，继续超声30分钟，用分子量100～500的透析袋透析24小时以除去多余的三(羟甲基)氨基甲烷。冻干后得到化合物Trisporfin。
称取化合物Trisporfin(5毫克)加入5毫升无水甲醇，旋转蒸发仪(30转/分钟,40摄氏度)旋干，超声条件下加入毫升去离子水，继续超声30分钟，过 水系滤膜(0.22微米)除去游离二氢卟吩e6，最后得到澄清的Trisporfin纳米胶束溶液。
纳米光敏剂Trisporfin的 1H NMR谱如图1所示。
实施例2
称取三(羟甲基)氨基甲烷(10毫克)和二氢卟吩e6(5毫克)于圆底烧瓶中，加入5毫升无水四氢呋喃，超声60分钟使二者通过静电作用充分结合。用旋转蒸发仪(30转/分钟，50摄氏度)旋干除去有机溶剂，超声条件下加入5毫升去离子水，继续超声30分钟，用分子量100～500的透析袋透析24小时以除去多余的三(羟甲基)氨基甲烷。冻干机冻干后得到化合物Trisporfin。
称取化合物Trisporfin(5毫克)加入5毫升无水甲醇，旋转蒸发仪(30转/分钟，40摄氏度)旋干，超声条件下加入5毫升去离子水，继续超声30分钟，过水系滤膜(孔径为0.45微米)除去游离二氢卟吩e6，最后得到澄清的Trisporfin纳米胶束溶液。
实施例3
称取三(羟甲基)氨基甲烷(20毫克)和二氢卟吩e6(5毫克)于圆底烧瓶中，加入5毫升二氯甲烷，超声30分钟使二者通过静电作用充分结合。用旋转蒸发仪(100转/分钟，35摄氏度)旋干除去有机溶剂，超声条件下加入5毫升去离子水，继续超声60分钟，用分子量1500的透析袋透析12小时以除去多余的三(羟甲基)氨基甲烷。冻干机冻干后得到化合物Trisporfin。
称取化合物Trisporfin(10毫克)加入10毫升无水甲醇，旋转蒸发仪(30转/分钟，50摄氏度)旋干，超声条件下加入10毫升去离子水，继续超声30分钟，过水系滤头(孔径为0.22微米)除去游离二氢卟吩e6，最后得到澄清的Trisporfin纳米胶束溶液。
实施例4
称取三(羟甲基)氨基甲烷(15毫克)和二氢卟吩e6(15毫克)于圆底烧瓶中，加入15毫升四氢呋喃，超声60分钟使二者通过静电作用充分结合。用旋转蒸发仪(100转/分钟，50摄氏度)旋干除去有机溶剂，超声条件下加入15毫升去离子水，继续超声45分钟，用分子量100～500的透析袋透析12小时以除去多余的三(羟甲基)氨基甲烷。冻干后得到化合物Trisporfin。
称取化合物Trisporfin(15毫克)加入10毫升无水甲醇，旋转蒸发仪(60转/分钟，50摄氏度)旋干，超声条件下加入10毫升去离子水，继续超声30分钟，过水系滤头(孔径为0.45微米)除去游离二氢卟吩e6，最后得到澄清的Trisporfin纳米胶束溶液。
实施例5
称取三(羟甲基)氨基甲烷(5毫克)和二氢卟吩e6(5毫克)于圆底烧瓶中，加入5毫升N,N-二甲基甲酰胺，超声30分钟使二者通过静电作用充分结合。用旋转蒸发仪(30转/分钟，40摄氏度)旋干除去有机溶剂，超声条件下加入5毫升去离子水，继续超声30分钟，用分子量100～500的透析袋透析24小时以除去多余的三(羟甲基)氨基甲烷。冻干机冻干后得到化合物Trisporfin。
