CN111265544A - A kind of nanometer calcium carbonate particle and its preparation method and application - Google Patents
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- 239000002245 particle Substances 0.000 title claims abstract description 53
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- A61K33/00—Medicinal preparations containing inorganic active ingredients
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- A61K33/10—Carbonates; Bicarbonates
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Abstract
本发明涉及生物技术领域，本发明提供了一种本发明提供了一种纳米碳酸钙微粒，以聚乳酸‑羟基乙酸(PLGA)和聚乳酸‑羟基乙酸‑聚乙二醇(PLGA‑PEG)为壳层，以碳酸钙为核层。本发明提供的纳米碳酸钙微粒(聚乳酸‑羟基乙酸碳酸钙制剂)由聚乳酸‑羟基乙酸、聚乳酸‑羟基乙酸‑聚乙二醇和碳酸钙组成，粒径均一，在水中分散良好，在水中粒径主要集中在120nm左右。实验表明本发明所述聚乳酸‑羟基乙酸碳酸钙微粒有良好的增强肿瘤免疫治疗的效果，能够作为肿瘤免疫治疗的佐剂。The present invention relates to the field of biotechnology, and the present invention provides a kind of nano-calcium carbonate particles, comprising polylactic acid-glycolic acid (PLGA) and polylactic acid-glycolic acid-polyethylene glycol (PLGA-PEG) as Shell layer, with calcium carbonate as the core layer. The nanometer calcium carbonate particles (polylactic acid-glycolic acid calcium carbonate preparation) provided by the present invention are composed of polylactic acid-glycolic acid, polylactic acid-glycolic acid-polyethylene glycol and calcium carbonate, have uniform particle size, and are well dispersed in water. The particle size is mainly concentrated around 120nm. Experiments show that the polylactic acid-glycolic acid calcium carbonate particles of the present invention have a good effect of enhancing tumor immunotherapy, and can be used as an adjuvant for tumor immunotherapy.
Description
技术领域technical field
本发明涉及生物技术领域，尤其是涉及一种纳米碳酸钙微粒及其制备与 应用。The present invention relates to the field of biotechnology, in particular to a nanometer calcium carbonate particle and its preparation and application.
背景技术Background technique
肿瘤(tumour)是指机体在各种致瘤因子作用下，局部组织细胞增生所形 成的新生物(neogrowth)，因为这种新生物多呈占位性块状突起，也称赘生 物(neoplasm)。根据新生物的细胞特性及对机体的危害性程度，又将肿瘤分 为良性肿瘤和恶性肿瘤两大类，而癌症即为恶性肿瘤的总称。与良性肿瘤相 比，恶性肿瘤生长速度快，呈浸润性生长，易发生出血、坏死、溃疡等，并 常有远处转移，造成人体消瘦、无力、贫血、食欲不振、发热以及严重的脏 器功能受损等，最终造成患者死亡。由于人口老龄化等原因，当前我国癌症 发病率、死亡率呈持续增长趋势。世界癌症报告估计，2012年中国癌症发病 人数为306.5万，约占全球发病人数的五分之一；癌症死亡人数为220.5万，约 占全球癌症死亡人数的四分之一。今后20年，我国癌症的发病数和死亡数还 将持续上升：根据国际癌症研究署预测，如不采取有效措施，我国癌症发病 数和死亡数到2020年将上升至400万人和300万人；2030年将上升至500万人和 350万人。Tumor refers to a new organism (neogrowth) formed by the proliferation of local tissue cells under the action of various tumorigenic factors, because this new organism is mostly space-occupying lumpy protrusions, also known as neoplasms. . According to the cell characteristics of new organisms and the degree of harm to the body, tumors are divided into two categories: benign tumors and malignant tumors, and cancer is the general term for malignant tumors. Compared with benign tumors, malignant tumors grow rapidly and are invasive, prone to bleeding, necrosis, ulcers, etc., and often have distant metastasis, resulting in weight loss, weakness, anemia, loss of appetite, fever, and severe organ damage. Functional impairment, etc., eventually lead to the death of the patient. Due to the aging of the population and other reasons, the incidence and mortality of cancer in my country are currently increasing. The World Cancer Report estimates that in 2012, the number of cancer cases in China was 3.065 million, accounting for about one-fifth of the global incidence; the number of cancer deaths was 2.205 million, accounting for about a quarter of the global cancer deaths. In the next 20 years, the number of cancer incidence and deaths in my country will continue to rise: according to the International Agency for Research on Cancer, if no effective measures are taken, the number of cancer incidence and deaths in my country will rise to 4 million and 3 million by 2020. ; rising to 5 million and 3.5 million in 2030.
