WO2021083370A1 - 一种特异性激活免疫系统的纳米材料的制备和应用 - Google Patents

一种特异性激活免疫系统的纳米材料的制备和应用 Download PDF

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WO2021083370A1
WO2021083370A1 PCT/CN2020/125506 CN2020125506W WO2021083370A1 WO 2021083370 A1 WO2021083370 A1 WO 2021083370A1 CN 2020125506 W CN2020125506 W CN 2020125506W WO 2021083370 A1 WO2021083370 A1 WO 2021083370A1
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cancer
cell membrane
nps
tumor
peg
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蔡林涛
孙枝红
邓冠军
龚萍
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Shenzhen Institute of Advanced Technology of CAS
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    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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    • A61K47/46—Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
    • A61K49/0032—Methine dyes, e.g. cyanine dyes
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    • A61K49/0069—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form
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    • A61K49/22—Echographic preparations; Ultrasonic imaging preparations
    • A61K49/222—Echographic preparations; Ultrasonic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
    • A61K49/225—Microparticles, microcapsules
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    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/58—Medicinal preparations containing antigens or antibodies raising an immune response against a target which is not the antigen used for immunisation
    • A61K2039/585—Medicinal preparations containing antigens or antibodies raising an immune response against a target which is not the antigen used for immunisation wherein the target is cancer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
    • A61K2239/38—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
    • A61K2239/46—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterised by the cancer treated
    • A61K2239/49—Breast

Definitions

  • the invention relates to the field of bio-nano materials, in particular to an antigen-loaded DC cell membrane-wrapped nano-particle, and a nano-delivery carrier containing the nano-particle.
  • Cancer or malignant tumor, has become one of the important diseases threatening human health worldwide.
  • the current mainstream cancer treatment methods include surgical resection, chemotherapy, chemotherapy, and radiotherapy.
  • surgical resection has a good therapeutic effect on early solid tumors, it is effective in treating early solid tumors.
  • the treatment effect of metastatic tumors is limited.
  • a large amount of normal tissue adjacent to the tumor is often removed during the operation to ensure the efficacy, which causes obvious damage to the patient's body; chemotherapy is a method of systemic drug delivery.
  • Radiotherapy is a commonly used clinical cancer treatment method that induces the death of cancer cells by irradiating cancer cells with radionuclides or ionizing radiation. Because radiation, that is, the range of irradiation has a certain controllability, the whole body caused by radiotherapy The toxicity is significantly lower than that of systemic chemotherapy, but radiotherapy still causes the normal tissues around the tumor to be irradiated to varying degrees, causing obvious side effects.
  • Tumor optical therapy is a new type of cancer treatment method with good specificity and non-invasiveness that has been extensively studied in recent years. According to its specific mechanism of action, it can be divided into photothermal therapy (Photothermal Therapy, PTT) and photodynamic therapy (Photodynamic therapy). Therapy, PDT).
  • PTT refers to a treatment that uses photothermal materials to convert light energy into heat energy, which increases the local temperature and kills tumor cells. When the ambient temperature is higher than 50 °C, tumor cells will gradually undergo apoptosis and necrosis, thereby achieving the effect of eliminating tumors.
  • PDT refers to the conversion of oxygen in the environment into singlet oxygen (Singlet Oxygen, SO) or reactive oxygen clusters (Reactive Oxygen) by exciting a photosensitizer with light.
  • Species, ROS to make tumor cells apoptosis and necrosis, to achieve the role of tumor treatment.
  • a good photothermal reagent is the key to obtaining excellent therapeutic effects. Specifically, it means that the photothermal reagent needs to have strong optical absorption, high photothermal conversion efficiency, excellent optical stability, good tumor targeting and excellent biocompatibility in the near-infrared region.
  • inorganic nanomaterials have achieved excellent therapeutic results in animal experiments and did not cause obvious toxic and side effects at the experimental doses, inorganic nanomaterials are difficult to be catabolized in the animal body, and are easily retained for a long time. The chronicity and other issues still cannot be ignored, which to a large extent restricts the transformation of such materials into clinical practice.
  • organic nanomaterials can be effectively metabolized and excreted in the body, greatly reducing its toxic and side effects.
  • the molar extinction coefficient of organic nanomaterials is generally much higher than that of inorganic nanomaterials, and the photothermal effect is also more excellent.