称取化合物Trisporfin(5毫克)加入5毫升无水甲醇，旋转蒸发仪(30转/分钟，60摄氏度)旋干，超声条件下加入5毫升去离子水，继续超声30分钟，过水系滤头(孔径为0.22微米)除去游离二氢卟吩e6，最后得到澄清的Trisporfin纳米胶束溶液。
实施例6
称取三(羟甲基)氨基甲烷(5毫克)和二氢卟吩e6(5毫克)于圆底烧瓶中，加入5毫升无水甲醇，超声30分钟使二者通过静电作用充分结合。用旋转蒸发仪(30转/分钟，20摄氏度)旋干除去有机溶剂，超声条件下加入5毫升去离子水，继续超声30分钟，用分子量100～500的透析袋透析24小时以除 去多余的三(羟甲基)氨基甲烷。冻干机冻干后得到化合物Trisporfin。
称取化合物Trisporfin(5毫克)加入5毫升无水甲醇，旋转蒸发仪(30转/分钟，60摄氏度)旋干，超声条件下加入5毫升去离子水，继续超声30分钟，过水系滤膜(孔径为0.22微米)除去游离二氢卟吩e6，最后得到澄清的Trisporfin纳米胶束溶液。
实施例7
称取三(羟甲基)氨基甲烷(5毫克)溶于5毫升四氢呋喃于圆底烧瓶1，二氢卟吩e6(5毫克)溶于5毫升无水甲醇于圆底烧瓶2，超声条件下将2缓慢滴入1中，继续超声30分钟使二者通过静电作用充分结合。用旋转蒸发仪(30转/分钟，20摄氏度)旋干除去有机溶剂，超声条件下加入5毫升去离子水，继续超声30分钟，用分子量100～500的透析袋透析24小时以除去多余的三(羟甲基)氨基甲烷。冻干机冻干后得到化合物Trisporfin。
称取化合物Trisporfin(5毫克)加入5毫升无水甲醇，旋转蒸发仪(30转/分钟，60摄氏度)旋干，超声条件下加入5毫升去离子水，继续超声30分钟，过水系滤膜(孔径为0.22微米)除去游离二氢卟吩e6，最后得到澄清的Trisporfin纳米胶束溶液。
实施例8
称取三(羟甲基)氨基甲烷(5毫克)溶于5毫升无水甲醇于圆底烧瓶1，二氢卟吩e6(5毫克)溶于5毫升无水甲醇于圆底烧瓶2，超声条件下将2转移缓慢滴入1中，继续超声30分钟使二者通过静电作用充分结合。用旋转蒸发仪(30转/分钟，20摄氏度)旋干除去有机溶剂，超声条件下加入5毫升去离子水，继续超声30分钟，用分子量100～500的透析袋透析24小时以除去多余的三(羟甲基)氨基甲烷。冻干机冻干后得到化合物Trisporfin。
称取化合物Trisporfin(5毫克)加入5毫升无水甲醇，旋转蒸发仪(30转/分钟，60摄氏度)旋干，超声条件下加入5毫升去离子水，继续超声30分 钟，过水系滤膜(孔径为0.22微米)除去游离二氢卟吩e6，最后得到澄清的Trisporfin纳米胶束溶液。
实施例9
称取三(羟甲基)氨基甲烷(5毫克)溶于5毫升二氯甲烷于圆底烧瓶1，二氢卟吩e6(5毫克)溶于5毫升无水甲醇于圆底烧瓶2，超声条件下将2缓慢滴入1中，继续超声30分钟使二者通过静电作用充分结合。用旋转蒸发仪(30转/分钟，20摄氏度)旋干除去有机溶剂，超声条件下加入5毫升去离子水，继续超声30分钟，用分子量100～500的透析袋透析24小时以除去多余的三(羟甲基)氨基甲烷。冻干机冻干后得到化合物Trisporfin。
