CN117357464A - 一种温度敏感的双药共载水凝胶、制备方法及其应用 - Google Patents
一种温度敏感的双药共载水凝胶、制备方法及其应用 Download PDFInfo
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Abstract
本发明公开了一种温度敏感的双药共载水凝胶、制备方法及其应用,涉及抗肿瘤药物技术领域。双药共载水凝胶包括:聚乙二醇与藤黄酸的酯化反应合成物、IDO抑制剂和温敏型凝胶,以温敏型凝胶包载藤黄酸和IDO抑制剂制得。将IDO抑制剂与化疗药物藤黄酸共同递送,协同抑制了肿瘤生长,其疗效大于单一药物的治疗效果。室温下温度敏感的双药共载水凝胶呈现溶液状态,体温下呈凝胶状态,可以满足注射的需求。
Description
技术领域
本发明涉及抗肿瘤药物技术领域,具体而言,涉及一种温度敏感的双药共载水凝胶、制备方法及其应用。
背景技术
乳腺癌是女性中发病率最高的恶性肿瘤,严重威胁女性健康。2020年乳腺癌发病率已超过肺癌,新增病例230万人(11.7%)。目前乳腺癌的治疗仍以手术切除、放疗、化疗等传统治疗手段为主,特别是三阴性乳腺癌,疗效尚不如人意,且不良反应众多。因此迫切需要探索新的乳腺癌治疗策略以提高治疗效果。
随着细胞生物学和肿瘤免疫学的发展,对肿瘤免疫治疗的研究已实现临床转化,免疫治疗在某些癌症的临床实践中显示出良好的抗肿瘤效果,但获益群体仍然非常有限(~20%)。乳腺癌作为一个“冷”肿瘤(非T细胞浸润),其免疫抑制微环境限制了免疫治疗的应用。化疗-免疫联合疗法为提高治疗效力提供了一种新的方法,但仍病灶处药物含量低、毒副作用大等问题。利用先进的药剂学技术,开发定向输送到病灶处、高效低毒的创新药物,是解决现有临床治疗局限的有效策略。
近年来,药理研究发现从天然产物中提取的活性单体藤黄酸(Gambogic acid,GA)在白血病、肝癌、黑素瘤、乳腺癌、胃癌、胰腺癌、前列腺癌、肺癌等多种肿瘤中均表现出较强的抗肿瘤活性。其作用机制主要包括诱导肿瘤细胞凋亡、抑制肿瘤细胞增殖等方面。最近的研究发现GA不仅可以直接杀伤肿瘤细胞,还能够诱导免疫原性的细胞死亡(Immunogeniccell death,ICD)。ICD的发生包括肿瘤细胞分泌三磷酸腺苷(Adenosine triphosphate,ATP),作为“find me”信号,招募抗原递呈细胞(APCs)到肿瘤免疫微环环境(TME)中;钙网蛋白(Calreticulin,CRT)从内质网外翻至细胞膜表面,作为一种“eat me”信号,促进树突状细胞(Dendritic cells,DCs)吞噬死亡的肿瘤细胞;从肿瘤细胞中释放出的高迁移率族蛋白1(High-mobility group box1,HMGB1)和DCs表面的TLR-4受体结合,促进抗原呈递到T细胞,从而激活抗肿瘤免疫反应;进一步促进细胞毒性T淋巴细胞(Cytotoxic TLymphocytes,CTLs)浸润TME,分泌干扰素-γ(Interferon-γ,IFN-γ)。然而,ICD发生后,TME中上调的IFN-γ会诱导一种抑制性免疫检查点——吲哚胺2,3-双加氧酶(IDO)的合成。IDO在多种肿瘤细胞(如乳腺癌、宫颈癌、膀胱癌和肺癌等)中高度表达,并催化必需氨基酸色氨酸(Tryptophan,Trp)转化为犬尿氨酸(Kynurenine,Kyn)。