  • ICG indocyanine green
  • PL-PEG phospholipidized polyethylene glycol
  • NIR Near-infrared light
  • ICG indocyanine green
  • IR-797 has a more excellent photothermal therapy effect.
  • the characteristics of high-contrast and strong tissue penetrating biological near-infrared fluorescence imaging and photoacoustic imaging can be used for the diagnosis of tumors before treatment, the tracking during treatment and the evaluation of curative effect after treatment.
  • the present invention proposes a new nanoparticle that can be used for tumor photothermal therapy and medical imaging. It uses the characteristics of the antigen-loaded DC cell membrane to compare it with the near-infrared photothermal material IR-797. Combined to form nanoparticles (DC-NPs), the DC-NPs further improve the effect of low-temperature photothermal anti-tumor treatment by enhancing the body's immune function. Specifically, the present invention wraps the antigen-loaded DC cell membrane outside the phospholipid polyethylene glycol amino (DSPE-PEG) and IR-797 triggered by NIR to form a framework that can promote the enrichment and proliferation of T cells at the tumor site.
  • DSPE-PEG phospholipid polyethylene glycol amino
  • DC-NPs Activated and near-infrared light absorption polyethylene glycol-IR-797-DC cell membrane nanoparticles
  • An object of the present invention is to provide a DC cell membrane-encapsulated nanoparticle (DC-NPs), the nanoparticle encapsulates heptamethine cyanine dye with a polymer as the core, and the polymer and the heptamethine cyanine dye
  • the outer layer of the inner core is also wrapped with a DC cell membrane; preferably, the particle size of the nanoparticles is less than 200 nm, more preferably 50-120 nm, and preferably 86 ⁇ 4 nm.
  • the polymer is a high molecular polymer, preferably polylactic acid-glycolic acid copolymer (PLGA), polylactic acid (PLA), polycaprolactone (PCL), polyacrylamide, N- (2-Hydroxypropyl)methacrylamide (HPMA) or phospholipid polyethylene glycol (DSPE-PEG), more preferably phospholipid polyethylene glycol (DSPE-PEG).
  • PLGA polylactic acid-glycolic acid copolymer
  • PLA polylactic acid
  • PCL polycaprolactone
  • HPMA N- (2-Hydroxypropyl)methacrylamide
  • DSPE-PEG phospholipid polyethylene glycol
  • DSPE-PEG more preferably phospholipid polyethylene glycol
  • the heptajiachuan cyanine dye is selected from at least one of IR-780, IR-775, IR-797, IR-792, IR-806 or IR-808, preferably IR-797.
  • the DC cell membrane is a DC cell membrane loaded with an antigen; preferably the antigen is a tumor antigen; more preferably, the tumor is breast cancer, lung cancer, liver cancer, gastric cancer, colon cancer, rectal cancer, nasopharyngeal cancer, pancreas Cancer, thyroid cancer, prostate cancer, leukemia, lymphoma, kidney tumor, sarcoma or blastoma.
  • the antigen is a tumor antigen
  • the tumor is breast cancer, lung cancer, liver cancer, gastric cancer, colon cancer, rectal cancer, nasopharyngeal cancer, pancreas Cancer, thyroid cancer, prostate cancer, leukemia, lymphoma, kidney tumor, sarcoma or blastoma.
  • Another object of the present invention is to provide a method for preparing DC cell membrane-encapsulated nanoparticles, which includes the following steps:
  • the mass ratio of DSPE-PEG to IR-797 in the method is 1:1, preferably 2mg DSPE-PEG and 2mg IR-797 are dissolved in 2ml chloroform.
  • the preparation method of the DC cell model includes the following steps: after lysing the DC cells with a lysis solution, sonicating, followed by centrifugation at 12000g for 20min to remove insolubles, collecting the supernatant, and then performing 100000g of the supernatant, High-speed centrifugation for 40 minutes causes the cell membrane to settle to the bottom, and the supernatant is poured.
  • the resulting precipitate is the DC cell membrane;
  • the DC cell membrane is a DC cell membrane loaded with antigen, preferably a DC cell membrane loaded with tumor antigen.
  • step (3) in the method is repeated 20 times, after the cell membrane is evenly wrapped on the nanoparticles, the resulting solution needs to be transferred into a dialysis bag with a molecular weight of 5000 and sealed, and placed in distilled water for dialysis for 72 hours. The liquid was changed once in 8 hours to precipitate free substances and prepare nanoparticles.