称取化合物Trisporfin(5毫克)加入5毫升无水乙醇，旋转蒸发仪(30转/分钟，60摄氏度)旋干，超声条件下加入5毫升去离子水，继续超声30分钟，过水系滤膜(孔径为0.45微米)除去游离二氢卟吩e6，最后得到澄清的Trisporfin纳米胶束溶液。
实施例10
称取三(羟甲基)氨基甲烷(5毫克)溶于5毫升二氯甲烷于圆底烧瓶1，二氢卟吩e6(5毫克)溶于5毫升无水甲醇于圆底烧瓶2，超声条件下将2缓慢滴入1中，继续超声30分钟使二者通过静电作用充分结合。用旋转蒸发仪(30转/分钟，20摄氏度)旋干除去有机溶剂，超声条件下加入5毫升去离子水，继续超声30分钟，用分子量100～500的透析袋透析24小时以除去多余的三(羟甲基)氨基甲烷。冻干机冻干后得到化合物Trisporfin。
称取化合物Trisporfin(5毫克)加入5毫升无水甲醇，旋转蒸发仪(30转/分钟，60摄氏度)旋干，超声条件下加入5毫升去离子水，继续超声30分钟，过水系滤膜(孔径为0.22微米)除去游离二氢卟吩e6，最后得到澄清的Trisporfin纳米胶束溶液。
实施例11
称取三(羟甲基)氨基甲烷(5毫克)溶于5毫升二氯甲烷于圆底烧瓶1，二氢卟吩e6(5毫克)溶于5毫升无水甲醇于圆底烧瓶2，超声条件下将2缓慢滴入1中，继续超声10分钟使二者通过静电作用充分结合。用旋转蒸发仪(30转/分钟，20摄氏度)旋干除去有机溶剂，超声条件下加入5毫升去离子水，继续超声10分钟，用分子量100～500的透析袋透析24小时以除去多余的三(羟甲基)氨基甲烷。冻干机冻干后得到化合物Trisporfin。
称取化合物Trisporfin(5毫克)加入5毫升无水甲醇，旋转蒸发仪(30转/分钟，60摄氏度)旋干，超声条件下加入5毫升去离子水，继续超声10分钟，过水系滤膜(孔径为0.22微米)除去游离二氢卟吩e6，最后得到澄清的Trisporfin纳米胶束溶液。
实施例12
称取三(羟甲基)氨基甲烷(5毫克)溶于5毫升二氯甲烷于圆底烧瓶1，二氢卟吩e6(5毫克)溶于5毫升无水甲醇于圆底烧瓶2，超声条件下将2缓慢滴入1中，继续超声20分钟使二者通过静电作用充分结合。用旋转蒸发仪(30转/分钟，20摄氏度)旋干除去有机溶剂，超声条件下加入5毫升去离子水，继续超声20分钟，用分子量1500的透析袋透析12小时以除去多余的三(羟甲基)氨基甲烷。冻干机冻干后得到化合物Trisporfin。
称取化合物Trisporfin(5毫克)加入5毫升无水甲醇，旋转蒸发仪(30转/分钟，60摄氏度)旋干，超声条件下加入5毫升去离子水，继续超声20分钟，过水系滤头膜(孔径为0.45微米)去游离二氢卟吩e6，最后得到澄清的Trisporfin纳米胶束溶液。
实施例13
称取三(羟甲基)氨基甲烷(20毫克)和二氢卟吩e6(5毫克)于圆底烧瓶中，加入25毫升二氯甲烷，超声30分钟使二者通过静电作用充分结合。用 旋转蒸发仪(100转/分钟，35摄氏度)旋干除去有机溶剂，超声条件下加入5毫升去离子水，继续超声30分钟，用分子量100～500的透析袋透析24小时以除去多余的三(羟甲基)氨基甲烷。冻干后得到化合物Trisporfin。
称取化合物Trisporfin(5毫克)加入5毫升无水甲醇，旋转蒸发仪(30转/分钟，50摄氏度)旋干，超声条件下加入5毫升去离子水，继续超声30分钟，过水系滤膜(孔径为0.22微米)除去游离二氢卟吩e6，最后得到澄清的Trisporfin纳米胶束溶液。
