CN114269387A - 生物可降解性超ph敏感性聚合物 - Google Patents
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Abstract
本公开内容涉及含有对pH敏感的疏水性和亲水性链段的可降解聚合物。在一些方面中,所述聚合物形成对pH敏感的胶束,并且具有能够在体内进行降解的骨架。在一些方面中,本公开内容还提供了使用这些可降解聚合物用于递送药物的方法。
Description
本申请要求于日期为2019年6月22日的美国临时申请No.62/865,187的优先权,其全部内容通过引用并入于此。
背景技术
本发明是在国立卫生研究院(National Institutes of Health)授予的基金号R01 CA216839和U01 CA218422的政府支持下完成的。政府对本发明享有一定的权利。
1.技术领域
本公开内容总体上涉及分子和细胞生物学、药物递送以及纳米技术领域。更具体地,其涉及可用于递送治疗剂的可降解聚合物。
2.相关技术的描述
近年来,刺激响应性材料已迅速发展到广泛的医学应用中(Blum et al.,2015;Reineke,2016;Torchilin,2014;Yang et al.,2016)。已经设计了多种pH敏感性聚合物和纳米粒,并研究了其用于肿瘤成像和药物递送应用(Moitra et al.,2013;Moitra et al.,2014;Zhang et al.,2015)。对于许多生物学应用,不同成熟状态下的细胞器pH之间的差异(例如早期内体vs.晚期内体,或肿瘤微环境与正常组织pH之间的差异)很小,包括小如小于1个pH单位的pH差异,(Casey et al.,2009;Gerweck和Seetharaman,1996),这使得常规小分子或聚合物pH传感器得以区分具有挑战性。近年来,开发了对环境pH具有二元响应的一系列超pH敏感性(ultra-pH sensitive,UPS)共聚物。将可电离基团例如具有不同疏水性取代基的叔胺引入到聚(甲基丙烯酸甲酯)(poly(methyl methacrylate),PMMA)聚合物的骨架上。理论上,疏水性胶束化有助于急剧的pH响应(例如,0.25pH单位内的荧光开启/关闭激活(on/off activation))。所得晶体管状纳米粒(transistor-like nanoparticle)在多种生物学应用中显示出提高的精确度,所述生物学应用包括肿瘤成像和手术(Zhou et al.,2011a;Zhou et al.,2011b;Wang et al.,2013;Zhao et al.,2016)、内吞细胞器和溶酶体分解代谢的图像和扰动(Wang et al.,2015;Wang et al.,2017)以及用于癌症免疫治疗的纳米疫苗(Wang et al.,2016;Luo et al.,2017)。
如上所述,目前的UPS共聚物是使用不可降解的PMMA聚合物骨架合成的,这阻碍了这些聚合物待从体内清除的能力。对于某些医学应用,例如癌症手术,使用频率(即手术前单次注射)和显像剂(例如吲哚菁绿)的低毒性使得PMMA设计对人使用是安全的。然而,在其中需要重复注射的其他应用,例如药物或基因递送中,PMMA设计可导致体内物质积累过度,并限制这些UPS共聚物长期临床使用的安全性。
因此,仍然需要开发和制备可用于使用来递送治疗剂的能够在体内降解的聚合物系统。
发明内容
在一些方面中,本公开内容提供了下式聚合物或其可药用盐:
其中:
R1是氢、烷基(C≤8)、经取代烷基(C≤8)或巯基反应性基团;
m是1至8的整数;
p和q各自独立地是1、2或3;
x是10至200的整数;
y是20至200的整数;
z是0至200的整数;
其中y或z的单体随机分布在所述聚合物中;
X1、X2、X1’和X2’各自独立地是O或NRa,其中:
Ra是烷基(C≤6)或经取代烷基(C≤6);
R2和R2’各自独立地是氢、烷基(C≤8)或经取代烷基(C≤8);
R3是氢、烷基(C≤8)或经取代烷基(C≤8);
X3和X3’各自独立地是O或NRb,其中:
Rb是氢、烷基(C≤6)或经取代烷基(C≤6);
L和L’各自独立地是下式基团:
-X4-S(O)n-X5-
其中:
n是0、1或2;并且
X4和X5各自独立地是烷二基(C≤8)或经取代烷二基(C≤8);并且
Y1、Y2、Y1’和Y2’各自独立地是烷基(C≤12)、经取代烷基(C≤12)、烯基(C≤12)或经取代烯基(C≤12);或者Y1和Y2或Y1’和Y2’合在一起,并且是烷二基(C≤12)、烯二基(C≤12)或任一基团的经取代形式。
在一些实施方案中,聚合物被进一步限定为以下或其可药用盐:
其中:
R1是氢、烷基(C≤8)、经取代烷基(C≤8)或巯基反应性基团;
m是1至8的整数;
p和q各自独立地是1、2或3;
x是10至200的整数;
y是20至200的整数;
X1和X2各自是O或NRa,其中:
Ra是氢、烷基(C≤6)或经取代烷基(C≤6);
R2是氢、烷基(C≤8)或经取代烷基(C≤8);
R3是氢、烷基(C≤8)或经取代烷基(C≤8);
X3是O或NRb,其中:
Rb是氢、烷基(C≤6)或经取代烷基(C≤6);
L是下式基团:
-X4-S(O)n-X5-
其中:
n是0、1或2;并且
X4和X5各自独立地是烷二基(C≤8)或经取代烷二基(C≤8);并且
Y1和Y2各自独立地是烷基(C≤12)、经取代烷基(C≤12)、烯基(C≤12)或经取代烯基(C≤12);或者Y1和Y2合在一起,并且是烷二基(C≤12)、烯二基(C≤12)或任一基团的经取代形式。
在一些实施方案中,聚合物被进一步限定为以下或其可药用盐:
其中:
R1是氢、烷基(C≤8)、经取代烷基(C≤8)或巯基反应性基团;
m是1至8的整数;
x是10至200的整数;
y是20至200的整数;
X1和X2各自是O或NRa,其中:
Ra是氢、烷基(C≤6)或经取代烷基(C≤6);
R2是氢、烷基(C≤8)或经取代烷基(C≤8);
R3是氢、烷基(C≤8)或经取代烷基(C≤8);
X3是O或NRb,其中:
Rb是氢、烷基(C≤6)或经取代烷基(C≤6);
L是下式基团:
-X4-S(O)n-X5-
其中:
n是0、1或2;并且
X4和X5各自独立地是烷二基(C≤8)或经取代烷二基(C≤8);并且
Y1和Y2各自独立地是烷基(C≤12)、经取代烷基(C≤12)、烯基(C≤12)或经取代烯基(C≤12);或者Y1和Y2合在一起,并且是烷二基(C≤12)、烯二基(C≤12)或任一基团的经取代形式。
在一些实施方案中,聚合物被进一步限定为以下或其可药用盐:
其中:
R1是氢、烷基(C≤8)、经取代烷基(C≤8)或巯基反应性基团;
x是10至200的整数;
y是20至200的整数;
X1和X2各自是O或NRa,其中:
Ra是氢、烷基(C≤6)或经取代烷基(C≤6);
R2是氢、烷基(C≤8)或经取代烷基(C≤8);
R3是氢、烷基(C≤8)或经取代烷基(C≤8);