  • the particle size of the nanoparticles prepared by the method is less than 200 nm, preferably 50-120 nm, preferably 86 ⁇ 4 nm.
  • Another object of the present invention is to provide a nano-delivery vehicle, which comprises the above-mentioned DC-NPs or the nano-particle prepared by the above-mentioned method.
  • Another object of the present invention is to provide an application of the above-mentioned DC-NPs, nanoparticles or nano-delivery vehicles, the application being selected from one of the following (1)-(3):
  • the tumor is breast cancer, lung cancer, liver cancer, gastric cancer, colon cancer, rectal cancer, nasopharyngeal cancer, pancreatic cancer, thyroid cancer , Prostate cancer, leukemia, lymphoma, kidney tumor, sarcoma or blastoma; more preferably the tumor is breast cancer;
  • the combination therapy including photothermal therapy, photodynamic therapy, chemotherapy, and/or radiotherapy.
  • the present invention has the following beneficial effects:
  • the present invention develops an antigen-loaded DC cell membrane-wrapped nanoparticles (DC-NPs), which can synergistically improve the effect of low-temperature photothermal anti-tumor treatment by enhancing the body's immune function, as follows:
  • IR-797 is an organic molecule with ultra-high molar extinction coefficient in the near-infrared spectral region. Compared with the traditional photothermal material indocyanine green, it is an excellent choice for photothermal therapeutic agents, and experiments have proved The prepared DC-NPs have better and excellent photothermal treatment effects.
  • Nanoparticles wrapped with antigen-loaded DC cell membrane have the ability to specifically activate the body’s immune system and can promote the effect of photothermal therapy.
  • the antigen-loaded DC cell membrane can work well with the photothermal therapy agent IR-797 Synergistic treatment effect.
  • DC-NPs can also be used for biofluorescence imaging and/or photoacoustic imaging to provide a basis for clinical research.
  • the DC-NPs prepared by the present invention can exist stably, and no sedimentation or flocculation phenomenon occurs after 15 days.
  • the preparation method of the invention is simple and easy to implement, and is convenient for operation and promotion.
  • Figure 1 is a schematic diagram of the preparation of DC-NPs.
  • Figure 2 is a transmission electron micrograph of DC-NPs, showing that DC cell membranes are successfully wrapped on the surface of nanoparticles.
  • Figure 3 shows the hydrated particle size of DC-NPs, which is 86 ⁇ 4 nm.
  • Figure 4 is the UV-visible absorption spectrum of DC-NPs, which is consistent with the IR-797 absorption peak and both have an absorption peak at 797 nm.
  • Figure 5 is the fluorescence emission spectrum.
  • the fluorescence emission peak of DC-NPs is 810 nm, which can be used for in-vivo near-infrared fluorescence imaging.
  • Figure 6 is a comparison chart of the stability of I-NPs and DC-NPs. Compared with the I-NPs group, the leakage of IR-797 from DC-NPs was significantly reduced.
  • Figure 7 is a comparison chart of the temperature curves of IR-797, I-NPs, DC-NPs and PBS.
  • 808nm laser 0.2 W/cm2
  • the photothermal effect of IDC-NPs is higher than that of other groups.
  • Figure 8 is an SDS-PAGE electrophoresis analysis of the surface protein map of DC-NPs.
  • the composition of DC-NPs is the same as that of DCM, indicating that it has part of the function of DCM.
  • the phospholipid polyethylene glycol (DSPE-PEG) is used as the nanoparticle skeleton to prepare membrane-encapsulated nanoparticles, and at the same time IR-797 is used for NIR-triggered photothermal therapy and imaging.
  • the preparation flow chart is shown in Figure 1, which specifically includes The following steps:
  • DC-NPs can be prepared by controlling the relative molecular mass of DSPE-PEG and the pore size of PVDF membrane, so that the particle size of 100% of DC-NPs is less than 200nm.
  • the morphology and structure of DC-NPs nanoparticles were observed by transmission electron microscopy.
  • the zeta potential meter analyzed the charge changes of the nanoparticles before and after the DC cell membrane was loaded, and the particle size analyzer analyzed the particle size distribution of the nanoparticles before and after the DC cell membrane was loaded. The results are shown in the figure. As shown in 2-3, the DC cell membrane was successfully wrapped on the surface of the nanoparticles, and the hydrated particle size of DC-NPs was 86 ⁇ 4 nm.
  • the ultraviolet-visible absorption spectrum shows that the absorption peaks of DC-NPs and IR-797 are consistent, and both have absorption peaks at 797nm.