一方面,Trp是T细胞活化和增殖分解代谢的基础氨基酸,在IDO的参与下Trp降解,从而通过上调一般性调控阻遏蛋白激酶2(General control nonderepressible 2,GCN2)和下调哺乳动物雷帕霉素靶蛋白复合1(Mammalian target of rapamycin complex 1,mTORC1)介导T细胞免疫抑制;另一方面,IDO在肿瘤组织中的过表达和Kyn的积累可以通过与芳基烃受体(Aryl hydrocarbonreceptor,AHR)结合激活调节性T(Regulatory T cells,Tregs)细胞,激活下游基因表达和骨髓源性抑制细胞(Myeloid-derived suppressor cells,MDSCs),从而抑制效应T细胞和自然杀伤细胞的功能,促进实体瘤血管新生。近年来研究人员开发了各种IDO抑制剂(如Incyte公司的Epacadostat、Newlink公司的Indoximod以及BMS公司的BMS-986205等),均可通过与IDO的特异性结合,使该酶失活,从而恢复T细胞增殖。尽管IDO抑制剂的使用可以激活人体免疫系统,但是肿瘤组织也会通过其他的方式进行免疫逃逸,IDO抑制剂单独使用的治疗效果有限。
鉴于此,特提出本发明。
发明内容
本发明的目的在于提供一种温度敏感的双药共载水凝胶、制备方法及其应用以解决上述技术问题。
本发明是这样实现的:
第一方面,本发明提供了一种温度敏感的双药共载水凝胶,其包括:聚乙二醇与藤黄酸的酯化反应合成物、IDO抑制剂和温敏型凝胶,以温敏型凝胶包载藤黄酸和IDO抑制剂制得;温敏型凝胶中含0.006-0.01M藤黄酸和0.01-0.02M IDO抑制剂;IDO抑制剂为1-甲基-D-色氨酸(1-methyl-D-tryptophan,1MT)、帕卡司他(epacadostat,INCB24360)、纳考莫德(navoximod,GDC-0919,NLG919)、Linrodostat(BMS-986205)、DO-IN-2、PF-06840003、INCB024360、Exiguamine A或苯并咪唑。
发明人将IDO抑制剂与化疗药物藤黄酸共同递送,基于IDO抑制剂具有解除肿瘤组织中IDO引起的效应T细胞和自然杀伤细胞的免疫抑制活性,从而使得制得的双药共载水凝胶既具有逆转肿瘤免疫抑制微环境的功能,又具有藤黄酸的抗肿瘤的活性。发明人研究表明:IDO抑制剂与化疗药物藤黄酸协同抑制了肿瘤生长,其疗效大于单一药物的治疗效果,且优于阳性对照药物紫杉醇白蛋白。
此外,室温下温度敏感的双药共载水凝胶呈现溶液状态,体温下呈凝胶状态,满足注射的需求。且温度敏感的双药共载水凝胶具有良好的生物安全性。在体内体外可使药物长时间驻留在肿瘤部位,起到储库效应。
因此,本发明提供的温度敏感的双药共载水凝胶具有良好的抗肿瘤药物应用前景。
在藤黄酸上连接聚乙二醇有助于提升藤黄酸的水分散性,提高藤黄酸的利用率,延长药物的半衰期,更便于制备温度敏感的双药共载水凝胶。
在本发明应用较佳的实施方式中,温敏型凝胶是以天然阳离子聚合物和交联剂形成的具有三维网状结构的水凝胶。
在一种可选的实施方式中,天然阳离子聚合物选自半乳甘露聚糖或壳聚糖;交联剂选自β-甘油磷酸钠。
壳聚糖(Chitosan,CS)是一种天然阳离子聚合物,具有抗菌活性、良好的生物相容性和生物降解性等优点。其分子结构上含有大量的氨基和羟基,可以与交联剂β-甘油磷酸钠(β-Glycerol phosphate disodium salt pentahydrate,β-GP)形成共价键交联的可注射的具有三维网状结构的水凝胶。
在本发明应用较佳的实施方式中,温敏型凝胶中壳聚糖与β-甘油磷酸钠混合体积比为10:1-1:1。发明人发现,温敏型凝胶中壳聚糖与β-甘油磷酸钠混合体积比对于成胶时间以及水凝胶的稳定性尤为关键。