X3是O或NRb,其中:
Rb是氢、烷基(C≤6)或经取代烷基(C≤6);
L是下式基团:
-X4-S(O)n-X5-
其中:
n是0、1或2;并且
X4和X5各自独立地是烷二基(C≤8)或经取代烷二基(C≤8);并且
Y1和Y2各自独立地是烷基(C≤12)、经取代烷基(C≤12)、烯基(C≤12)或经取代烯基(C≤12);或者Y1和Y2合在一起,并且是烷二基(C≤12)、烯二基(C≤12)或任一基团的经取代形式。
在一些实施方案中,聚合物被进一步限定为以下或其可药用盐:
其中:
R1是氢、烷基(C≤8)、经取代烷基(C≤8)或巯基反应性基团;
x是10至200的整数;
y是20至200的整数;
R2是氢、烷基(C≤8)或经取代烷基(C≤8);
R3是氢、烷基(C≤8)或经取代烷基(C≤8);
L是下式基团:
-X4-S(O)n-X5-
其中:
n是0、1或2;并且
X4和X5各自独立地是烷二基(C≤8)或经取代烷二基(C≤8);并且
Y1和Y2各自独立地是烷基(C≤12)、经取代烷基(C≤12)、烯基(C≤12)或经取代烯基(C≤12);或者Y1和Y2合在一起,并且是烷二基(C≤12)、烯二基(C≤12)或任一基团的经取代形式。
在一些实施方案中,聚合物被进一步限定为以下或其可药用盐:
其中:
x是10至200的整数;
y是20至200的整数;
R2是氢、烷基(C≤8)或经取代烷基(C≤8);
L是下式基团:
-X4-S(O)n-X5-
其中:
n是0、1或2;并且
X4和X5各自独立地是烷二基(C≤8)或经取代烷二基(C≤8);并且
Y1和Y2各自独立地是烷基(C≤12)、经取代烷基(C≤12)、烯基(C≤12)或经取代烯基(C≤12);或者Y1和Y2合在一起,并且是烷二基(C≤12)、烯二基(C≤12)或任一基团的经取代形式。
在一些实施方案中,p是1。在一些实施方案中,q是1。在一些实施方案中,m是1、2或3,例如2。在一些实施方案中,X1是O。在一些实施方案中,X2是O。在一些实施方案中,X3是O。
在一些实施方案中,R1是烷基(C≤8)或经取代烷基(C≤8)。在一些实施方案中,R1是烷基(C≤8)例如甲基。在一些实施方案中,R3是氢。在一些实施方案中,R2是烷基(C≤8)或经取代烷基(C≤8)。在一些实施方案中,R2是烷基(C≤8)例如甲基。
在一些实施方案中,L的X4是烷二基(C≤6)或经取代烷二基(C≤6)。在一些实施方案中,L的X4是烷二基(C≤6)例如-CH2CH2-。在一些实施方案中,L的X5是烷二基(C≤6)或经取代烷二基(C≤6)。在一些实施方案中,L的X5是烷二基(C≤6)例如-CH2CH2-。在一些实施方案中,n是0。
在一些实施方案中,Y1是烷基(C≤12)或经取代烷基(C≤12)。在一些实施方案中,Y1是烷基(C2-12)或经取代烷基(C2-12)。在一些实施方案中,Y1是烷基(C2-12)。在一些实施方案中,Y1是甲基、乙基、正丙基或正丁基。在一些实施方案中,Y2是烷基(C≤12)或经取代烷基(C≤12)。在一些实施方案中,Y2是烷基(C2-12)或经取代烷基(C2-12)。在一些实施方案中,Y2是烷基(C2-12)。在一些实施方案中,Y2是甲基、乙基、正丙基或正丁基。在一些实施方案中,Y1和Y2合在一起并且是烷二基(C≤12)或经取代烷二基(C≤12)。在一些实施方案中,Y1和Y2合在一起并且是烷二基(C≤8)或经取代烷二基(C≤8)。在一些实施方案中,Y1和Y2合在一起并且是烷二基(C≤8),例如,当Y1和Y2合在一起时并且是-CH2CH2CH2CH2-、-CH2CH2CH2CH2CH2-或-CH2CH2CH2CH2CH2CH2-。
在一些实施方案中,聚合物被进一步限定为以下或其可药用盐:
在一些实施方案中,x是40至160的整数,例如80至150的整数。在一些实施方案中,y是40至180的整数,例如80至150的整数。
在另一个方面中,本公开内容提供了包含多种本文中所述聚合物的胶束。
在又一个方面中,本公开内容提供了组合物,其包含:
(A)本文中所述聚合物;以及
(B)治疗剂;
其中所述聚合物包封所述治疗剂。
在一些实施方案中,聚合物形成胶束。在一些实施方案中,胶束完全包封治疗剂。在一些实施方案中,治疗剂是影响免疫系统的药剂,例如细胞因子或免疫系统调节剂。在一些实施方案中,细胞因子为IL-1β、IL-2、IL-12或IL-15。在另一些实施方案中,免疫系统调节剂为cGAMP或1型干扰素。在另一些实施方案中,治疗剂是抗原,例如抗癌抗原。在一些实施方案中,抗癌抗原为E7肽。
在一些实施方案中,组合物被配制为药物组合物,并且还包含赋形剂。在一些实施方案中,所述药物组合物被配制用于以下施用:经口、脂肪内(intraadiposally)、动脉内、关节内、颅内、皮内、病灶内、肌内、鼻内、眼内、心包内、腹膜内、胸膜内、前列腺内、直肠内、鞘内、气管内、肿瘤内、脐带内、阴道内、静脉内、囊内、玻璃体内、经脂质体、局部、经黏膜、肠胃外、经直肠、结膜下、皮下、舌下、表面、经口含化(transbuccally)、经皮、阴道、作为乳膏(in creme)、作为脂质组合物、通过导管、通过灌洗、通过连续输注、通过输注、通过吸入、通过注射、通过局部递送或通过局部灌注。在一些实施方案中,所述药物组合物被配制用于通过注射施用,例如被配制用于动脉内施用、肌内施用、腹膜内施用、肿瘤内施用或静脉内施用。在一些实施方案中,赋形剂是载剂,例如适合于注射的水溶液剂。
在另一个方面中,本公开内容提供了治疗疾病或病症的方法,其包括向有此需要的患者施用治疗有效量的本文中所述的组合物,其中治疗剂足以治疗疾病或病症。在一些实施方案中,疾病或病症为癌症。在一些实施方案中,治疗剂能够调节免疫系统以靶向癌症。在一些实施方案中,治疗剂产生针对一种或更多种癌细胞的免疫应答。
本文中使用的“pH响应性胶束”、“pH敏感性胶束”、“pH可激活胶束(pH-activatable micelle)”和“pH可激活胶束(pH-activatable micellar,pHAM)纳米粒”在本文中可互换使用,以表示包含一种或更多种嵌段共聚物的胶束,其取决于pH(例如,高于或低于一定pH)而解离。作为一个非限制性实例,在一定pH下,嵌段共聚物基本上呈胶束形式。随着pH变化(例如,降低),胶束开始解离,并且随着pH进一步变化(例如,进一步降低),嵌段共聚物基本上以解离(非胶束)形式存在。
本文中使用的“pH转变范围”表示其中胶束解离的pH范围。
本文中使用的“pH转变值”(pHt)表示一半胶束解离的pH。
考虑到本文中所述的任何方法或组合物可相对于本文中所述的任何其他方法或组合物来实施。
术语“包含”(以及任何形式的“包含”)、“具有”(以及任何形式的“具有”)、“含有”(以及任何形式的“含有”)和“包括”(以及任何形式的“包括”)是开放式连接动词。因此,“包含”、“具有”、“含有”或“包括”一个或更多个列举的步骤或要素的方法、组合物、试剂盒或系统具有那些所列出的步骤或要素,但不限于仅具有那些步骤或要素;其可具有(即,覆盖)未列举的要素或步骤。同样地,“包含”、“具有”、“含有”或“包括”一个或更多个所列出的特征的方法、组合物、试剂盒或系统的要素具有那些特征,但不限于仅具有那些特征;其可具有未列出的特征。