  • the fluorescence emission spectrum shows that the fluorescence emission peak of DC-NPs is 810nm, which can be used for in-vivo near-infrared fluorescence imaging. .
  • the tumor volume calculation formula is: tumor length ⁇ (tumor width) 2 /2.
  • 200 ⁇ L of DC-NPs IR-797 concentration is 100 ⁇ g/mL
  • 808nm near-infrared laser with a power density of 0.3W/cm 2 was irradiated for 30 minutes to maintain The temperature of the illuminated part is 42°C.
  • the 808nm near-infrared laser with a power density of 0.3W/cm 2 treated tumor-bearing mice without DC-NPs injection for 15 days and the tumor grew to about 1350 mm 3 , while the tumor was basically eliminated after 20 days of laser irradiation of DC-NPs. .

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Abstract

一种可用于肿瘤光热治疗及医学成像的纳米颗粒，以及一种采用将负载抗原的DC细胞膜包裹在磷脂聚乙二醇氨基（DSPE-PEG）和近红外光触发的IR-797形成的颗粒骨架外，形成具有促进T细胞在肿瘤部位富集、增殖、活化和近红外光吸收的聚乙二醇-IR-797-DC细胞膜（DC-NPs）纳米颗粒的制备方法，其通过增强机体免疫反应而协同提高低温光热抗肿瘤治疗效果。

Description

一种特异性激活免疫系统的纳米材料的制备和应用 技术领域
本发明涉及生物纳米材料领域，具体涉及一种抗原负载的DC细胞膜包裹的纳米颗粒，以及含有该纳米颗粒的纳米递送载体。
 背景技术
癌症即恶性肿瘤，已成为全世界范围内威胁人类健康的重要疾病之一。现有的主流癌症治疗方法包括手术切除、化学药物治疗即化疗，以及放射治疗，但是这些治疗手段都具有其自身的局限性，其中手术切除尽管对早期实体瘤具有良好的治疗效果，但是其对己发生转移的肿瘤的治疗效果有限，此外，手术过程中为保证疗效往往会切除大量的与肿瘤相邻的正常组织，从而对患者机体造成明显的损伤；化疗是一种通过系统给药的方式来控制肿瘤生长的临床常用治疗手段，其在杀死癌细胞的同时也会杀死大量的正常细胞，并且容易诱导癌细胞对化疗药物产生耐受性而常常导致治疗的失败；放射治疗，即放疗，是通过利用放射性核素或电离辐射对癌细胞进行辐照而诱导癌细胞死亡的一种临床常用的癌症治疗手段，由于辐射即辐照范围具有一定的可控性，因而放疗造成的全身毒性明显低于全身系统给药的化疗，但是放疗仍会使肿瘤周围的正常组织受到不同程度的照射而造成明显的副作用。
有鉴于此，在现有癌症治疗方法的基础之上，结合肿瘤生物学、材料科学、仪器制造等多学科的优势，发展新型癌症治疗已成为目前临床癌症患者的迫切需求。肿瘤光学治疗是一种近年来广泛研究的具有良好特异性和非侵入性的新型癌症治疗方法，根据其具体作用机制可分为光热治疗(Photothermal Therapy，PTT)和光动力治疗(Photodynamic Therapy，PDT)。PTT 是指通过光热材料将光能转换为热能，使局部温度升高从而杀死肿瘤细胞的治疗方式，环境温度高于 50 ℃时肿瘤细胞会逐渐凋亡和坏死，从而达到消除肿瘤的作用。与 PTT 不同，PDT 是指通过光照激发光敏剂将环境中的氧气转换成单线态氧(Singlet Oxygen，SO)或活性氧簇(Reactive Oxygen Species， ROS)从而使肿瘤细胞凋亡和坏死，达到治疗肿瘤的作用。