在一种可选的实施方式中,温敏型凝胶中壳聚糖与β-甘油磷酸钠混合体积比为3:1。当壳聚糖与β-甘油磷酸钠混合体积比为3:1时,成胶时间为1-2min,且稳定性更好。在4℃条件下能够长期保持澄清透明的溶液状态。
在本发明应用较佳的实施方式中,酯化反应合成物中的聚乙二醇的相对分子质量为1000-4000Da。
在一种可选的实施方式中,温度敏感的双药共载水凝胶在0℃-10℃条件下呈溶液状态,在36℃以上条件下呈凝胶状态。这样有助于原位注射。
第二方面,本发明还提供了一种温度敏感的双药共载水凝胶的制备方法,其包括如下步骤:
将包括聚乙二醇与藤黄酸的酯化反应合成物和IDO抑制剂的混合溶液与用于制备温敏型凝胶的原料的溶液混合,制得温度敏感的双药共载水凝胶。
上述制备方法简单易行,温度敏感的双药共载水凝胶稳定性好,可以长期保存,易于推广应用。
在本发明应用较佳的实施方式中,上述制备方法包括:将酯化反应合成物和IDO抑制剂的混合溶液与由天然阳离子聚合物和交联剂组成的未载药水凝胶溶液共混制得温度敏感的双药共载水凝胶。
在本发明应用较佳的实施方式中,上述制备方法包括:先将酯化反应合成物和IDO抑制剂的混合溶液与天然阳离子聚合物溶液混合制得载药水凝胶前体,然后将载药水凝胶前体与交联剂溶液混合制得温度敏感的双药共载水凝胶。
在本发明应用较佳的实施方式中,上述天然阳离子聚合物的质量体积浓度为2-3%(100mL中含2-3g),交联剂溶液的质量体积浓度为40%-60%;
温敏型凝胶中壳聚糖与β-甘油磷酸钠混合体积比为10:1-1:1。
第三方面,本发明还提供了一种组合物,其包括:温度敏感的双药共载水凝胶或由上述温度敏感的双药共载水凝胶的制备方法制得的温度敏感的双药共载水凝胶。
组合物还包括药学上可接受的辅料。
在其他实施方式中,上述药物组合物还包括药学上可行的辅料包括但不限于填充剂、润滑剂、崩解剂、粘合剂、助流剂等。
本发明的优选技术方案中,药学上可接受的辅料,包括但不限于聚乙烯吡咯烷酮及其衍生物、聚乙烯醇及其衍生物、甲基纤维素及其衍生物、乙基纤维素及其衍生物、羟丙基纤维素及其衍生物、淀粉及其衍生物、聚乙二醇及其衍生物、乳糖、蔗糖、甘露醇、海藻糖、山梨糖醇、糊精、微晶纤维素、丙烯酸树脂、磷酸氢钙、硬脂酸钙、硬脂酰富马酸钠、二氧化硅、二氧化钛、滑石粉、色靛中的一种或其组合。
本发明的优选技术方案中,组合物为注射剂。
第四方面,本发明还提供了温度敏感的双药共载水凝胶或由上述温度敏感的双药共载水凝胶的制备方法制得的温度敏感的双药共载水凝胶在制备抗肿瘤药物或试剂中的用途,肿瘤选自口腔癌、肺癌、肝癌、结肠癌、乳腺癌、骨肉瘤、脑瘤、黑素瘤、胃癌、胰腺癌和前列腺癌中的任意一种;
在一种可选的实施方式中,抗肿瘤药物或试剂具有如下至少一种的用途:
(1)诱导肿瘤发生ICD;
(2)促进树突状细胞(Dendritic cells,DCs)成熟;
(3)增加肿瘤微环境中的T细胞浸润;
(4)抑制色氨酸的降解;
(5)下调Tregs细胞比例;
(6)上调细胞毒性T淋巴细胞比例;
(7)逆转肿瘤免疫抑制微环境;
(8)提升肿瘤细胞中的如下至少一种细胞因子的水平:TNF-α、IFN-γ和IL-6。
本发明具有以下有益效果:
(1)发明人将IDO抑制剂与化疗药物藤黄酸共同递送,基于IDO抑制剂具有解除肿瘤组织中IDO引起的效应T细胞和自然杀伤细胞的免疫抑制活性,从而使得制得的双药共载水凝胶既具有逆转肿瘤免疫抑制微环境的功能,又具有藤黄酸的抗肿瘤的活性。发明人研究表明:IDO抑制剂与化疗药物藤黄酸协同抑制了肿瘤生长的效果,其疗效大于单一药物的治疗效果,且优于阳性对照药物紫杉醇白蛋白。