本发明方法、组合物、试剂盒和系统中的任一者的任何实施方案均可以由所述的步骤和/或特征组成或者基本上由所述的步骤和/或特征组成,而不是包含/包括/含有/具有所述的步骤和/或特征。因此,在权利要求书中的任一项中,术语“由……组成”或“基本上由……组成”可代替上述任一种开放式连接动词,以相对于在其他情况下使用开放式连接动词的范围改变给定权利要求的范围。
除非明确指出仅指代替代方案或替代方案是互相排斥的,否则在权利要求书中术语“或/或者”的使用用于意指“和/或”,尽管本公开内容支持仅指代替代方案和“和/或”的限定。
在本申请通篇,术语“约”用于指示值包括用于确定该值的装置或方法之误差的标准偏差。
根据长期的专利法,在权利要求书或说明书中与词语“包含/括”结合使用时,没有数量词修饰的名词表示一个/种或更多个/种,除非特别指出。
根据以下详细描述,本公开内容的其他目的、特征和优点将变得明显。然而,应理解,详细描述和具体实例尽管指出了本公开内容的一些具体实施方案,但仅通过举例说明的方式给出,因为根据该详细描述,在本公开内容的精神和范围内的多种改变和修改对于本领域技术人员而言将变得明显。
附图说明
以下附图构成本说明书的一部分,并且被包括在内以进一步表明本公开内容的某些方面。通过参照这些附图中的一幅或更多幅并结合本文中所示具体实施方案的详细描述,本公开内容可被更好地理解。
图1A至1C示出了生物可降解UPS共聚物的超pH敏感性响应的表征。(图1A)pH变化作为具有不同叔胺取代基的PEO-b-P(MAC-SR)共聚物的质子化度的函数。PEO123-b-P(MAC-SDMA)135的数据分别呈现在图4中。(图1B)pKa值与P(MAC-SR)链段(中性/脱质子化状态)重复单元的log P负相关。蓝色和粉色点分别表示具有线性和环状二烷基叔胺作为侧基的共聚物。(图1C)pH转变锐度(pH transition sharpness)(ΔpH10%至90%)作为PEO-b-P(MAC-SR)嵌段共聚物log P的函数。示出了常用的多碱(polybase)(聚(乙烯亚胺)、壳聚糖、聚组氨酸、聚赖氨酸)以用于比较(Li et al.,2016)。
图2A和2B示出了从可溶单聚体状态到胶束状态的相变驱动了共聚物的超pH敏感性响应。(图2A)在PEO123-b-P(MAC-SC7A)135共聚物的pH滴定期间,数加权流体动力学直径(number-weighted hydrodynamic diameter)和光散射计数率作为质子化度的函数。(图2B)在高于和低于临界胶束化质子化度(critical micellization protonation degree)时,在质子化度为95%和85%下的PEO123-b-P(MAC-SC7A)135的TEM图像和数加权流体动力学直径分布。
图3A至3E示出了PEO123-b-P(MAC-SC7A)135共聚物在pH 6.5和7.4下的氘化缓冲溶液中的降解研究。(图3A)共聚物及其降解产物的化学结构。PEO123-b-P(MAC-SC7A)135共聚物在(图3B)pH 6.5和(图3C)pH 7.4氘化缓冲溶液中随时间推移的1H NMR谱。为了清楚起见,仅呈现了谱的选定区域。完整的谱在图6和7中示出。(图3D)在pH 6.5氘化缓冲溶液中,峰(d1+d2)和峰(d3+d4)相对于PEO链段的归一化质子信号的积分比(integration ratio)。(图3E)在pH 6.5和7.4氘化缓冲溶液中,峰(d3+d4)相对于PEO链段的归一化质子信号的积分比。
图4示出了pH变化作为PEO123-b-P(MAC-SDMA)135和PEO123-b-P(MAC-SC7A)135质子化度的函数。
图5A和5B示出了(图5A)在PEO123-b-P(MAC-SDMA)135共聚物的pH滴定期间,数加权流体动力学直径和光散射计数率作为质子化度的函数。(图5B)在高于和低于CMPD(约50%)时在质子化度为55%和45%下的PEO123-b-P(MAC-SDMA)135的TEM图像和数加权流体动力学直径分布。比例尺:50nm。
图6示出了PEO123-b-P(MAC-SC7A)135共聚物在pH 6.5氘化缓冲溶液中在55天内的完整1H NMR谱。
图7示出了PEO123-b-P(MAC-SC7A)135共聚物在pH 7.4氘化缓冲溶液中在55天内的完整1H NMR谱。
图8示出了通过HEK-BlueTM IL-2报道细胞在体外评价的归一化的IL-2功能。IL-2浓度:200、50、10、2、0.5、0.2、0.05、0.01ng/mL;PEG-b-P(MAC-SDPA)浓度:40、10、2、0.4、0.1、0.04、0.01、0.002μg/mL。
图9示出了在通过IL-2治疗的不同处理下的B16F10肿瘤生长曲线。在第1天和第5天时肿瘤内或静脉内注射游离IL-2或PEG-b-P(MAC-SDPA)-IL-2(IL-2:1μg/次注射;PEG-b-P(MAC-SDPA):200μg/次注射)。
图10示出了11天内的体重变化曲线。在第1天和第5天时肿瘤内或静脉内注射游离IL-2或PEG-b-P(MAC-SDPA)@IL-2(IL-2:1μg/次注射;PEG-b-P(MAC-SDPA):200μg/次注射)。
图11示出了cGAMP在1.0mg/mL生物可降解PEG-b-P(MAC-SC7A)胶束纳米粒中的负载效率。
图12A至12C示出了dUPS聚合物的STING结合和激活。图12A等温滴定量热法(isothermal titration calorimetry,ITC)示出了与PSDEA相比,PSC7A共聚物与STING的结合亲和力高得多。Kd:表观解离常数。图12B:来自ITC实验的不同dUPS聚合物对STING的Kb值(结合亲和力,Kd的倒数)总结。图12C:与dUPS共聚物(0.5μM,进行48小时)孵育的THP1-ISG细胞的干扰素(IFN)诱导水平,其与STING结合亲和力相关。通过t检验计算统计学显著性:***P<0.001,**P<0.01,*P<0.05。
图13A和13B示出了PSC7A纳米疫苗可在荷瘤小鼠中抑制肿瘤生长并延长存活。将接种2×105个图13A TC-1或图13B B16-F10黑素瘤细胞的C57BL/6小鼠(n=9/组)在上述特定时间点用PBS、仅肿瘤抗原肽、PSC7A NP、低剂量PSC7A疫苗(Vax.低)或高剂量PSC7A疫苗(Vax.高)进行处理。疫苗接种诱导了高效肿瘤生长抑制并延长这些小鼠的存活。对于肿瘤生长研究,数据以平均值±s.e.m.呈现,并通过t检验计算统计学显著性:***P<0.001,**P<0.01,*P<0.05。