在光热治疗中，良好的光热试剂是获得优异治疗效果的关键。具体是指光热试剂需要在近红外区域具有较强的光学吸收、较高的光热转化效率、优异的光学稳定性、良好的肿瘤靶向性以及优良的生物相容性。现有技术中，尽管已有报道无机纳米材料在动物实验中取得了优异的治疗结果且在实验剂量下未引起明显的毒副作用，但是无机纳米材料在动物体内难以被分解代谢，容易长期滞留而产生慢性度等等问题仍然不容忽视，在很大程度上制约了这类材料向临床转化。相反，有机纳米材料可以在体内进行有效的代谢和排泄，极大的降低了其毒副作用。同时，有机纳米材料的摩尔消光系数一般都远高于无机纳米材料，光热效应也更加优异。如Zheng等人（Mol. Pharm. 2011，8，447-56.）利用光热分子吲哚菁绿(ICG)和磷脂化聚乙二醇(PL-PEG)制备了一种可用与光热治疗的纳米胶束。Cheng等人（Adv. Funct. Mater. 2013，23，5893-5902）用两亲性高分子 C18PMH-PEG 包裹 IR825 形成胶束，极大的增加了 IR825 的生物相容性和稳定性，降低了其在体内的毒副作用。
近红外光(Near-infrared light，NIR)响应是近年来备受关注的一种远程剌激响应机制，由于其低损害、局域响应等优点，在生命医疗领域，尤其是近红外光介导的光热疗法展示出了很好的应用前景。这是由于生物组织对近红外光的吸收量少，从而使其具有较大的生物组织穿透深度。目前近红外光吸收材料的种类繁多，其中光热转换材料的吲哚菁绿(Indocyanine Green，ICG) 易于被机体代谢且具有较高的摩尔消光系数，因此成为了光热材料中较佳的选择。然而，现有技术中对于新型有机光热材料 IR-797 在光热治疗中的应用研究较少，相比于传统光热材料吲哚菁绿，IR-797具有更加优异的光热治疗疗效果，高对比度和强组织穿透性的生物近红外荧光成像和光声成像的特性，可用于肿瘤治疗前的诊断，治疗中的追踪和治疗后的疗效评价。
发明内容
基于上述现有技术的种种缺陷，本发明提出了一种可用于肿瘤光热治疗及医学成像的全新的纳米颗粒，利用负载抗原的DC细胞膜特性，将其与近红外光热材料IR-797相联合形成纳米颗粒（DC-NPs），所述DC-NPs通过增强机体免疫功能而进一步提高低温光热抗肿瘤治疗效果。具体地，本发明将负载抗原的DC细胞膜包裹在磷脂聚乙二醇氨基（DSPE-PEG）和NIR触发的IR-797形成的颗粒骨架外，形成具有促进T细胞在肿瘤部位富集、增殖、活化和近红外光吸收的聚乙二醇-IR-797-DC细胞膜纳米颗粒（DC-NPs），旨在通过增强机体免疫反应而提高低温光热抗肿瘤治疗效果。
本发明的一个目的在于提供一种DC细胞膜包裹的纳米颗粒（DC-NPs），所述纳米颗粒以聚合物为内核包载七甲川花菁染料，所述聚合物与所述七甲川花菁染料以非共价方式结合，在所述内核外层还包裹有DC细胞膜；优选地所述纳米颗粒的粒径小于200nm，进一步优选为50-120nm，较佳地为86±4 nm。
优选地，所述聚合物为高分子聚合物，较佳地为聚乳酸-羟基乙酸共聚物(PLGA)、聚乳酸(PLA)、聚己酸内酯(PCL)、聚丙稀醜胺、N-(2-Hydroxypropyl)methacrylamide (HPMA) 或磷脂聚乙二醇（DSPE-PEG），更佳地为磷脂聚乙二醇（DSPE-PEG）。
优选地，所述七甲川花菁染料选自IR-780、IR-775、IR-797、IR-792、IR-806或IR-808中的至少一种，较佳地为IR-797。
优选地，DC细胞膜为负载抗原的DC细胞膜；较佳地所述抗原为肿瘤抗原；更佳地，所述肿瘤为乳腺癌、肺癌、肝癌、胃癌、结肠癌、直肠癌、鼻咽癌、胰腺癌、甲状腺癌、前列腺癌、白血病、淋巴瘤、肾脏肿瘤、肉瘤或母细胞瘤。