(2)室温下温度敏感的双药共载水凝胶呈现溶液状态,体温下呈凝胶状态,可以满足注射的需求。且温度敏感的双药共载水凝胶具有良好的生物安全性。在体内体外可使药物长时间驻留在肿瘤部位,起到储库效应。
(3)温度敏感的双药共载水凝胶的制备方法简单易行,双药共载水凝胶稳定性好,可以长期保存,易于推广应用。
附图说明
为了更清楚地说明本发明实施例的技术方案,下面将对实施例中所需要使用的附图作简单地介绍,应当理解,以下附图仅示出了本发明的某些实施例,因此不应被看作是对范围的限定,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据这些附图获得其他相关的附图。
图1为本发明实施例1制得的空白水凝胶(gel)和温度敏感的双药共载水凝胶的在不同温度下的两种状态图;
图2为扫描电镜考察空载水凝胶gel(a)和双药共载水凝胶GM-1MT@gel(b)的微观形貌图;
图3为水凝胶流变学分析结果图;
图4为小鼠体内残余水凝胶的体积分布和重量分析图;
图5为药物在小鼠体内的组织分布图;
图6为藤黄酸GA和聚乙二醇与藤黄酸的酯化反应合成物GM的肿瘤细胞凋亡诱导率
图7为小鼠乳腺癌模型在不同处理条件下0-18天的肿瘤体积统计图;
图8为不同给药组小鼠的肿瘤质量统计图;
图9为肿瘤微环境中的T淋巴细胞(CD3+CD8+)的流式细胞图;
图10为图9的柱状统计分析图;
图11为肿瘤微环境中的Tregs的流式细胞图;
图12为图11的柱状统计分析图;
图13为小鼠肿瘤组织中的IFN-γ、TNF-α和IL-6水平的统计结果图。
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚,下面将对本发明实施例中的技术方案进行清楚、完整地描述。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市售购买获得的常规产品。
以下结合实施例对本发明的特征和性能作进一步的详细描述。
实施例1
温度敏感的双药共载水凝胶的制备方法如下:
称取一定量的CS(壳聚糖)和β-GP(β-甘油磷酸钠),将CS溶解在0.1mol/L的乙酸中,配成2.2%(W/V)的CS溶液。将β-GP溶解在水中,配成56%(W/V,g/100mL)的β-GP溶液,放置在4℃冰箱过夜。CS溶液和β-GP溶液以不同的比例混合,将β-GP溶液滴加至CS溶液中,搅拌15min,即得空白水凝胶(gel)。
本实施例在制备温度敏感的双药共载水凝胶时,采用分步混合的方法,在其他实施方式中,也可以直接将共价连接有聚乙二醇的藤黄酸(GM)与1MT(1-甲基-D-色氨酸)的混合溶液直接与上述的空白水凝胶共混制得。
具体地,先将藤黄酸和IDO抑制剂溶解于2.2%的CS溶液中,将β-GP溶液滴加至上述溶液中,搅拌15min,即得载药水凝胶(GM-1MT@gel)。
先将12mg GM和9mg 1MT溶解于3mL的2.2%(W/V)的CS溶液混合制得2.2%的含药CS溶液,再加入56%的β-GP溶液,使得总的混合液中2.2%的CS溶液和56%的β-GP溶液以3:1的比例混合,搅拌15min,即得载药水凝胶(GM-1MT@gel)。
参照图1所示,所制备的gel和GM-1MT@gel在室温下均为流动的液体,具有可注射性,加热至37℃后,形成稳定的凝胶,实现溶胶-凝胶转变。具有良好的温度敏感性。