图14A和14B示出了PSC7A纳米疫苗在两种动物肿瘤模型中抑制肿瘤生长。使用不可降解的PC7A纳米疫苗以进行比较。将接种2×105个图14A TC-1或图14B B16-F10黑素瘤细胞的C57BL/6小鼠(n=9/组)在特定时间点用PBS、肿瘤抗原肽、PSC7A疫苗或PC7A疫苗进行处理。数据以平均值±s.e.m.呈现,并通过t检验计算统计学显著性:***P<0.001,**P<0.01,*P<0.05。
图15A至15C示出了可降解PSC7A NP和不可降解PC7A NP的短期安全性评价。图15A:向C57BL/6小鼠(n=4/组)右侧胁腹下皮下注射PBS、300μg PSC7A NP或300μg PC7ANP。图15B:在注射之后24小时,通过AbcamTM测定试剂盒定量测量丙氨酸氨基转移酶(Alanine Aminotransferase,ALT)、天冬氨酸氨基转移酶(Aspartate Aminotransferase,AST)、尿素和肌酐水平的血清浓度。图15C:在注射之后24小时,通过BDTM CBA小鼠炎症试剂盒定量测量白介素-6(IL-6)、白介素-10(IL-10)、单核细胞趋化蛋白-1(MonocyteChemoattractant Protein-1,MCP-1)、干扰素-γ(IFN-γ)、肿瘤坏死因子(TNF)和白介素-12p70(IL-12p70)蛋白水平的血清浓度。通过t检验计算统计学显著性:***P<0.001,**P<0.01,*P<0.05。
图16示出了用于PSC7A NP的短期安全性评价的关键器官的组织学分析。来自在右侧胁腹上皮下注射PBS、300μg PSC7A NP或300μg PC7A NP之后C57BL/6小鼠的器官的代表性H&E切片。在施用之后24小时处死小鼠并收集器官。与PBS相比,在用任一聚合物处理之后心脏、肝、脾和肾的组织学均是不显著的。对于每个器官组,比例尺:5mm(顶部)和250μm(底部)。
图17A至17D示出了可降解PSC7A NP和不可降解PC7A NP的长期安全性评价。图17A:向C57BL/6小鼠右侧胁腹皮下注射PBS、300μg PSC7A NP或300μg PC7A NP。在PSC7A NP和PC7A NP组中在注射部位形成炎性结节。基于椭圆模型(ellipse model)计算结节的表面积。图17B:结节表面积随时间推移的变化。图17C左:第60天从注射部位拍摄的皮肤组织照片,从上到下为用PC7A NP、PSC7A NP和PBS处理的小鼠。右:来自PSC7A和PC7A组的皮肤组织的放大。图17C左:第60天经福尔马林固定、经石蜡包埋的皮肤组织(注射部位)的H&E染色,从上到下为用PC7A NP、PSC7A NP和PBS处理的小鼠。比例尺:2.5mm。中:来自PC7A组的被肉芽肿性炎症围绕的结节的放大。比例尺:250μm。插图:由正方形标记的区域的放大。左下、左上和右箭头分别表示巨噬细胞、淋巴细胞和嗜中性粒细胞。比例尺:50μm。右:来自PSC7A组的皮肤组织的放大。比例尺:250μm。
图18示出了用于PSC7A NP的长期安全性评价的皮肤组织(注射部位)的组织学分析。来自在右侧胁腹皮下注射PBS、300μg PSC7A NP或300μg PC7A NP之后C57BL/6小鼠的皮肤组织(注射部位)的代表性H&E切片。在施用之后第1、15和30天处死小鼠并收集皮肤组织。插图:由正方形标记的区域的放大。深灰色、浅灰色和中灰色箭头分别表示巨噬细胞、淋巴细胞和嗜中性粒细胞。比例尺:2.5mm(顶部)、1mm(中部和底部)、50μm(插图)。
图19示出了pH转变锐度(ΔpH10%至90%)作为dUPS聚合物的log P的函数。示出了常用的多碱(聚(乙烯亚胺)、壳聚糖、聚组氨酸、聚赖氨酸)以用于比较。
具体实施方式
在一些方面中,本公开内容提供了可形成在高于特定的转变pH时分解(dissemble)并含有可降解骨架的pH响应性纳米粒的聚合物。在一些实施方案中,这些聚合物具有急剧的pH转变值,并且含有一个或更多个可降解基团,这加快了聚合物的清除。这些聚合物可具有广泛的pH转变点,以允许广泛的应用,例如将药物化合物递送至特定组织。在一些方面中,本公开内容提供了在如上所述的pH响应性系统中使用这些聚合物,例如将治疗剂递送至身体的方法,包括这样的治疗剂,例如可用于治疗癌症的免疫系统调节剂。
A.化学定义
当在化学基团的情况下使用时:“氢”意指-H;“羟基”意指-OH;“氧代”意指=O;“羰基”意指-C(=O)-;“羧基”意指-C(=O)OH(也写作-COOH或-CO2H);“卤素”意指独立地-F、-Cl、-Br或-I;“氨基”意指-NH2;“羟基氨基”意指-NHOH;“硝基”意指-NO2;亚氨基意指=NH;“氰基”意指-CN;“异氰基(isocyanyl)”意指-N=C=O;“叠氮基”意指-N3;在单价的情况下,“磷酸酯(phosphate)”意指-OP(O)(OH)2或其去质子化形式;在二价的情况下,“磷酸酯”意指-OP(O)(OH)O-或其去质子化形式;“巯基”意指-SH;以及“硫代”意指=S;“硫代羰基”意指-C(=S)-;“磺酰基”意指-S(O)2-;以及“亚磺酰基”意指-S(O)-。
在化学式的情况下,符号“-”意指单键,“=”意指双键,以及“≡”意指三键。符号“----”表示任选键,其如果存在的话是单键或双键。符号表示单键或双键。因此,式涵盖,例如,并且可以理解,没有一个这样的环原子形成多于一个双键的一部分。此外,注意,当连接一个或两个立体原子时,共价键符号“-”并不表示任何优选的立体化学。相反地,其涵盖所有立体异构体及其混合物。符号当与键垂直相交绘出时(例如,对于甲基,)指示基团的连接点。注意,连接点通常仅对于较大的基团以这种方式指示以便帮助读者明确地识别连接点。符号意指单键,其中连接至楔形的厚端的基团在“在页面外”。符号意指单键,其中连接至楔形的厚端的基团在“在页面内”。符号意指单键,其中双键周围的几何性状(例如E或Z)未确定。因此预期了两种选择及其组合。本申请中所示结构的原子上的任何未限定的化合价隐含地表示与该原子键合的氢原子。碳原子上的粗点表示连接至该碳的氢定向为从纸平面向外。
当环体系上的变量被描述为“浮动基团(floating group)”时,例如,下式中的基团“R”:
则所述变量可替代与任何环原子连接的任何氢原子,包括示出的、暗含的或明确限定的氢,只要形成稳定的结构即可。当稠环体系上的变量被描述为“浮动基团”时,如例如下式中的基团“R”:
则除非另有说明,否则该变量可替代与任一稠环的任何环原子连接的任何氢。可替代的氢包括示出的氢(例如,上式中与氮连接的氢)、暗含的氢(例如,上式的未示出但被理解为存在的氢)、明确限定的氢以及其存在取决于环原子的身份的任选的氢(例如,当X等于-CH-时,与基团X连接的氢),只要形成稳定的结构即可。在所示的实例中,R可位于稠环体系的5元环或6元环上。在上式中,紧跟着括在括号内的R的下标字母“y”表示数值变量。除非另有指明,否则该变量可以为0、1、2或大于2的任何整数,其仅受环或环体系的可替代氢原子的最大数目限制。