肿瘤免疫治疗是一种通过激活人体自身免疫系统来抑制肿瘤生 长的治疗手段，其核心在于有效激活肿瘤患者体内的T淋巴细胞的抗 肿瘤反应，实现对肿瘤生长的特异性抑制和杀灭。其中，免疫检查点 阻断疗法是激活治疗性抗肿瘤免疫最有前途的方法，在临床取得了较 好的治疗效果。但是，目前仍面临着响应率较低的问题，限制了其临 床应用。由于肿瘤细胞的快速增殖、代谢途径改变、肿瘤血管发育畸 形等原因，实体肿瘤常有着乏氧、微酸、间隙压高、高活性氧、免疫 耐受等一系列与正常组织不同的微环境特征。其中，肿瘤微酸不但可 以通过降低T细胞分泌IFN-β和TNF-α等效应性细胞因子、并诱导T 淋巴细胞凋亡等途径来抑制机体的抗肿瘤免疫功能，还会导致抗体降 解与失活，进而对基于anti-PD-1/PD-L1等免疫检查点阻断疗法的疗效 产生负面影响。目前大量科学家致力于开发调节肿瘤微环境的药物和 治疗方法，以实现增强的肿瘤免疫治疗。Tumor immunotherapy is a treatment method that inhibits tumor growth by activating the body's own immune system. Its core is to effectively activate the anti-tumor response of T lymphocytes in tumor patients to achieve specific inhibition and killing of tumor growth. Among them, immune checkpoint blockade therapy is the most promising method to activate therapeutic anti-tumor immunity, and has achieved good therapeutic effects in clinical practice. However, it still faces the problem of low response rate, which limits its clinical application. Due to the rapid proliferation of tumor cells, changes in metabolic pathways, and abnormal development of tumor blood vessels, solid tumors often have a series of microenvironment characteristics different from normal tissues, such as hypoxia, slightly acid, high interstitial pressure, high reactive oxygen species, and immune tolerance. . Among them, tumor microacid can not only inhibit the anti-tumor immune function of the body by reducing the secretion of effector cytokines such as IFN-β and TNF-α by T cells, and induce T lymphocyte apoptosis, but also lead to the degradation and loss of antibodies. It can negatively affect the efficacy of immune checkpoint blockade therapy based on anti-PD-1/PD-L1. A large number of scientists are currently working on developing drugs and therapeutics that modulate the tumor microenvironment to achieve enhanced tumor immunotherapy.
发明内容SUMMARY OF THE INVENTION
有鉴于此，本发明要解决的技术问题在于提供一种纳米碳酸钙微粒，本 发明提供的纳米碳酸钙微粒具有良好的调节肿瘤微酸环境的效果，能够增强 肿瘤免疫治疗效果。In view of this, the technical problem to be solved by the present invention is to provide a kind of nanometer calcium carbonate particles, the nanometer calcium carbonate particles provided by the present invention have a good effect of regulating the slightly acidic environment of tumors, and can enhance the effect of tumor immunotherapy.
本发明提供了一种纳米碳酸钙微粒，以聚乳酸-羟基乙酸(PLGA)和聚 乳酸-羟基乙酸-聚乙二醇(PLGA-PEG)为壳层，以碳酸钙为核层。The present invention provides a kind of nanometer calcium carbonate particle, which uses polylactic acid-glycolic acid (PLGA) and polylactic acid-glycolic acid-polyethylene glycol (PLGA-PEG) as shell layers and calcium carbonate as core layer.
优选的，所述纳米碳酸钙微粒粒径为100～120nm。Preferably, the particle size of the nano calcium carbonate particles is 100-120 nm.
本发明提供了一种纳米碳酸钙微粒的制备方法，包括：The invention provides a preparation method of nano calcium carbonate particles, comprising:
A)将聚乳酸-羟基乙酸、聚乳酸-羟基乙酸-聚乙二醇在溶剂中混合，得到 PLGA和PLGA-PEG混合溶液；A) mixing polylactic acid-glycolic acid and polylactic acid-glycolic acid-polyethylene glycol in solvent to obtain PLGA and PLGA-PEG mixed solution;
B)将PLGA和PLGA-PEG混合溶液与NaHCO3溶液混合，乳化，得到 第一乳液；B) mix PLGA and PLGA - PEG mixed solution with NaHCO solution, emulsify, obtain the first emulsion;
将PLGA和PLGA-PEG混合溶液与CaCl2水溶液混合，乳化，得到第 二乳液；Mix the PLGA and PLGA-PEG mixed solution with the CaCl 2 aqueous solution, and emulsify to obtain the second emulsion;
C)将第一乳液和第二乳液混合，乳化，得到第三乳液；C) mix the first emulsion and the second emulsion, and emulsify to obtain the third emulsion;
D)将第三乳液分散于聚乙烯醇水溶液中，搅拌、洗涤得到 CaCO3@PLGA-PEG。D) Disperse the third emulsion in an aqueous solution of polyvinyl alcohol, stir and wash to obtain CaCO 3 @PLGA-PEG.