本发明的另一目的在于提供一种DC细胞膜包裹的纳米颗粒的制备方法，包括如下步骤：
（1）将DSPE-PEG和IR-797溶于氯仿中，吹打混匀，将氯仿溶液转移到盛有蒸馏水的烧杯底部，然后通入氮气，以吹走氯仿，得到DSPE-PEG/ IR-797纳米颗粒骨架；
（2）随后将烧杯里的液体转移至透析袋内，并用蒸馏水透析，期间换水，以除去没有形成颗粒的DSPE-PEG和IR-797；
（3）将提取的DC细胞膜通过挤压附着于PVDF膜上，再将DSPE-PEG/IR-797纳米颗粒挤压通过PVDF膜，重复10-30次，使细胞膜包裹在所述纳米颗粒上，制备得到DC细胞膜包裹的纳米颗粒。
优选地，所述方法中DSPE-PEG与IR-797的质量比为1:1，较佳地为2mg DSPE-PEG和2mg IR-797溶于2ml氯仿中。
优选地，所述DC细胞模的制备方法包括如下步骤：用裂解液将DC细胞裂解后，超声，随后经12000g，20min的离心除去不溶物，收集上清液，再对上清液进行100000g，40min的高速离心，使细胞膜沉淀到底部，倒去上清液，所得沉淀即为DC细胞膜；所述DC细胞膜为负载抗原的DC细胞膜，较佳地为负载肿瘤抗原的DC细胞膜。
优选地，所述方法中步骤（3）重复20次，使细胞膜均匀包裹在所述纳米颗粒上后，还需要将所得溶液转入分子量5000的透析袋中密闭，置于蒸馏水中透析72h，每8h进行一次换液，使游离物质析出，制备得到纳米颗粒。
优选地，所述方法制备得到的纳米颗粒的粒径小于200nm，优选为50-120nm，较佳地为86±4 nm。
本发明的另一目的在于提供一种纳米递送载体，其包括上述DC-NPs或上述方法制备的纳米颗粒。
本发明的另一目的在于提供一种上述DC-NPs、纳米颗粒或纳米递送载体的应用，所述应用选自如下（1）-（3）之一：
（1）在制备肿瘤光热治疗和/或诊断试剂或药物中的应用，优选地所述肿瘤为乳腺癌、肺癌、肝癌、胃癌、结肠癌、直肠癌、鼻咽癌、胰腺癌、甲状腺癌、前列腺癌、白血病、淋巴瘤、肾脏肿瘤、肉瘤或母细胞瘤；更优选地所述肿瘤为乳腺癌；
（2）在医学成像中的应用，所述医学成像包括生物荧光成像和/或光声成像；
（3）在制备联合治疗的试剂或药物中的应用，所述联合治疗包括光热治疗与光动力治疗、化疗和/或放疗的联合治疗。
与现有技术相比，本发明具有以下有益效果：
本发明开发了一种负载抗原的DC细胞膜包裹的纳米颗粒（DC-NPs），其可通过增强机体免疫功能而协同提高低温光热抗肿瘤治疗效果，具体如下：
（1）采用了新型有机光热材料 IR-797，IR-797 是一种在近红外光谱区有超高摩尔消光系数的有机分子，相比于传统光热材料吲哚菁绿，是光热治疗剂的绝佳选择，且实验证明制备所得DC-NPs具有更佳优异的光热治疗疗效果。
（2）采用负载抗原的DC细胞膜包裹的纳米颗粒，具有特异性激活机体免疫系统的能力，能够促进光热治疗效果，负载抗原的DC细胞膜能够与光热治疗剂IR-797起到很好的协同治疗效果。DC-NPs还可用于生物荧光成像和/或光声成像，为临床研究提供基础。
（3）本发明制备的DC-NPs能够稳定存在，15天后未出现沉降、凝絮现象。
（4）本发明制备方法简便易行，便于操作推广。
 附图说明
图1 是DC-NPs制备示意图。
图2是DC-NPs的透射电镜图，显示DC细胞膜成功包裹在纳米颗粒表面。
图3 是DC-NPs的水合粒径大小，为86±4 nm。
图4是DC-NPs紫外-可见吸收光谱图，其与IR-797吸收峰一致均在797nm处具有吸收峰。
图5是荧光发射光谱，DC-NPs的荧光发射峰为810nm，其可用于体内近红外荧光成像。
图6是I-NPs和DC-NPs的稳定性对比图，与I-NPs组相比，IR-797从DC-NPs的泄漏明显减少。
图7是IR-797、I-NPs、DC-NPs和PBS的温度曲线对比图，在808nm激光（0.2 W/cm2）照射8分钟，IDC-NPs的光热效应高于其它组。
图8是SDS-PAGE电泳分析DC-NPs表面蛋白图，DC-NPs组成与DCM相同，表明其具有DCM部分功能。