分别对制备的gel和GM-1MT@gel进行扫描电镜观察,具体分别将两种水凝胶样品经冷冻固定、冷冻断裂并导电性喷涂后,置于冷冻扫描电镜中观察得到的表面形貌。参照图2所示,结果表明水凝胶内部呈相互贯通的三维网状结构,为负载多样化的药物提供了基础。水凝胶负载药物后(图2中的(b)),表面变粗糙,但其内部微观结构基本未改变,表明药物负载对水凝胶骨架的形成无明显影响。
实施例2
本实施例对实施例1中的GM-1MT@gel进行水凝胶流变学性质的考察:采用流变仪研究不同温度下(10-60℃)和37℃条件下水凝胶的流变学行为。
(1)检测中升温速率为1℃/min,温度范围为10-60℃,在恒定频率1.0Hz和应变幅度1%下采集数据,观测储能模量(G'),损耗模量(G")随着温度的变化。
(2)温度设置为37℃,在恒定频率1.0Hz和应变幅度1%下采集数据,观测储能模量(G'),损耗模量(G")随着时间的变化。
对水凝胶进行流变学分析,结果参照图3所示,当G″/G′值接近0表示凝胶状态类似于固体,接近1表示凝胶状态类似于液体。水凝胶表现出类固体行为,随着温度的升高,水凝胶的G'大于G";在37℃条件下,随着时间的增加,G'一直大于G",表明水凝胶可以在生理温度下快速凝胶化,并在37℃下可以形成稳定的凝胶体系。
实施例3
本实施例进行水凝胶的体内降解的研究。
为了研究水凝胶在体内降解性能,选择6-8周的Balb/c雌性小鼠,在小鼠右侧背部皮下注射100μL的水凝胶,分别在第0d、3d、7d、14d、21d定时处死3只小鼠,解剖注射水凝胶部位的皮肤,观察水凝胶的降解情况和周围皮肤组织的状态,拍照记录,并称量残余凝胶的重量。
结果参照图4所示,实验结果表明:随着时间的推移,水凝胶在小鼠体内的体积和重量均逐渐减小,21d后水凝胶(GM-1MT@gel)降解完全。此外,水凝胶注射部位周围的皮肤没有出现红肿、溃烂等病变。具有良好的生物相容性。
实施例4
GM-1MT@gel体内分布实验。
用荧光分子ICG代替药物,制备负载荧光染料的水凝胶ICG@gel。待肿瘤体积长至约200mm3后,随机分为两组。分别在肿瘤部位注射100μL游离ICG(用生理盐水稀释溶解)和ICG@gel,分别在给药后第4h,8h,12h,24h,48h,72h进行活体成像,检测小鼠肿瘤部位ICG的荧光强度。第72h的活体成像拍摄完成后,立即处死小鼠,把小鼠的心、肝、脾、肺、肾和肿瘤解剖出来,并用4%多聚甲醛中固定,进行离体成像,检测各组织中ICG的荧光强度。
实验结果参照图5所示,结果显示:随着时间的推移,ICG组中肿瘤部位的ICG荧光强度逐渐减弱并且下降速度较快,而ICG@gel组的ICG荧光强度下降速度相对缓慢。从24h起ICG@gel组的荧光强度开始与游离ICG组出现显著性差异(P<0.05)。在72h后解剖出小鼠的心、肝、脾、肺、肾和肿瘤进行离体成像,游离ICG组在肿瘤部位已不存在ICG荧光,而ICG@gel组的ICG荧光强度仍然很高。这些数据表明,药物可较长时间富集在肿瘤部位,并通过“储库效应”可以延长药物在体内的释放时间。
实施例5
藤黄酸GA和聚乙二醇与藤黄酸的酯化反应合成物GM诱导肿瘤细胞凋亡的情况,图6,GA和GM均能有效诱导肿瘤细胞凋亡,且二者之间无显著性差异,说明GM通过聚乙二醇共价连接GA后,不仅改善了GA的水分散性,并且不影响其杀伤肿瘤的效果,与现有专利202110671673X通过制备脂质体来提升水溶性的方法不同。
实施例6
GM-1MT@gel体内抗肿瘤实验。