对于化学基团和化合物类别,基团或类别中碳原子数如下所示:″Cn″或“C=n”限定在该基团/类别中碳原子的确切数目(n)。“C≤n”限定了可在该基团/类别中的最大碳原子数(n),且最小数目对于所讨论的基团/类别尽可能小。例如,可理解,在基团“烷基(C≤8)”、“环烷二基(C≤8)”、“杂芳基(C≤8)”和“酰基(C≤8)”中的碳原子的最小数目为1个;在基团“烯基(C≤8)”、“炔基(C≤8)”和“杂环烷基(C≤8)”中的碳原子的最小数目为2个;在基团“环烷基(C≤8)”中的碳原子的最小数目为3个;以及在基团“芳基(C≤8)”和“芳二基(C≤8)”中的碳原子的最小数目为6个。“Cn-n’”限定了基团中碳原子的最小数目(n)和最大数目(n’)二者。因此,“烷基(C2-10)”表示具有2至10个碳原子的那些烷基。这些碳数目指示符可在其修饰的化学基团或类别之前或之后,并且其可括在或可不括在括号中,而不代表任何含义改变。因此,术语“C5烯烃”、“C5-烯烃”、“烯烃(C5)”和“烯烃C5”都是同义的。除如下所述之外,对每个碳原子进行计数以确定基团或化合物是否落入指定的碳原子数中。例如,基团二己基氨基是二烷基氨基(C=12)基团的一个实例;然而,它不是二烷基氨基(C=6)基团的实例。同样,苯基乙基是芳烷基(C=8)基团的一个实例。当本文中限定的任何化学基团或化合物类别被术语“经取代”修饰时,不对替代氢原子的部分中的任何碳原子进行计数。因此,具有总共7个碳原子的甲氧基己基是经取代烷基(C1-6)的一个实例。除非另有说明,否则权利要求书中所列出的没有碳原子界限的任何化学基团或化合物类别的碳原子界限为小于或等于12。
当术语“饱和的”用于修饰化合物或化学基团时意指该化合物或化学基团不含碳-碳双键并且不含碳-碳三键,除如下所述之外。当该术语用于修饰原子时,其意指该原子不是任何双键或三键的一部分。在饱和基团的经取代形式的情况下,可存在一个或更多个碳氧双键或碳氮双键。并且当存在这样的键时,则不排除可能作为酮-烯醇互变异构或亚胺/烯胺互变异构的一部分出现的碳-碳双键。当术语“饱和的”用于修饰物质的溶液时,其意指不能有更多的该物质可溶解在该溶液中。
术语“脂族”表示经如此修饰的化合物或化学基团是无环或环状但非芳族的化合物或基团。在脂族化合物/基团中,碳原子可以以直链、支链或非芳族环(脂环)连接在一起。脂族化合物/基团可以是饱和的,即,通过碳-碳单键连接(烷烃/烷基);或者是不饱和的,具有一个或更多个碳-碳双键(烯烃/烯基)或具有一个或更多个碳-碳三键(炔烃/炔基)。
术语“烷基”是指单价饱和脂族基团,其以碳原子作为连接点,具有直链或支链的无环结构,并且不含碳和氢之外的原子。基团-CH3(Me)、-CH2CH3(Et)、-CH2CH2CH3(n-Pr或丙基)、-CH(CH3)2(i-Pr、iPr或异丙基)、-CH2CH2CH2CH3(n-Bu)、-CH(CH3)CH2CH3(仲丁基)、-CH2CH(CH3)2(异丁基)、-C(CH3)3(叔丁基、t-丁基、t-Bu或tBu)以及-CH2C(CH3)3(新戊基)是烷基的一些非限制性实例。术语“烷二基”是指二价饱和脂族基团,其以一个或两个饱和碳原子作为连接点,具有直链或支链的无环结构,不含碳-碳双键或三键,并且不含碳和氢之外的原子。基团-CH2-(亚甲基)、-CH2CH2-、-CH2C(CH3)2CH2-和-CH2CH2CH2-是烷二基的一些非限制性实例。术语“亚烷基”是指二价基团=CRR’,其中R和R’独立地为氢或烷基。亚烷基的一些非限制性实例包括:=CH2、=CH(CH2CH3)和=C(CH3)2。“烷烃”是指具有式H-R的化合物类别,其中R是烷基,如该术语在上文定义的。
术语“烯基”是指单价不饱和脂族基团,其以碳原子作为连接点,具有直链或支链的无环结构,具有至少一个非芳族碳-碳双键,不含碳-碳三键,并且不含碳和氢之外的原子。一些非限制性实例包括:-CH=CH2(乙烯基)、-CH=CHCH3、-CH=CHCH2CH3、-CH2CH=CH2(烯丙基)、-CH2CH=CHCH3以及-CH=CHCH=CH2。术语“烯二基”是指二价不饱和脂族基团,其以两个碳原子作为连接点,具有直链或支链的无环结构,具有至少一个非芳族碳-碳双键,不含碳-碳三键,并且不含碳和氢之外的原子。基团-CH=CH-、-CH=C(CH3)CH2-、-CH=CHCH2-和-CH2CH=CHCH2-是烯二基的一些非限制性实例。应注意,虽然烯二基是脂族的,但一旦在两端连接,不排除该基团形成芳族结构的一部分。术语“链烯”和“烯烃”是同义的并且是指具有式H-R的化合物类别,其中R是烯基,如该术语在上文定义的。类似地,术语“末端烯烃”和“α-烯烃”是同义的并且是指仅具有一个碳-碳双键的烯烃,其中该键是在分子末端的乙烯基的一部分。
当化学基团与“经取代”的修饰语一起使用时,一个或更多个氢原子在每种情况下都被以下独立取代:-OH、-F、-Cl、-Br、-I、-NH2、-NO2、-CO2H、-CO2CH3、-CO2CH2CH3、-CN、-SH、-OCH3、-OCH2CH3、-C(O)CH3、-NHCH3、-NHCH2CH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3、-C(O)N(CH3)2、-OC(O)CH3、-NHC(O)CH3、-S(O)2OH或-S(O)2NH2。例如,以下基团是经取代烷基的一些非限制性实例:-CH2OH、-CH2Cl、-CF3、-CH2CN、-CH2C(O)OH、-CH2C(O)OCH3、-CH2C(O)NH2、-CH2C(O)CH3、-CH2OCH3、-CH2OC(O)CH3、-CH2NH2、-CH2N(CH3)2和-CH2CH2Cl。术语“卤代烷基”是经取代烷基的一个子集,其中氢原子替代限于卤素(即-F、-Cl、-Br或-I),以使得除碳、氢和卤素之外不存在其他原子。基团-CH2Cl是卤代烷基的一个非限制性实例。术语“氟烷基”是经取代烷基的一个子集,其中氢原子替代限于氟,以使得除碳、氢和氟之外不存在其他原子。基团-CH2F、-CF3和-CH2CF3是氟烷基的一些非限制性实例。
术语“巯基反应性基团”是能够与巯基(-SH)发生反应以形成共价键的官能团。这样的基团在文献中是公知的。两种原型基团包括卤代乙酰胺,例如碘代乙酰胺和马来酰亚胺。这些基团可用于与半胱氨酸残基的巯基反应,以形成与硫原子的共价键。
B.嵌段共聚物
本文中公开的pH响应性胶束和纳米粒包含嵌段共聚物。嵌段共聚物包含亲水性聚合物链段和疏水性聚合物链段。疏水性聚合物链段是pH敏感性的。例如,疏水性聚合物链段可包含可电离的胺基以提供pH敏感性。嵌段共聚物基于这些可电离嵌段共聚物的超分子自组装形成pH可激活的胶束(pHAM)纳米粒。在较高的pH下,嵌段共聚物组装成胶束,而在较低的pH下,疏水性聚合物链段中的胺基的离子化导致胶束的解离。可电离基团可在不同pH值下用作可调亲水性/疏水性嵌段,这可直接影响胶束的动态自组装。