优选的，所述PLGA与PLGA-PEG的质量比为1～2:1～2；所述PLGA与 PLGA-PEG的混合溶液的浓度为25～35mg/ml；所述溶剂为二氯甲烷。Preferably, the mass ratio of the PLGA to the PLGA-PEG is 1-2:1-2; the concentration of the mixed solution of the PLGA and the PLGA-PEG is 25-35 mg/ml; and the solvent is dichloromethane.
优选的，所述NaHCO3浓度为0.6～0.7M，所述CaCl2溶液浓度为1～1.5M。Preferably, the concentration of the NaHCO 3 is 0.6-0.7M, and the concentration of the CaCl 2 solution is 1-1.5M.
优选的，所述PLGA和PLGA-PEG混合溶液与NaHCO3溶液的体积比为 2～3:1；所述PLGA和PLGA-PEG混合溶液与CaCl2水溶液的体积比为3～4:1。Preferably, the volume ratio of the PLGA and PLGA-PEG mixed solution to the NaHCO 3 solution is 2 to 3:1; the volume ratio of the PLGA and PLGA-PEG mixed solution to the CaCl 2 aqueous solution is 3 to 4:1.
优选的，步骤C)所述乳化为超声乳化，所述超声功率为80～120W；所 述超声时间为250～350s。Preferably, the emulsification in step C) is phacoemulsification, the ultrasonic power is 80-120W, and the ultrasonic time is 250-350s.
优选的，步骤C)所述聚乙烯醇水溶液的质量分数为1％～2％；所述搅拌 的时间为10～14h；所述洗涤为14000～15000rpm的条件下离心20～30min，用 超纯水洗涤2～3次。Preferably, the mass fraction of the polyvinyl alcohol aqueous solution in step C) is 1%-2%; the stirring time is 10-14h; Wash with water 2 to 3 times.
本发明提供了上述技术方案任意一项所述的纳米碳酸钙微粒或上述技术 方案任意一项所述的制备方法制备得到的纳米碳酸钙微粒在制备肿瘤免疫治 疗的佐剂中的应用。The present invention provides the application of the nano-calcium carbonate particles according to any one of the above technical solutions or the nano-calcium carbonate particles prepared by the preparation method according to any one of the above technical solutions in the preparation of adjuvants for tumor immunotherapy.
本发明提供了一种肿瘤免疫治疗佐剂，包括上述技术方案任意一项所述 的纳米碳酸钙微粒或上述技术方案任意一项所述的制备方法制备得到的纳米 碳酸钙制剂。The present invention provides a tumor immunotherapy adjuvant, comprising the nano calcium carbonate particles described in any one of the above technical solutions or the nano calcium carbonate preparation prepared by the preparation method described in any one of the above technical solutions.
与现有技术相比，本发明提供了一种纳米碳酸钙微粒，以聚乳酸-羟基乙 酸(PLGA)和聚乳酸-羟基乙酸-聚乙二醇(PLGA-PEG)为壳层，以碳酸钙 为核层。本发明提供的纳米碳酸钙微粒(聚乳酸-羟基乙酸碳酸钙制剂)由聚 乳酸-羟基乙酸、聚乳酸-羟基乙酸-聚乙二醇和碳酸钙组成，粒径均一，在水 中分散良好，在水中粒径主要集中在120nm左右。实验表明本发明所述聚乳 酸-羟基乙酸碳酸钙微粒有良好的增强肿瘤免疫治疗的效果，能够作为肿瘤免 疫治疗的佐剂。Compared with the prior art, the present invention provides a kind of nanometer calcium carbonate particles, which uses polylactic acid-glycolic acid (PLGA) and polylactic acid-glycolic acid-polyethylene glycol (PLGA-PEG) as shell layers, and uses calcium carbonate as shell layers. for the nuclear layer. The nano calcium carbonate particles (polylactic acid-glycolic acid calcium carbonate preparation) provided by the present invention are composed of polylactic acid-glycolic acid, polylactic acid-glycolic acid-polyethylene glycol and calcium carbonate, have uniform particle size, and are well dispersed in water. The particle size is mainly concentrated around 120nm. Experiments show that the polylactic acid-glycolic acid calcium carbonate particles of the present invention have a good effect of enhancing tumor immunotherapy, and can be used as an adjuvant for tumor immunotherapy.