乳腺癌模型构建:消化并收集处于对数生长期且生长状态良好的4T1细胞,用不含血清和双抗的1640培养基清洗1次,然后重悬在不含血清和双抗的1640培养基中,计数并调整细胞浓度为3×106个/mL。吸取100μL细胞悬液,依次注射在小鼠第二乳腺垫皮下,建立小鼠乳腺癌模型。
分组:待肿瘤体积长至约100mm3时,随机分为7组,每组5只小鼠(n=5)。分组如下:①生理盐水(Saline),②gel,③游离药物(GM+1MT),④GM@gel,⑤1MT@gel,⑥GM-1MT@gel,⑦阳性对照药紫杉醇白蛋白(PTX)。
治疗:采用瘤周注射方式给药,从第0d开始,每两天用游标卡尺测量小鼠肿瘤的长径(a)和短径(b),并计算小鼠的肿瘤体积。在第18d时结束治疗,并处死小鼠,收集各组小鼠的肿瘤,称量肿瘤重量并计算抑瘤率。
每两天测量一次小鼠肿瘤体积,各组小鼠肿瘤体积生长曲线参照图7所示,Saline组肿瘤生长最快,与Saline组相比,其余各组均显示出不同程度的抑制作用。gel、GM+1MT组和1MT@gel组表现出轻微的抑制肿瘤生长效果,GM@gel组和PTX组表现出中等程度的抑制肿瘤生长效果。阳性药PTX经尾静脉注射给药2次,对肿瘤生长的抑制较弱。双药联合给药GM-1MT@gel组的抑制肿瘤生长效果最强,平均肿瘤体积低至198mm3。表明本发明提供的GM-1MT@gel具有比阳性药物更优的体内抗肿瘤效果。
治疗结束后,采集各组小鼠肿瘤用于进一步分析,首先称量肿瘤重量并计算抑瘤率。参照图8所示,Saline组的肿瘤最重为1.73±0.08g,gel、GM+1MT和1MT@gel组的瘤重与Saline组均无显著性差异(p>0.05),表明单独的IDO抑制剂治疗肿瘤效果不佳,游离药物由于不能长时间蓄积在肿瘤部位,不能有效抑制肿瘤生长。
抑瘤率如下表1所示:
表1各治疗组的抑瘤率
表1可知,GM@gel和PTX均存在不同程度的抑瘤效果,抑瘤率分别为58.75和44.96%。尤其以GM-1MT@gel的抗肿瘤效果最强,肿瘤重量仅为0.07±0.03g,抑瘤率高达96.18%,与其余各组均存在显著性差异(p<0.05)。
实施例7
GM-1MT@gel调控肿瘤免疫微环境.
治疗结束后,收集小鼠的肿瘤,一部分用于提取肿瘤单细胞悬液,通过流式细胞术检测肿瘤微环境中的T淋巴细胞(CD3+CD4+/CD8+)和调节性T细胞(CD3+CD4+CD25+Foxp3+)。另一部分研磨为组织匀浆,采用细胞因子微球检测技术(Cytometric Bead Arry,CBA)测定肿瘤中细胞因子的含量。
(1)流式细胞术检测肿瘤微环境中的T淋巴细胞。
CTLs(CD3+CD8+)通过释放穿孔素和颗粒酶等膜溶物质直接杀伤肿瘤细胞。检测小鼠肿瘤微环境中的CD3+CD8+T淋巴细胞含量。如图9-图10所示,Saline组的CD3+CD8+T淋巴细胞比例较低,仅为5.69±1.77%;gel、GM+1MT和PTX组的CD3+CD8+T淋巴细胞比例与Saline组无显著性差异;而1MT@gel、GM@gel和GM-1MT@gel治疗后CD3+CD8+T淋巴细胞比例有均有不同程度增加。1MT通过解除IDO的免疫抑制作用,增加CTLs浸润,GM通过诱导肿瘤发生ICD,激活T细胞,从而增加CTLs浸润。GM-1MT@gel充分发挥1MT和GM的协同作用,进一步增加CTLs浸润,肿瘤中CD3+CD8+T淋巴细胞比例达到23.08±1.60%,是Saline组的4倍。且GM-1MT@gel与1MT@gel和GM@gel均存在显著性差异(p<0.01)。以上结果表明,GM-1MT@gel主要增加CD3+CD8+T淋巴细胞浸润TME,从而增强抗肿瘤免疫,促使CTLs杀伤肿瘤细胞。