在一些实施方案中,本发明聚合物包含一个或更多个嵌段,其使用可降解聚合物基础(例如聚碳酸酯或聚脲)构建。这些组分可用于构建疏水性聚合物链段。在一些实施方案中,这些聚合物链段包含一个单体单元以形成均聚物。在另一些实施方案中,聚合物链段可包含两个或更多个单体单元以形成聚合物链段。如果聚合物链段包含两个或更多个单体单元,则单体单元可以是一个单元的单嵌段,随后是每个另外单体单元或不同单体单元的独特嵌段可随机分散在整个聚合物嵌段中。
本文中所述的聚合物例如在上面的发明内容部分和所附的权利要求书中示出。它们可使用实施例部分中概述的合成方法来制备。这些方法可使用如本领域技术人员应用的有机化学的原理和技术进一步修改和优化。这样的原理和技术例如在Smith,March’sAdvanced Organic Chemistry:Reactions,Mechanisms,and Structure,(2013)中教导,其通过引用并入本文。另外,合成方法可使用本领域技术人员应用的工艺化学的原理和技术进一步修改和优化,以用于制备型、中试规模或大规模的生产(无论是分批还是连续的)。例如,在Anderson,Practical Process Research&Development-A Guide for OrganicChemists(2012)中教导了这样的原理和技术,其通过引用并入本文。
本文中所述的聚合物可含有一个或更多个不对称取代的碳或氮原子,并且可以以光学活性或外消旋形式分离。因此,除非明确地指出具体的立体化学或异构形式,否则预期了化学式的所有手性、非对映体、外消旋形式、差向异构形式和所有几何异构形式。聚合物可作为外消旋体和外消旋混合物、单一对映体、非对映体混合物和单独的非对映体存在。在一些实施方案中,获得单一非对映体。聚合物的手性中心可具有S或R构型。在一些实施方案中,本发明聚合物可包含两个或更多个具有确定的立体化学取向的原子。
用于表示本文中所述聚合物的化学式将通常仅示出了可能的数种不同互变异构体中的一种。例如,已知许多类型的酮基团与相应的烯醇基团平衡存在。类似地,许多类型的亚胺基团与烯胺基团平衡存在。无论对于给定化合物描述了哪种互变异构体,并且无论哪一种是最普遍的,都预期了给定化学式的所有互变异构体。
另外,构成本文中所述聚合物的原子旨在包括这样的原子的所有同位素形式。本文中使用的同位素包括具有相同的原子序数但质量数不同的那些原子。作为一般实例而非限制,氢的同位素包括氚和氘,并且碳的同位素包括13C和14C。
在一些实施方案中,本文中所述聚合物以盐或非盐形式存在。关于盐形式,在一些实施方案中,形成本文中提供的聚合物的任何盐形式的一部分的特定阴离子或阳离子并不重要,只要该盐作为整体是药理学上可接受的即可。可药用盐另外的实例及其制备和使用方法在Handbook of Pharmaceutical Salts:Properties,and Use(2002)中给出,其通过引用并入本文。
C.胶束系统和组合物
本文中公开的系统和组合物利用单一胶束或调节至不同pH水平的一系列胶束。此外,胶束具有窄pH转变范围。在一些实施方案中,胶束的pH转变范围为小于约1pH单位。在多个实施方案中,胶束的pH转变范围为小于约0.9、小于约0.8、小于约0.7、小于约0.6、小于约0.5、小于约0.4、小于约0.3、小于约0.25、小于约0.2或小于约0.1pH单位。窄pH转变范围有利地提供了更急剧的pH响应,其可导致荧光团的完全开启以及pH的细微变化。
胶束的尺寸将通常为纳米级(即,直径为约1nm至1μm)。在一些实施方案中,胶束的尺寸为约10至约200nm。在一些实施方案中,胶束的尺寸为约20至约100nm。在一些实施方案中,胶束的尺寸为约30至约50nm。
D.靶向部分
胶束和纳米粒可还包含靶向部分。靶向部分可用于将纳米粒或胶束靶向至例如特定的细胞表面受体、细胞表面标志物或靶向至细胞器(例如,细胞核、线粒体、内质网、叶绿体、质外体或过氧化物酶体)。这样的靶向部分将在受体再循环、标志物再循环、胞内pH凋节、内吞运输的研究中是有利的。
靶向部分可以是例如抗体或抗体片段(例如Fab’片段)、蛋白质、肽(例如信号肽)、适配体或小分子(例如叶酸)。可通过本领域已知的方法将靶向部分与嵌段共聚物缀合(例如,与亲水性聚合物链段缀合)。靶向部分的选择将取决于特定的靶标。例如,抗体、抗体片段、小分子或结合伴侣可更适合于靶向细胞表面受体和细胞表面标志物,而肽,特别是信号肽,可更适合于靶向细胞器。
E.抗原
在一些方面中,本公开内容提供了具有一种或更多种抗原性组分的组合物。抗原是促进免疫应答的物质,从而特异性地产生针对该物质的抗体。一些物质具有更高的免疫原性,且因此免疫系统将很容易产生适当的免疫应答,但其他物质需要帮助以产生足以产生针对抗原之抗体的免疫应答。大多数癌症可需要额外的激活以增强针对抗原之抗体的产生。抗原的一些非限制性实例包括癌症特异性表面蛋白或癌细胞过表达的表面蛋白质的蛋白质或其片段。
i.癌症
多种不同的肽、蛋白质片段或蛋白质可用作本发明组合物中的抗原。一些非限制性实例包括5T4、707-AP(707丙氨酸脯氨酸)、9D7、AFP(甲胎蛋白)、AlbZIP HPG1、α5β1-整联蛋白、α5β6-整联蛋白、α-甲基酰基-辅酶A消旋酶、ART-4(由T细胞4识别的腺癌抗原)、B7H4、BAGE-1(B抗原)、BCL-2、BING-4、CA 15-3/CA 27-29、CA 19-9、CA 72-4、CA125、钙网蛋白、CAMEL(黑素瘤上的CTL识别抗原)、CASP-8(胱天蛋白酶-8)、组织蛋白酶B、组织蛋白酶L、CD19、CD20、CD22、CD25、CD30、CD33、CD40、CD52、CD55、CD56、CD80、CEA(癌胚抗原)、CLCA2(钙激活氯通道-2)、CML28、毛状蛋白样蛋白(Coactosin-like protein)、胶原蛋白XXIII、COX-2、CT-9/BRD6(溴结构域睾丸特异性蛋白)、Cten(C端张力蛋白样蛋白)、细胞周期蛋白B1、细胞周期蛋白D1、cyp-B(亲环蛋白B)、CYPB1(细胞色素P450 1B1)、DAM-10/MAGE-B1(分化抗原黑素瘤10)、DAM-6/MAGE-B2(分化抗原黑素瘤6)、EGFR/Her1、EMMPRIN(肿瘤细胞相关胞外基质基质金属蛋白酶诱导物)、EpCam(上皮细胞黏附分子)、EphA2(肝配蛋白A型受体2)、EphA3(肝配蛋白A型受体3)、ErbB3、EZH2(Zeste同源物2的增强子)、FGF-5(成纤维细胞生长因子-5)、FN(纤连蛋白)、Fra-1(Fos相关抗原-1)、G250/CAIX(糖蛋白250)、GAGE-1(G抗原1)、GAGE-2(G抗原2)、GAGE-3(G抗原3)、GAGE-4(G抗原4)、GAGE-5(G抗原5)、GAGE-6(G抗原6)、GAGE-7b(G抗原7b)、GAGE-8(G抗原8)、GDEP(前列腺中差异表达的基因)、GnT-V(N-乙酰葡糖胺转移酶V)、gp100(糖蛋白100kDa)、GPC3(磷脂酰肌醇蛋白聚糖3)、HAGE(解旋酶抗原)、HAST-2(人印戒肿瘤-2)、hepsin、Her2/neu/ErbB2(人表皮受体-2/神经)、HERV-K-MEL、HNE(人嗜中性粒细胞弹性蛋白酶)、同源框NKX3.1、HOM-TES-14/SCP-1、HOM-TES-85、HPV-E6、HPV-E7、HST-2、hTERT(人端粒酶逆转录酶)、iCE(肠羧基酯酶)、IGF-1R、IL-13Ra2(白介素13受体α2链)、IL-2R、IL-5、未成熟层黏连蛋白受体、激肽释放酶2、激肽释放酶4、Ki67、KIAA0205、KK-LC-1(北九州肺癌抗原1(Kita-kyushu