附图说明Description of drawings
为了更清楚地说明本发明实施例或现有技术中的技术方案，下面将对实 施例或现有技术描述中所需要使用的附图作简单地介绍。In order to illustrate the embodiments of the present invention or the technical solutions in the prior art more clearly, the following briefly introduces the accompanying drawings that are required to be used in the description of the embodiments or the prior art.
图1示实施例2聚乳酸-羟基乙酸碳酸钙制剂的透射电镜图；Fig. 1 shows the transmission electron microscope picture of embodiment 2 polylactic acid-glycolic acid calcium carbonate preparation;
图2示实施例2聚乳酸-羟基乙酸碳酸钙制剂在水中的粒径分布；Fig. 2 shows the particle size distribution of the polylactic acid-glycolic acid calcium carbonate preparation of Example 2 in water;
图3示实施例3不同分组的小鼠肿瘤在免疫治疗后肿瘤的生长曲线及存 活曲线；其中包括对照组(仅注生理盐水)，注射aPD-1免疫治疗组；注射聚 乳酸-羟基乙酸碳酸钙以及aPD-1免疫治疗组。Figure 3 shows the tumor growth curve and survival curve of the mice in different groups of Example 3 after immunotherapy; including the control group (only normal saline), the aPD-1 immunotherapy group; the polylactic acid-glycolic acid carbonate injection Calcium and aPD-1 immunotherapy groups.
具体实施方式Detailed ways
本发明提供了一种纳米碳酸钙微粒及其制备与应用，本领域技术人员可 以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的 替换和改动对本领域技术人员来说是显而易见的，它们都属于本发明保护的 范围。本发明的方法及应用已经通过较佳实施例进行了描述，相关人员明显 能在不脱离本发明内容、精神和范围内对本文的方法和应用进行改动或适当 变更与组合，来实现和应用本发明技术。The present invention provides a kind of nanometer calcium carbonate particle and its preparation and application, those skilled in the art can refer to the content of this paper for reference, and appropriately improve process parameters to realize. It should be particularly pointed out that all similar replacements and modifications are obvious to those skilled in the art, and they all belong to the protection scope of the present invention. The method and application of the present invention have been described through the preferred embodiments, and it is obvious that relevant persons can make changes or appropriate changes and combinations of the methods and applications herein without departing from the content, spirit and scope of the present invention, so as to realize and apply the present invention. Invention technology.
本发明提供了一种纳米碳酸钙微粒，以聚乳酸-羟基乙酸(PLGA)和聚 乳酸-羟基乙酸-聚乙二醇(PLGA-PEG)为壳层，以碳酸钙为核层。The present invention provides a kind of nanometer calcium carbonate particle, which uses polylactic acid-glycolic acid (PLGA) and polylactic acid-glycolic acid-polyethylene glycol (PLGA-PEG) as shell layers and calcium carbonate as core layer.
本发明提供的纳米碳酸钙微粒以聚乳酸-羟基乙酸(PLGA)和聚乳酸-羟 基乙酸-聚乙二醇(PLGA-PEG)为壳层。The nanometer calcium carbonate particles provided by the present invention use polylactic acid-glycolic acid (PLGA) and polylactic acid-glycolic acid-polyethylene glycol (PLGA-PEG) as shell layers.
在本发明的壳层中，为PLGA-PLGA-PEG，其中，PEG亲水基团在最外 层，PLGA-PLGA疏水基团在内层。In the shell layer of the present invention, it is PLGA-PLGA-PEG, wherein the PEG hydrophilic group is in the outermost layer, and the PLGA-PLGA hydrophobic group is in the inner layer.
本发明提供的纳米碳酸钙微粒以碳酸钙为核层。The nano calcium carbonate particles provided by the present invention use calcium carbonate as the core layer.
本发明所述纳米碳酸钙微粒的粒径优选为100～120nm；更优选为105～120 nm。The particle size of the nano calcium carbonate particles of the present invention is preferably 100-120 nm; more preferably 105-120 nm.
本发明提供了一种纳米碳酸钙微粒的制备方法，包括：The invention provides a preparation method of nano calcium carbonate particles, comprising:
A)将聚乳酸-羟基乙酸、聚乳酸-羟基乙酸-聚乙二醇在溶剂中混合，得到 PLGA和PLGA-PEG混合溶液；A) mixing polylactic acid-glycolic acid and polylactic acid-glycolic acid-polyethylene glycol in solvent to obtain PLGA and PLGA-PEG mixed solution;
B)将PLGA和PLGA-PEG混合溶液与NaHCO3溶液混合，乳化，得到 第一乳液；B) mix PLGA and PLGA - PEG mixed solution with NaHCO solution, emulsify, obtain the first emulsion;
将PLGA和PLGA-PEG混合溶液与CaCl2水溶液混合，乳化，得到第 二乳液；Mix the PLGA and PLGA-PEG mixed solution with the CaCl 2 aqueous solution, and emulsify to obtain the second emulsion;
C)将第一乳液和第二乳液混合，乳化，得到第三乳液；C) mix the first emulsion and the second emulsion, and emulsify to obtain the third emulsion;
D)将第三乳液分散于聚乙烯醇水溶液中，搅拌、洗涤得到 CaCO3@PLGA-PEG。D) Disperse the third emulsion in an aqueous solution of polyvinyl alcohol, stir and wash to obtain CaCO 3 @PLGA-PEG.