实施例14
称取三(羟甲基)氨基甲烷(20毫克)和二氢卟吩e6(10毫克)于圆底烧瓶中，加入5毫升N,N-二甲基甲酰胺，超声30分钟使二者通过静电作用充分结合。用旋转蒸发仪(30转/分钟，40摄氏度)旋干除去有机溶剂，超声条件下加入5毫升去离子水，继续超声30分钟，用分子量100～500的透析袋透析24小时以除去多余的三(羟甲基)氨基甲烷。冻干机冻干后得到化合物Trisporfin。
称取化合物Trisporfin(5毫克)加入5毫升N,N-二甲基甲酰胺，旋转蒸发仪(30转/分钟，40摄氏度)旋干，超声条件下加入5毫升去离子水，继续超声30分钟，过水系滤膜(孔径为0.22微米)除去游离二氢卟吩e6，最后得到澄清的Trisporfin纳米胶束溶液。
实施例15
称取三(羟甲基)氨基甲烷(20毫克)和二氢卟吩e6(5毫克)于圆底烧瓶中，加入5毫升N,N-二甲基甲酰胺，超声5分钟使二者通过静电作用充分结合。用旋转蒸发仪(30转/分钟，60摄氏度)旋干除去有机溶剂，超声条件下加入5毫升去离子水，继续超声5分钟，用分子量1500的透析袋透析36小时以除去多余的三(羟甲基)氨基甲烷。冻干机冻干后得到化合物Trisporfin。
称取化合物Trisporfin(5毫克)加入5毫升N,N-二甲基甲酰胺，旋转蒸发 仪(30转/分钟，70摄氏度)旋干，超声条件下加入5毫升去离子水，继续超声5分钟，过水系滤膜(孔径为0.22微米)除去游离二氢卟吩e6，最后得到澄清的Trisporfin纳米胶束溶液。
实施例16
称取三(羟甲基)氨基甲烷(20毫克)和二氢卟吩e6(5毫克)于圆底烧瓶中，加入5毫升N,N-二甲基甲酰胺，超声5分钟使二者通过静电作用充分结合。用旋转蒸发仪(60转/分钟，60摄氏度)旋干除去有机溶剂，超声条件下加入5毫升去离子水，继续超声5分钟，用分子量100～500的透析袋透析24小时以除去多余的三(羟甲基)氨基甲烷。冻干后得到化合物Trisporfin。
称取化合物Trisporfin(5毫克)加入5毫升N,N-二甲基甲酰胺，旋转蒸发仪(60转/分钟，60摄氏度)旋干，超声条件下加入5毫升去离子水，继续超声5分钟，过水系滤膜(孔径为0.22微米)除去游离二氢卟吩e6，最后得到澄清的Trisporfin纳米胶束溶液。
图2为二氢卟吩e6和纳米光敏剂Trisporfin在水中的状态。从图中可以看出，通过静电作用得到的光敏剂Trisporfin相对于二氢卟吩e6水溶性显著提高。
采用薄膜分散法制备纳米光敏剂Trisporfin，利用动态光散射仪(DLS)和透射电镜对纳米光敏剂Trisporfin进行表征。从图3和图4中可以看出，纳米光敏剂Trisporfin具有均一的纳米尺寸。
进一步对目标产物进行光谱性质进行了测定，参见图5-7，纳米光敏剂Trisporfin的最大吸收波长在664nm。以锌酞菁(ZnPc)为参比，纳米光敏剂Trisporfin荧光量子产率为0.35。
为了进一步探究在光照条件下Trisporfin的单线态氧生成效率，利用1,3-二苯基异苯并呋喃(DPBF)作为单线态氧探针对其进行定量测试，以锌酞菁(ZnPc)为参比，所得结果如图8所示。DPBF能与单线态氧发生高效的化学反应，从而导致其415nm吸收峰发生明显下降。实验发现Trisporfin溶液的 415nm吸收峰随时间发生了明显的淬灭，计算得Trisporfin的单线态氧量子产率为0.38。