具体实施方式
以下通过具体实施例对本发明作进一步详细说明，以使本领域技术人员能够更好地理解本发明并予以实施，但实施例并不作为本发明的限定。
以下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  负载抗原的DC细胞膜包裹IR-797纳米颗粒（DC-NPs）的制备
以磷脂聚乙二醇（DSPE-PEG）为纳米颗粒骨架制备膜包裹纳米颗粒，同时包载IR-797用于NIR触发的光热治疗和成像，制备流程图如附图1所示，具体包括如下步骤：
（1）将2mg DSPE-PEG和2mg IR-797溶于2ml氯仿中，吹打混匀，将氯仿混合物转移到盛有15ml蒸馏水的烧杯底部，往烧杯底部通入氮气，吹走氯仿，使IR-797因疏水作用而DSPE-PEG中的亲脂基团结合而被包载其中而形成纳米颗粒，所得溶液即为DSPE-PEG/IR-797溶液。
（2）用裂解液将DC细胞裂解后，超声10min，随后经12000g，20min的离心除去不溶物，收集上清液，再对上清液进行100000g，40min的高速离心，使细胞膜沉淀到底部，倒去上清液，所得沉淀即为DC细胞膜。
（3）将DC细胞膜用水溶液充分溶解后，挤压通过PVDF膜，使细胞膜附着在PVDF膜上，再挤压使DSPE-PEG/IR-797溶液通过PVDF膜，使DC细胞膜因挤压而包载在DSPE-PEG/IR-797纳米颗粒上，重复20次使包载均匀。随后将所得溶液转入分子量5000的透析袋中密闭，置于蒸馏水中透析72h，每8h进行一次换液，使游离物质析出。
可通过控制DSPE-PEG的相对分子质量、PVDF膜的孔径大小而制备DC-NPs, 使得100%的DC-NPs的粒径小于200nm。
实施例 2  DC-NPs的表征
DC-NPs纳米颗粒的形貌结构采用透射电镜来观察， zeta电位仪分析包载DC细胞膜前后的纳米颗粒的电荷变化，粒径仪分析DC细胞膜包载前后纳米颗粒的粒径分布，结果如图2-3所示，DC细胞膜成功包裹在纳米颗粒表面，DC-NPs的水合粒径大小为86±4 nm。利用荧光光谱仪检测DC-NPs纳米颗粒的荧光光谱以确定成像条件，紫外-可见吸收光谱仪检测纳米颗粒的紫外-可见吸收光谱以确定颗粒光热治疗的激光波长，结果如图4-5所示，紫外-可见吸收光谱图显示，DC-NPs与IR-797吸收峰一致，均在797nm处具有吸收峰，荧光发射光谱显示，DC-NPs的荧光发射峰为810nm，其可用于体内近红外荧光成像。检测DC-NPs纳米颗粒在PBS、水溶液和血清中不同介质中的稳定性，分离小鼠血液，将DC-NPs纳米颗粒加入并评估其溶血性反应性，结果如图6所示，与I-NPs组相比，IR-797从DC-NPs的泄漏明显减少；IR-797、I-NPs、DC-NPs和PBS的温度曲线对比结果，如图7所示，在808nm激光（0.2 W/cm2）照射8分钟的条件下，IDC-NPs的光热效应高于其它组。聚丙烯酰氨凝胶（SDS-PAGE）电泳和蛋白组学大数据分析DC-NPs纳米颗粒的蛋白质的成分，结果如图8所示，SDS-PAGE电泳分析DC-NPs表面蛋白，其组成与DCM相同，表明其具有DCM部分功能。
实施例 3  DC-NPs的光热治疗
雌性BALB/c（4-6周，体重为15-20g）皮下注射1 × 10 6 个4T1乳腺癌细胞。肿瘤体积计算公式为：肿瘤长度×(肿瘤宽度) 2/2。待肿瘤体积达到100-200mm 3左右时，静脉注射200μL DC-NPs（IR-797浓度为100 μg/mL），3天后才用0.3W/cm 2的功率密度的808nm近红外激光照射30min，维持光照部位温度42℃。
0.3W/cm 2的功率密度的808nm近红外激光对未注射DC-NPs组的荷瘤小鼠处理15天后肿瘤长大至约1350 mm 3，而DC-NPs加以激光照射处理20天后肿瘤基本消除。