lung cancer antigen 1))、KM-HN-1、LAGE-1(L抗原)、生存蛋白(livin)、MAGE-A1(黑素瘤抗原-A1)、MAGE-A10(黑素瘤抗原-A10)、MAGE-A12(黑素瘤抗原-A12)、MAGE-A2(黑素瘤抗原-A2)、MAGE-A3(黑素瘤抗原-A3)、MAGE-A4(黑素瘤抗原-A4)、MAGE-A6(黑素瘤抗原-A6)、MAGE-A9(黑素瘤抗原-A9)、MAGE-B1(黑素瘤抗原-B1)、MAGE-B10(黑素瘤抗原-B 10)、MAGE-B16(黑素瘤抗原-B16)、MAGE-B17(黑素瘤抗原-B17)、MAGE-B2(黑素瘤抗原-B2)、MAGE-B3(黑素瘤抗原-B3)、MAGE-B4(黑素瘤抗原-B4)、MAGE-B5(黑素瘤抗原-B5)、MAGE-B6(黑素瘤抗原-B6)、MAGE-C1(黑素瘤抗原-C1)、MAGE-C2(黑素瘤抗原-C2)、MAGE-C3(黑素瘤-抗原-C3)、MAGE-D1(黑素瘤抗原-D1)、MAGE-D2(黑素瘤抗原-D2)、MAGE-D4(黑素瘤抗原-D4)、MAGE-E1(黑素瘤抗原-E1)、MAGE-E2(黑素瘤抗原-E2)、MAGE-F1(黑素瘤抗原-F1)、MAGE-H1(黑素瘤抗原-H1)、MAGEL2(MAGE样2)、乳腺珠蛋白A、MART-1/Melan-A(由T细胞-1识别的黑素瘤抗原/黑素瘤抗原A)、MART-2(由T细胞-2识别的黑素瘤抗原)、基质蛋白22、MC1R(黑皮质素1受体)、M-CSF(巨噬细胞集落刺激因子基因)、间皮素、MG50/PXDN、MMP 11(M期磷蛋白11)、MN/CA IX-抗原、MRP-3(多药抗性相关蛋白3)、MUC1(黏蛋白1)、MUC2(黏蛋白2)、NA88-A(患者M88的NA cDNA克隆)、N-乙酰葡糖氨转移酶-V、新-PAP(新聚(A)聚合酶)、NGEP、NMP22、NPM/ALK(核仁磷蛋白/间变性淋巴瘤激酶融合蛋白)、NSE(神经特异性烯醇化酶)、NY-ESO-1(纽约食管1)、NY-ESO-B、OA1(眼白化病1型蛋白)、OFA-iLRP(癌胚抗原-未成熟层黏连蛋白受体)、OGT(O-连接的N-乙酰葡糖胺转移酶基因)、OS-9、骨钙蛋白、骨桥蛋白、p15(蛋白15)、p15、p190次要bcr-abl、p53、PAGE-4(前列腺GAGE样蛋白-4)、PAI-1(纤溶酶原激活物抑制剂1)、PAI-2(纤溶酶原激活物抑制剂2)、PAP(前列腺酸性磷酸酶)、PART-1、PATE、PDEF、Pim-1-激酶、Pin1(丙基异构酶)、POTE、PRAME(优先表达的黑素瘤抗原)、prostein、蛋白酶-3、PSA(前列腺特异性抗原)、PSCA、PSGR、PSM、PSMA(前列腺特异性膜抗原)、RAGE-1(肾抗原)、RHAMM/CD168(透明质酸介导的能动性受体)、RU1(肾普遍存在1)、RU2(肾普遍存在1)、S-100、SAGE(肉瘤抗原)、SART-1(鳞状抗原排斥肿瘤1)、SART-2(鳞状抗原排斥肿瘤1)、SART-3(鳞状抗原排斥肿瘤1)、SCC(鳞状细胞癌抗原)、Sp17(精子蛋白17)、SSX-1(滑膜肉瘤X断点1)、SSX-2/HOM-MEL-40(滑膜肉瘤X断点)、SSX-4(滑膜肉瘤X断点4)、STAMP-1、STEAP(六次跨膜上皮抗原前列腺)、存活,存活蛋白-2B(保留内含子2的存活蛋白)、TA-90、TAG-72、TARP、TGFb(TGFβ)、TGFbRII(TGFβ受体II)、TGM-4(前列腺特异性转谷氨酰胺酶)、TRAG-3(紫杉醇抗性相关蛋白3)、TRG(簇集素相关基因(testin-related gene))、TRP-1(酪氨酸相关蛋白1)、TRP-2/6b(TRP-2/新外显子6b)、TRP-2/INT2(TRP-2/内含子2)、Trp-p8、酪氨酸酶、UPA(尿激酶型纤溶酶原激活物)、VEGF(血管内皮生长因子)、VEGFR-2/FLK-1(血管内皮生长因子受体-2)、WT1(Wilm肿瘤基因),或者可包括例如癌症疾病中表达的突变抗原,其选自包括但不限于以下的组:α-辅肌动蛋白-4/m、ARTC1/m、bcr/abl(断点簇区域-Abelson融合蛋白)、β-联蛋白/m(β-联蛋白)、BRCA1/m、BRCA2/m、CASP-5/m、CASP-8/m、CDC27/m(细胞分裂周期27)、CDK4/m(细胞周期蛋白依赖性激酶4)、CDKN2A/m、CML66、COA-1/m、DEK-CAN(融合蛋白)、EFTUD2/m、ELF2/m(延伸因子2)、ETV6-AML1(Ets变体基因6/急性髓性白血病1基因融合蛋白)、FN1/m(纤连蛋白1)、GPNMB/m、HLA-A*0201-R170I(HLA-A2基因α2结构域α-螺旋的残基170处的精氨酸至异亮氨酸交换)、HLA-A11/m、HLA-A2/m、HSP70-2M(热休克蛋白70-2突变)、KIAA0205/m、K-Ras/m、LDLR-FUT(LDR-岩藻糖基转移酶融合蛋白)、MART2/m、ME1/m、MUM-1/m(黑素瘤普遍存在突变1)、MUM-2/m(黑素瘤普遍存在突变2)、MUM-3/m(黑素瘤普遍存在突变3)、I类肌球蛋白/m、新PAP/m、NFYC/m、N-Ras/m、OGT/m、OS-9/m、p53/m、Pml/RARα(早幼粒细胞性白血病/视黄酸受体α)、PRDX5/m、PTPRK/m(受体型蛋白酪氨酸磷酸酶κ)、RBAF600/m、SIRT2/m、SYT-SSX-1(突触结合蛋白I/滑膜肉瘤X融合蛋白)、SYT-SSX-2(突触结合蛋白I/滑膜肉瘤X融合蛋白)、TEL-AML1(易位Ets-家族白血病/急性髓性白血病1融合蛋白)、TGFβRII(TGFβ受体II)、TPI/m(磷酸丙糖异构酶)。
F.试剂盒
本公开内容还提供了试剂盒。本文中公开的任何组分均可组合在试剂盒中。在某些实施方案中,试剂盒包含如上所述的pH响应性系统或组合物。
试剂盒通常将包含至少一个小瓶、试管、烧瓶、瓶、注射器或其他容器,其中可放置组分,并且优选适当地等分。在试剂盒中存在多于一种组分的情况下,试剂盒通常还将包含第二、第三或其他另外的容器,其中可单独放置另外的组分。然而,组分的多种组合可包含在容器中。在一些实施方案中,一系列的胶束群中的全部均在单一容器中组合。在另一些实施方案中,一系列胶束群中的一些或全部在分开的容器中提供。
本公开内容的试剂盒通常还将包含用于容纳多个容器的包装,严格密封以用于商业销售。这样的包装可包括纸板或者注射或吹塑塑料包装,其中保存期望的容器。试剂盒还可包含用于使用试剂盒组分的说明。说明可包含可实施的变化。