前面的相关实验已测试了纳米光敏剂Trisporfin具有产生单线态氧能力。为了进一步探究纳米光敏剂对肿瘤细胞杀伤力，利用MTT法研究了纳米光敏剂Trisporfin在非光照和光照条件下对4T1肿瘤细胞的毒性，所得结果如图9-10所示。从图中可知，纳米光敏剂Trisporfin具有较好的细胞杀伤能力。
由以上测试结果可知，本发明制备的纳米光敏剂Trisporfin，在水体系以及生物体液中尺寸均一且稳定，具有较好的细胞杀伤能力。
以上所述实施例仅是为充分说明本发明而所举的较佳的实施例，本发明的保护范围不限于此。本技术领域的技术人员在本发明基础上所作的等同替代或变换，均在本发明的保护范围之内。本发明的保护范围以权利要求书为准。

Claims (10)

  1. 一种二氢卟吩纳米光敏剂的制备方法，其特征在于，包括以下步骤：
    将二氢卟吩光敏剂与三(羟甲基)氨基甲烷于有机溶剂中混合，在静电相互作用下，所述二氢卟吩光敏剂与三(羟甲基)氨基甲烷发生自组装，形成所述二氢卟吩纳米光敏剂；所述二氢卟吩光敏剂包括二氢卟吩e6、二氢卟吩e6铜化合物、二氢卟吩e6锌化合物和二氢卟吩e6锰化合物。
  2. 如权利要求1所述的二氢卟吩纳米光敏剂的制备方法，其特征在于，所述有机溶剂包括无水甲醇、四氢呋喃、二氯甲烷、N,N-二甲基甲酰胺。
  3. 如权利要求1所述的二氢卟吩纳米光敏剂的制备方法，其特征在于，所述二氢卟吩光敏剂为二氢卟吩e6，所述三(羟甲基)氨基甲烷与二氢卟吩e6的摩尔比≥3。
  4. 如权利要求1所述的二氢卟吩纳米光敏剂的制备方法，其特征在于，所述制备方法具体为：
    S1.按配比称取二氢卟吩光敏剂和三(羟甲基)氨基甲烷，溶于有机溶剂中并混合，超声，使得所述二氢卟吩光敏剂和三(羟甲基)氨基甲烷在溶剂中通过静电作用充分结合；
    S2.旋干除去溶剂，加入去离子水，继续超声，然后透析除去多余的三(羟甲基)氨基甲烷，冻干后得二氢卟吩纳米光敏剂。
  5. 如权利要求4所述的二氢卟吩纳米光敏剂的制备方法，其特征在于，采用蒸发装置除去有机溶剂。
  6. 如权利要求4所述的二氢卟吩纳米光敏剂的制备方法，其特征在于，采用分子量为100～3000的透析袋透析24小时以上。
  7. 根据权利要求1-6任一项所述的方法制备得到的二氢卟吩纳米光敏剂。
  8. 如权利要求7所述的二氢卟吩纳米光敏剂，其特征在于，所述二氢卟吩纳米光敏剂的结构式为：
    Figure PCTCN2020122323-appb-100001
  9. 一种二氢卟吩纳米光敏剂的纳米胶束溶液，其特征在于，所述纳米胶束溶液是经如下步骤制备得到的：
    将权利要求7或8所述的二氢卟吩纳米光敏剂溶于溶剂中，旋干后，在超声条件下加入去离子水，继续超声，过水系滤膜，得所述二氢卟吩纳米光敏剂的纳米胶束溶液。
  10. 权利要求7或8所述的二氢卟吩纳米光敏剂在光动力治疗中的应用。
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