本发明提供的纳米碳酸钙微粒的制备方法首先将聚乳酸-羟基乙酸、聚乳 酸-羟基乙酸-聚乙二醇在溶剂中混合，得到PLGA和PLGA-PEG混合溶液。The preparation method of the nanometer calcium carbonate particles provided by the invention firstly mixes polylactic acid-glycolic acid and polylactic acid-glycolic acid-polyethylene glycol in a solvent to obtain PLGA and PLGA-PEG mixed solution.
所述溶剂优选为二氯甲烷。即为：以二氯甲烷为溶剂，配置PLGA与 PLGA-PEG的混合溶液。The solvent is preferably dichloromethane. That is: using dichloromethane as a solvent, configure a mixed solution of PLGA and PLGA-PEG.
按照本发明，所述PLGA与PLGA-PEG的质量比优选为1～2:1～2；更优 选为1:1。According to the present invention, the mass ratio of PLGA to PLGA-PEG is preferably 1-2:1-2; more preferably 1:1.
所述PLGA与PLGA-PEG的混合溶液的浓度优选为25～35mg/mL；更优 选为27～32mg/mL；最优选为30mg/mL。The concentration of the mixed solution of PLGA and PLGA-PEG is preferably 25-35 mg/mL; more preferably 27-32 mg/mL; most preferably 30 mg/mL.
此时溶液由于以二氯甲烷为溶剂，为油相溶液。At this time, the solution was an oil-phase solution because dichloromethane was used as the solvent.
而后以水为溶剂，分别配制NaHCO3与CaCl2溶液。本发明所述NaHCO3浓度优选为0.6～0.7M，更优选为0.62～0.68M，最优选为0.625M。Then use water as solvent to prepare NaHCO 3 and CaCl 2 solutions respectively. The concentration of NaHCO 3 in the present invention is preferably 0.6-0.7M, more preferably 0.62-0.68M, and most preferably 0.625M.
将PLGA和PLGA-PEG混合溶液与NaHCO3溶液混合，乳化，得到第一 乳液；优选具体为：将NaHCO3水溶液与PLGA和PLGA-PEG的二氯甲烷混 合溶液混合，用超声细胞破碎仪超声乳化，得到第一乳液。 NaHCO3@PLGA-PEG)。Mix the PLGA and PLGA - PEG mixed solution with NaHCO solution, and emulsify to obtain the first emulsion; preferably specifically: mixing the NaHCO aqueous solution with the dichloromethane mixed solution of PLGA and PLGA-PEG, and phacoemulsification with an ultrasonic cell disruptor , to obtain the first emulsion. NaHCO 3 @PLGA-PEG).
本发明所述第一乳液为油包水乳液，即为PLGA和PLGA-PEG在外，为 油相，NaHCO3为水相。The first emulsion described in the present invention is a water-in-oil emulsion, that is, PLGA and PLGA-PEG are outside, which is an oil phase, and NaHCO 3 is an aqueous phase.
按照本发明，所述PLGA和PLGA-PEG混合溶液与NaHCO3溶液的体积 比优选为3～4:1；更优选为3:1。According to the present invention, the volume ratio of the PLGA and PLGA-PEG mixed solution to the NaHCO 3 solution is preferably 3-4:1; more preferably 3:1.
所述乳化优选为超声乳化，所述超声功率优选为80～120W；更优选为 90～110W；最优选为100W；所述超声时间优选为250～350s；更优选为 260～330s；最优选为280～310s；特别优选为297～300s。The emulsification is preferably phacoemulsification, and the ultrasonic power is preferably 80-120W; more preferably 90-110W; most preferably 100W; the ultrasonic time is preferably 250-350s; more preferably 260-330s; most preferably 280 to 310s; particularly preferably 297 to 300s.