(2)流式细胞术检测肿瘤微环境中的Tregs。
Tregs具有显著的免疫抑制作用,以表达Foxp3、CD25、CD4为细胞表型特征的T细胞亚群。Tregs能够抑制抗肿瘤免疫应答,不利于发挥免疫作用。因此通过流式细胞术检测小鼠肿瘤微环境中Tregs(CD3+CD4+CD25+Foxp3+)的比例。结果如图11-图12所示,Saline组小鼠肿瘤微环境中的Treg细胞比例最高,高达53.26±2.32%,说明小鼠乳腺癌细胞处于较高的免疫抑制状态。与Saline组相比,gel和PTX对Tregs细胞无显著影响(p>0.05)。GM+1MT、1MT@gel、GM@gel和GM-1MT@gel治疗后,Tregs细胞均有不同程度的减少,其中GM-1MT@gel组最低,仅为22.13±1.93%,且GM-1MT@gel与其余各组均存在显著性差异(p<0.05)。表明GM-1MT@gel具有逆转免疫抑制性肿瘤微环境的能力,进而增强CTLs的肿瘤杀伤效果。
(3)采用细胞因子微球检测技术(Cytometric Bead Arry,CBA)测定肿瘤中细胞因子(TNF-α、IFN-γ和IL-6)的含量。
T细胞被激活化后会释放TNF-α、IFN-γ和IL-6等细胞因子,从而进一步增强抗肿瘤免疫应答。发明人通过CBA法检测了小鼠肿瘤组织中的IFN-γ、TNF-α和IL-6的水平。结果如图13所示,与其他各组相比,GM-1MT@gel治疗组小鼠肿瘤中IFN-γ、TNF-α和IL-6的含量都高于其他组,分别是Saline组的4倍、2.4倍和3.1倍,并且于各组之间均存在显著性差异(p<0.05)。表明GM-1MT@gel能够激活T细胞,释放相关炎症因子,提高T细胞杀伤能力,进一步加强抗肿瘤免疫应答。
实施例8
进行凝胶的稳定性实验。
按照实施例1制备不同比例的水凝胶,选取不同比例混合后分别放置于4℃冰箱和室温环境下,每隔一段时间观察其状态。考察不同比例水凝胶的稳定性。
分别在4℃和室温环境下,考察不同比例水凝胶的稳定性。如表2所示:所有比例的水凝胶在室温条件下都会凝胶,2:1和3:1的比例所制备的水凝胶在4℃条件下最稳定,一直保持澄清透明的溶液状态,但2:1的比例所制备的水凝胶在室温条件下仅1h后就凝胶,不利于后续的实验操作。因此优选3:1的比例制备水凝胶。
表2不同比例水凝胶的成胶时间和稳定性
综上,本发明提供了一种双药共载水凝胶GM-1MT@gel,室温呈现溶液状态,体温凝胶状态,具有可注射下和良好的生物安全性。在体内体外可使药物长时间驻留在肿瘤部位,起到储库效应。在抗肿瘤效果研究中,GM-1MT@gel表现出了GM和1MT协同抑制肿瘤生长的效果,疗效大于单药治疗,并且优于阳性对照药物紫杉醇白蛋白。进一步检测小鼠肿瘤微环境中的T细胞和Treg细胞,发现GM-1MT@gel显著增加了CTLs的浸润,抑制IDO引起的免疫抑制作用,下调Treg细胞的比例,从而逆转肿瘤免疫抑制微环境,将乳腺癌的免疫“冷”环境转变为“热”环境。
以上所述仅为本发明的优选实施例而已,并不用于限制本发明,对于本领域的技术人员来说,本发明可以有各种更改和变化。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)