以上所述仅为本发明的较佳实施例，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、改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 一种DC细胞膜包裹的纳米颗粒（DC-NPs），所述DC-NPs以聚合物为内核包载七甲川花菁染料，所述聚合物与所述七甲川花菁染料以非共价方式结合，在所述内核外层还包裹有DC细胞膜；优选地，所述DC-NPs的粒径小于200nm，进一步优选为50-120nm，较佳地为86±4 nm。
  2. 根据权利要求1所述的DC-NPs，所述聚合物为高分子聚合物，较佳地所述聚合物选自聚乳酸-羟基乙酸共聚物(PLGA)、聚乳酸(PLA)、聚己酸内酯(PCL)、聚丙稀醜胺、N-(2-Hydroxypropyl)methacrylamide (HPMA) 或磷脂聚乙二醇（DSPE-PEG）中的至少一种，更佳地所述聚合物为磷脂聚乙二醇（DSPE-PEG）；所述七甲川花菁染料选自IR-780、IR-775、IR-797、IR-792、IR-806或IR-808中的至少一种，较佳地七甲川花菁染料为IR-797。
  3. 根据权利要求1所述的DC-NPs，所述DC细胞膜为负载抗原的DC细胞膜；较佳地，所述抗原为肿瘤抗原；更佳地，所述肿瘤为乳腺癌、肺癌、肝癌、胃癌、结肠癌、直肠癌、鼻咽癌、胰腺癌、甲状腺癌、前列腺癌、白血病、淋巴瘤、肾脏肿瘤、肉瘤或母细胞瘤。
  4. 一种纳米颗粒的制备方法，包括如下步骤：
    （1）将DSPE-PEG和IR-797溶于氯仿中，吹打混匀，将氯仿溶液转移到盛有蒸馏水的烧杯底部，然后通入氮气，以吹走氯仿，得到DSPE-PEG/ IR-797纳米颗粒骨架；
    （2）随后将烧杯里的液体转移至透析袋内，并用蒸馏水透析，期间换水，以除去没有形成颗粒的DSPE-PEG和IR-797；
    （3）将提取的DC细胞膜通过挤压附着于PVDF膜上，再将DSPE-PEG/IR-797纳米颗粒挤压通过PVDF膜，重复10-30次，使细胞膜包裹在所述纳米颗粒上，制备得到DC细胞膜包裹的纳米颗粒。
  5. 根据权利要求4所述的方法，所述方法中DSPE-PEG与IR-797的质量比为1:1，较佳地为2mg DSPE-PEG和2mg IR-797溶于2ml氯仿中。
  6. 根据权利要求4所述的方法，所述DC细胞模的制备方法包括如下步骤：用裂解液将DC细胞裂解后，超声，随后经12000g，20min的离心除去不溶物，收集上清液，再对上清液进行100000g，40min的高速离心，使细胞膜沉淀到底部，倒去上清液，所得沉淀即为DC细胞膜；优选地，所述DC细胞膜为抗原负载的DC细胞膜，较佳地，所述抗原为肿瘤抗原。
  7. 根据权利要求4所述的方法，所述方法中步骤（3）重复20次，使细胞膜均匀包裹在所述纳米颗粒上后，还需要将所得溶液转入分子量5000的透析袋中密闭，置于蒸馏水中透析72h，每8h进行一次换液，使游离物质析出，制备得到DC细胞膜包裹的纳米颗粒。
  8. 根据权利要求4-7任一项所述的方法，使制备得到的纳米颗粒的粒径小于200nm，优选为50-120nm，较佳地为86±4 nm。
  9. 一种纳米递送载体，其包括权利要求1-3任一项所述的DC-NPs或权利要求4-8任一项所述的方法制备的纳米颗粒。
  10. 权利要求1-3任一项所述的DC-NPs或权利要求4-8任一项所述的方法制备的纳米颗粒或权利要求9所述的纳米递送载体的应用，所述应用选自如下（1）-（3）之一：
    （1）在制备肿瘤光热治疗和/或诊断试剂或药物中的应用，优选地所述肿瘤为乳腺癌、肺癌、肝癌、胃癌、结肠癌、直肠癌、鼻咽癌、胰腺癌、甲状腺癌、前列腺癌、白血病、淋巴瘤、肾脏肿瘤、肉瘤或母细胞瘤；更优选地所述肿瘤为乳腺癌；
    （2）在医学成像中的应用，所述医学成像包括生物荧光成像和/或光声成像；
    （3）在制备联合治疗的试剂或药物中的应用，所述联合治疗包括光热治疗与光动力治疗、化疗和/或放疗的联合治疗。
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