将PLGA和PLGA-PEG混合溶液与CaCl2水溶液混合，乳化，得到第二 乳液。优选具体为：将CaCl2水溶液与PLGA和PLGA-PEG的二氯甲烷混合 溶液混合，用超声细胞破碎仪超声乳化，得到第二乳液。CaCl2@PLGA-PEG。The mixed solution of PLGA and PLGA-PEG was mixed with the aqueous solution of CaCl 2 and emulsified to obtain the second emulsion. Preferably, the solution is as follows: the aqueous solution of CaCl 2 is mixed with the mixed solution of PLGA and PLGA-PEG in dichloromethane, and the second emulsion is obtained by ultrasonic emulsification with an ultrasonic cell disruptor. CaCl 2 @PLGA-PEG.
按照本发明，所述PLGA和PLGA-PEG混合溶液与CaCl2水溶液的体积 比为3～4:1；更优选为3:1。According to the present invention, the volume ratio of the mixed solution of PLGA and PLGA-PEG to the aqueous solution of CaCl 2 is 3-4:1; more preferably, it is 3:1.
本发明所述CaCl2溶液浓度优选为1～1.5M；更优选为1.1～1.4M；最优选 为1.25～1.35M。The concentration of the CaCl 2 solution in the present invention is preferably 1-1.5M; more preferably 1.1-1.4M; most preferably 1.25-1.35M.
所述乳化优选为超声乳化，所述超声功率优选为80～120W；更优选为 90～110W；最优选为100W；所述超声时间优选为250～350s；更优选为 260～330s；最优选为280～310s；特别优选为297～300s。The emulsification is preferably phacoemulsification, and the ultrasonic power is preferably 80-120W; more preferably 90-110W; most preferably 100W; the ultrasonic time is preferably 250-350s; more preferably 260-330s; most preferably 280 to 310s; particularly preferably 297 to 300s.
本发明所述第二乳液为油包水乳液，即为PLGA和PLGA-PEG在外，为 油相CaCl2为水相。The second emulsion of the present invention is a water-in-oil emulsion, that is, PLGA and PLGA-PEG are outside, and the oil phase is CaCl 2 and the water phase is.
将第一乳液和第二乳液混合，乳化，得到第三乳液；The first emulsion and the second emulsion are mixed and emulsified to obtain the third emulsion;
本发明对于所述混合方式不进行限定，本领域技术人员熟知的即可。混 合后，NaHCO3和CaCl2反应，即为得到CaCO3@PLGA--PEG。得到碳酸钙为 水相，内层，核层。The present invention does not limit the mixing manner, as long as those skilled in the art are well-known. After mixing, NaHCO 3 and CaCl 2 react to obtain CaCO 3 @PLGA--PEG. Calcium carbonate is obtained as water phase, inner layer and core layer.
所述乳化优选为超声乳化，所述超声功率优选为80～120W；更优选为 90～110W；最优选为100W；所述超声时间优选为250～350s；更优选为 260～330s；最优选为280～310s；特别优选为297～300s。The emulsification is preferably phacoemulsification, and the ultrasonic power is preferably 80-120W; more preferably 90-110W; most preferably 100W; the ultrasonic time is preferably 250-350s; more preferably 260-330s; most preferably 280 to 310s; particularly preferably 297 to 300s.
将第三乳液分散于聚乙烯醇水溶液中，搅拌、洗涤得到CaCO3@PLGA-PEG。The third emulsion was dispersed in the polyvinyl alcohol aqueous solution, stirred and washed to obtain CaCO 3 @PLGA-PEG.
将第三乳液分散于聚乙烯醇水溶液中，连续搅拌去除二氯甲烷，洗涤， 得到产物CaCO3@PLGA-PEG。The third emulsion was dispersed in the polyvinyl alcohol aqueous solution, the dichloromethane was removed by continuous stirring, and washed to obtain the product CaCO 3 @PLGA-PEG.
按照本发明，所述聚乙烯醇水溶液的质量分数优选为1％～2％；更优选为 1％；所述搅拌的时间优选为10～14h；更优选为11～13h；最优选为12h。According to the present invention, the mass fraction of the polyvinyl alcohol aqueous solution is preferably 1%-2%; more preferably 1%; the stirring time is preferably 10-14h; more preferably 11-13h; most preferably 12h.
本发明所述洗涤优选为14000～15000rpm的条件下离心20～30min，用超 纯水洗涤2～3次；更优选为14200～14800rpm的条件下离心20～28min，用超 纯水洗涤2～3次；最优选为14500～14800rpm的条件下离心20～25min，用超 纯水洗涤3次。The washing in the present invention is preferably centrifuged at 14000-15000rpm for 20-30min, washed with ultrapure water for 2-3 times; more preferably centrifuged at 14200-14800rpm for 20-28min, washed with ultrapure water for 2-3 times times; most preferably, centrifuge at 14500-14800 rpm for 20-25 min, and wash with ultrapure water 3 times.