1.一种温度敏感的双药共载水凝胶,其特征在于,其包括:聚乙二醇与藤黄酸的酯化反应合成物、IDO抑制剂和温敏型凝胶,以温敏型凝胶包载藤黄酸和IDO抑制剂制得;所述温敏型凝胶中含0.006-0.01M藤黄酸和0.01-0.02M IDO抑制剂;所述IDO抑制剂为1-甲基-D-色氨酸(1-methyl-D-tryptophan,1MT)、帕卡司他(epacadostat,INCB24360)、纳考莫德(navoximod,GDC-0919,NLG919)、Linrodostat(BMS-986205)、DO-IN-2、PF-06840003、INCB024360、Exiguamine A或苯并咪唑。
2.根据权利要求1所述的温度敏感的双药共载水凝胶,其特征在于,所述温敏型凝胶是以天然阳离子聚合物和交联剂形成的具有三维网状结构的水凝胶;
优选地,所述天然阳离子聚合物选自半乳甘露聚糖或壳聚糖;所述交联剂选自β-甘油磷酸钠。
3.根据权利要求2所述的温度敏感的双药共载水凝胶,其特征在于,所述温敏型凝胶中壳聚糖与β-甘油磷酸钠混合体积比为10:1-1:1;
优选地,所述温敏型凝胶中壳聚糖与β-甘油磷酸钠混合体积比为3:1。
4.根据权利要求1或2所述的温度敏感的双药共载水凝胶,其特征在于,所述酯化反应合成物中的聚乙二醇的相对分子质量为1000-4000Da;
优选地,所述酯化反应合成物中的聚乙二醇的相对分子质量为2000;
优选地,所述温度敏感的双药共载水凝胶在0℃–10℃条件下呈溶液状态,在36℃以上条件下呈凝胶状态。
5.一种如权利要求1-4任一项所述的温度敏感的双药共载水凝胶的制备方法,其特征在于,其包括如下步骤:
将包括聚乙二醇与藤黄酸的酯化反应合成物和IDO抑制剂的混合溶液与用于制备温敏型凝胶的原料的溶液混合,制得温度敏感的双药共载水凝胶。
6.根据权利要求5所述的温度敏感的双药共载水凝胶的制备方法,其特征在于,所述制备方法包括:将所述酯化反应合成物和IDO抑制剂的混合溶液与由天然阳离子聚合物和交联剂组成的未载药水凝胶溶液共混制得温度敏感的双药共载水凝胶。
7.根据权利要求5所述的温度敏感的双药共载水凝胶的制备方法,其特征在于,所述制备方法包括:先将所述酯化反应合成物和IDO抑制剂的混合溶液与天然阳离子聚合物溶液混合制得载药水凝胶前体,然后将所述载药水凝胶前体与交联剂溶液混合制得温度敏感的双药共载水凝胶。
8.根据权利要求6或7所述的温度敏感的双药共载水凝胶的制备方法,其特征在于,所述天然阳离子聚合物的质量体积浓度为2-3%,所述交联剂溶液的质量体积浓度为40%-60%;
所述温敏型凝胶中壳聚糖与β-甘油磷酸钠混合体积比为10:1-1:1。
9.一种组合物,其特征在于,其包括:权利要求1-4任一项所述的温度敏感的双药共载水凝胶或由权利要求5-8任一项所述的温度敏感的双药共载水凝胶的制备方法制得的温度敏感的双药共载水凝胶;
优选地,所述组合物还包括药学上可接受的辅料;
优选地,所述组合物为注射剂。
10.如权利要求1-4任一项所述的温度敏感的双药共载水凝胶或由权利要求5-8任一项所述的温度敏感的双药共载水凝胶的制备方法制得的温度敏感的双药共载水凝胶在制备抗肿瘤药物或试剂中的用途,其特征在于,所述肿瘤选自口腔癌、肺癌、肝癌、结肠癌、乳腺癌、骨肉瘤、脑瘤、黑素瘤、胃癌、胰腺癌和前列腺癌中的任意一种;
优选地,所述抗肿瘤药物或试剂具有如下至少一种的用途:
(1)诱导肿瘤发生ICD;
(2)促进树突状细胞(Dendritic cells,DCs)成熟;
(3)增加肿瘤微环境中的T细胞浸润;
(4)抑制色氨酸的降解;
(5)下调Tregs细胞比例;
(6)上调细胞毒性T淋巴细胞比例;
(7)逆转肿瘤免疫抑制微环境;
(8)提升肿瘤细胞中的如下至少一种细胞因子的水平:TNF-α、IFN-γ和IL-6。
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