本发明提供了上述技术方案任意一项所述的纳米碳酸钙微粒或上述技术 方案任意一项所述的制备方法制备得到的纳米碳酸钙微粒在制备肿瘤免疫治 疗的佐剂中的应用。The present invention provides the application of the nano-calcium carbonate particles according to any one of the above technical solutions or the nano-calcium carbonate particles prepared by the preparation method according to any one of the above technical solutions in the preparation of adjuvants for tumor immunotherapy.
本发明提供了一种肿瘤免疫治疗佐剂，包括上述技术方案任意一项所述 的纳米碳酸钙微粒或上述技术方案任意一项所述的制备方法制备得到的纳米 碳酸钙微粒。The present invention provides a tumor immunotherapy adjuvant, comprising the nano-calcium carbonate particles according to any one of the above technical solutions or the nano-calcium carbonate particles prepared by the preparation method according to any one of the above technical solutions.
本发明提供了一种纳米碳酸钙微粒，以聚乳酸-羟基乙酸(PLGA)和聚 乳酸-羟基乙酸-聚乙二醇(PLGA-PEG)为壳层，以碳酸钙为核层。本发明提 供的纳米碳酸钙微粒(聚乳酸-羟基乙酸碳酸钙微粒)由聚乳酸-羟基乙酸、聚 乳酸-羟基乙酸-聚乙二醇和碳酸钙组成，粒径均一，在水中分散良好，在水中 粒径主要集中在120nm左右。实验表明本发明所述聚乳酸-羟基乙酸碳酸钙制 剂有良好的增强肿瘤免疫治疗的效果，能够作为肿瘤免疫治疗的佐剂。The present invention provides a kind of nanometer calcium carbonate particle, which uses polylactic acid-glycolic acid (PLGA) and polylactic acid-glycolic acid-polyethylene glycol (PLGA-PEG) as shell layers and calcium carbonate as core layer. The nano calcium carbonate particles (polylactic acid-glycolic acid calcium carbonate particles) provided by the present invention are composed of polylactic acid-glycolic acid, polylactic acid-glycolic acid-polyethylene glycol and calcium carbonate, have uniform particle size, and are well dispersed in water. The particle size is mainly concentrated around 120nm. Experiments show that the polylactic acid-glycolic acid calcium carbonate preparation of the present invention has a good effect of enhancing tumor immunotherapy, and can be used as an adjuvant for tumor immunotherapy.
为了进一步说明本发明，以下结合实施例对本发明提供的一种纳米碳酸 钙微粒及其制备与应用及其制备与应用进行详细描述。In order to further illustrate the present invention, a kind of nanometer calcium carbonate particle provided by the present invention and its preparation and application and its preparation and application are described in detail below in conjunction with embodiment.
实施例1、聚乳酸-羟基乙酸碳酸钙微粒的制备
将PLGA与PLGA-PEG按照质量比1:1的比例称取后，溶于二氯甲烷中， 配成30mg/ml的PLGA和PLGA-PEG混合溶液。称取NaHCO3与CaCl2分别 溶于水中制备0.625M NaHCO3水溶液与1.25M CaCl2水溶液。将制备的 NaHCO3水溶液与CaCl2水溶液分别与PLGA和PLGA-PEG二氯甲烷混合溶 液按照体积比1:3的比例混合，在超声功率为100W的条件下用超声细胞破碎仪超声乳化297s，得到乳液A(NaHCO3@PLGA-PEG)和乳液B (CaCl2@PLGA-PEG)。将乳液A与乳液B混合，在超声功率为100W的条件 下用超声细胞破碎仪超声乳化297s，得到乳液C(CaCO3@PLGA--PEG)。将得 到的乳液C分散在1％PVA水溶液中，连续搅拌12h除去二氯甲烷。在 14800rpm的条件下离心20min，用超纯水洗三次，得到产品聚乳酸-羟基乙酸 纳米碳酸钙制剂。After weighing PLGA and PLGA-PEG according to a mass ratio of 1:1, they were dissolved in dichloromethane to prepare a 30 mg/ml mixed solution of PLGA and PLGA-PEG. Weigh NaHCO 3 and CaCl 2 and dissolve them in water to prepare 0.625M NaHCO 3 aqueous solution and 1.25M CaCl 2 aqueous solution, respectively. The prepared NaHCO 3 aqueous solution and CaCl 2 aqueous solution were mixed with PLGA and PLGA-PEG dichloromethane mixed solution in a volume ratio of 1:3, respectively, and sonicated for 297 s with an ultrasonic cell disruptor under the condition of ultrasonic power of 100 W to obtain Emulsion A (NaHCO 3 @PLGA-PEG) and Emulsion B (CaCl 2 @PLGA-PEG). Emulsion A and emulsion B were mixed, and sonicated for 297 s with an ultrasonic cell disruptor under the condition of ultrasonic power of 100 W to obtain emulsion C (CaCO 3 @PLGA--PEG). The obtained emulsion C was dispersed in a 1% PVA aqueous solution, and the dichloromethane was removed by continuous stirring for 12 h. Centrifuge at 14800 rpm for 20 min, and wash with ultrapure water three times to obtain the product polylactic acid-glycolic acid nano-calcium carbonate preparation.
实施例2、聚乳酸-羟基乙酸碳酸钙微粒的性质检测Embodiment 2. Property detection of polylactic acid-glycolic acid calcium carbonate particles
对实施例1制得的聚乳酸-羟基乙酸碳酸钙微粒进行定性检测，分别进行 透射电镜检测、动态光散射。The polylactic acid-glycolic acid calcium carbonate particles prepared in Example 1 were qualitatively detected, and were respectively detected by transmission electron microscopy and dynamic light scattering.
其中，透射电镜检测的结果如图1所示，结果显示，实施例1制得的聚 乳酸-羟基乙酸碳酸钙微粒在水中呈单分散状态分布，表明本发明制得的聚乳 酸-羟基乙酸碳酸钙微粒的粒径均一，在水中分散良好。Among them, the results of transmission electron microscopy are shown in Figure 1. The results show that the polylactic acid-glycolic acid calcium carbonate particles prepared in Example 1 are distributed in a monodispersed state in water, indicating that the polylactic acid-glycolic acid carbonic acid prepared by the present invention The calcium particles are uniform in particle size and disperse well in water.
动态光散射检测的结果如图2所示，结果显示，实施例1制得的聚乳酸- 羟基乙酸碳酸钙微粒在水中粒径主要集中在120nm左右。The results of dynamic light scattering detection are shown in Figure 2. The results show that the particle size of the polylactic acid-glycolic acid calcium carbonate particles prepared in Example 1 in water is mainly concentrated around 120 nm.
实施例3、肿瘤的免疫治疗Example 3. Immunotherapy of tumors
将带有结肠癌皮下肿瘤模型的小鼠分为三组，其中包括：第一组，对照 组(仅注射生理盐水)；第二组，注射aPD-1免疫治疗组；第三组，注射聚乳 酸-羟基乙酸碳酸钙和aPD-1免疫治疗组。对小鼠进行相应的治疗后，测量其 肿瘤的生长，结果见于图3。结果表明，相比较对照组，第二组肿瘤生长仅得 到了部分抑制，而第三组的肿瘤生长则得到了有效的抑制。表明聚乳酸-羟基 乙酸碳酸钙制剂能够实现对肿瘤的增强的免疫治疗。The mice with colon cancer subcutaneous tumor models were divided into three groups, including: the first group, the control group (injected with normal saline only); the second group, the aPD-1 immunotherapy group was injected; the third group, the poly Lactate-glycolic acid calcium carbonate and aPD-1 immunotherapy group. After the mice were treated accordingly, tumor growth was measured and the results are shown in Figure 3. The results showed that compared with the control group, the tumor growth of the second group was only partially inhibited, while the tumor growth of the third group was effectively inhibited. It is shown that the polylactic-glycolic acid calcium carbonate preparation can achieve enhanced immunotherapy for tumors.
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。The above are only the preferred embodiments of the present invention. It should be pointed out that for those skilled in the art, without departing from the principles of the present invention, several improvements and modifications can be made. It should be regarded as the protection scope of the present invention.
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| CN202010967945.6A CN111888337B (en) | 2019-12-27 | 2020-09-15 | Calcium carbonate-based composite particles and their preparation and application |
| PCT/CN2020/121606 WO2022056986A1 (en) | 2019-12-27 | 2020-10-16 | Calcium carbonate-based compound micro particles, and preparation and application thereof |
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| WO2022056985A1 (en) * | 2019-12-27 | 2022-03-24 | 苏州大学 | Calcium carbonate poly(lactic acid-glycolic acid) composite microparticle, and preparation therefor and use thereof |
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| WO2022056986A1 (en) * | 2019-12-27 | 2022-03-24 | 苏州大学 | Calcium carbonate-based compound micro particles, and preparation and application thereof |
| WO2022056984A1 (en) * | 2019-12-27 | 2022-03-24 | 苏州大学 | Polylactic acid-glycolic acid calcium carbonate microparticle, preparation method therefor and use thereof |
| WO2022056985A1 (en) * | 2019-12-27 | 2022-03-24 | 苏州大学 | Calcium carbonate poly(lactic acid-glycolic acid) composite microparticle, and preparation therefor and use thereof |
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