G.实施例
包括以下实施例以说明本公开内容的一些优选实施方案。本领域技术人员应理解,在以下实施例中公开的技术代表本发明人发现在本公开内容的实践中发挥良好作用的技术,并因此可被认为构成了用于本公开内容实践的优选模式。然而,本领域技术人员根据本公开内容应理解,可在不脱离本公开内容的精神和范围的情况下,对所公开的具体实施方案作出许多变化而仍然获得相同或相似的结果。
实施例1:合成表征、材料和方法
1.材料
除非另有说明,否则所有试剂均购自商业来源或是合成的,并且无需进一步纯化即可使用。它们是聚(乙二醇)甲醚(mPEG5k-OH,Mn=5.4×103g/mol,通过1H NMR测量)、1-(3,5-双-三氟甲基-苯基)-3-环己基硫脲(TU,合成)(Natarajan et al.,2005)、1,8-二氮杂双环[5.4.0]十一-7-烯(DBU,>99%,Sigma-Aldrich)、二丙胺(DPA,99%,Sigma-Aldrich)、二丁胺(DBA,>99.5%,Sigma-Aldrich)、吡咯烷(C5A,>99%,Sigma-Aldrich)、哌啶(C6A,>99.5%)、六亚甲基亚胺(C7A,99%,Sigma-Aldrich)、乙烯硫化物(98%,Sigma-Aldrich)、2,2-二甲氧基-2-苯基乙酮(DMPA,99%,Sigma-Aldrich)。2-二甲氨基乙硫醇盐酸盐(DMA-SH·HCl,95%)和2-二乙氨基乙硫醇盐酸盐(DEA-SH·HCl,95%)购自SigmaAldrich。如报道(Hao et al.,2015)合成了其他氨基硫醇盐酸盐分子(以下示出)。
PEO-b-PMAC共聚物的合成
首先,如报道(Hu et al.,2007),合成了5-甲基-5-烯丙基氧基羰基-1,3-二氧六环-2-酮(MAC)单体。以mPEG5k-OH作为引发剂([单体]/[引发剂]=200),通过开环聚合(ringopening polymerization,ROP)合成了PEO-b-PMAC共聚物。通常来说,在填充纯化氩的手套箱(glove box)中,用0.4g mPEG5k-OH、3.2g MAC单体和16.0mL二氯甲烷(DCM)加入Schlenk反应烧瓶。在三次冷冻-泵-解冻循环之后,引入0.6g TU和0.16mL DBU以开始聚合。将反应置于30℃的油浴中15小时,然后通过添加苯甲酸淬灭。通过蒸发去除DCM溶剂,然后将浓缩的残余物沉淀到过量的冷乙醚中。将纯化过程重复两次,以去除任何未反应的起始物料和杂质。将所得PEO-b-PMAC共聚物通过400MHz 1H NMR、凝胶渗透色谱(gel permeationchromatography,GPC,Viscotech GPCmax,Polymer Labs的PLgel 5μm MIXED-D柱。使用以1.0mL/分钟的含1%v/v TEA的THF作为洗脱液)进行表征。对于PEG123-b-PMAC125,
1H NMR(400MHz,CDCl3,25℃):δ5.92-5.84(m,1H,-CH=CH2),5.33-5.23(m,2H,-CH=CH2),4.63(br,2H,-OCH2CH=CH2),4.38-4.22(m,4H,-OCH2-C-CH2O-),3.64(s,2H,-OCH2CH2),3.38(s,3H,-OCH3),1.28(s,3H,CH3),1.22(s,3H,C(CH3)CH2OH).GPC(THF,IR):Mn=2.58×104g/mol,Mw=3.47×104g/mol,Mw/Mn=1.35).
PEO-b-P(MAC-SR·HCl)共聚物的合成
通过含烯丙基的PEO-b-PMAC与氨基硫醇盐酸盐之间的硫醇-烯(thiol-ene)反应,合成了PEO-b-P(MAC-SR·HCl)共聚物。下面我们选择PEO-b-P(MAC-SDEA·HC1)的合成作为一个实施例。首先,将0.1g PEO123-b-PMAC125(0.419mmol)溶解在石英烧瓶(quartz flask)中的15mL DMF中,并在氮气下搅拌10至20分钟。然后向烧瓶中添加1.06g DEA-SH·HCl(6.29mmol)和21.5mg DMPA(0.084mmol)。在氮气吹扫另外20分钟之后,将烧瓶置于UV光(365nm)下以引发反应。在12小时之后,将反应混合物在蒸馏水中透析并冻干以获得白色粉末。PEO-b-P(MAC-SR·HCl)共聚物系列经1H NMR和GPC确证。结果总结在表1中。
表1:PEO-b-P(MAC-SR·HCl)共聚物的表征。
aPEO-b-PMAC共聚物前体的重复单元数为140。
bpEO-b-PMAC共聚物前体的重复单元数为125。
c在GPC中,通过使用聚苯乙烯作为标准品,以及THF(1%v/v TEA)作为洗脱溶剂,来获得Mw,GPC,Mn,GPC和PDI(Mw,GPC/Mn,GPC)。
PEO123-b-P(MAC-SDMA·HCl)135(PSDMA)1H NMR(400MHz,CDCl3,25℃):δ4.29(s,4H,-OCH2-C-CH2O-),4.25(t,2H,-OCH2CH2-),3.64(s,2H,-OCH2CH2),3.38(s,3H,-OCH3),3.35-3.31(t,2H,-SCH2CH2N-),3.02-2.98(m,2H,-SCH2CH2N-),2.92(s,6H,-N(CH3)2),2.66(t,2H,-OCH2CH2CH2S-),2.00-1.95(m,2H,-OCH2CH2CH2S-),1.28(s,3H,-CH3).
PEO123-b-P(MAC-SDEA·HCl)115(PSDEA)1H NMR(400MHz,CDCl3,25℃):δ4.29(s,4H,-OCH2-C-CH2O-),4.25(t,2H,-OCH2CH2-),3.64(s,2H,-OCH2CH2),3.38(s,3H,-OCH3),3.20-3.14(m,6H,-SCH2CH2N(CH2CH3)2-),3.03-3.00(m,2H,-SCH2CH2N-),2.66(t,2H,-OCH2CH2CH2S-),2.00-1.95(m,2H,-OCH2CH2CH2S-),1.38(t,6H,-N(CH2CH3)2),1.28(s,3H,-CH3).
PEO123-b-P(MAC-SDPA·HCl)115(PSDPA)1H NMR(400MHz,CDCl3,25℃):δ4.29(s,4H,-OCH2-C-CH2O-),4.25(t,2H,-OCH2CH2-),3.64(s,2H,-OCH2CH2),3.38(s,3H,-OCH3),3.19(s,2H,-SCH2CH2N-),3.04-2.98(m,2H,-SCH2CH2N-和-N(CH2CH2CH3)2),2.66(t,2H,-OCH2CH2CH2S-),2.00-1.95(m,2H,-OCH2CH2CH2S-),1.85-1.81(m,4H,-N(CH2CH2CH3)2),1.28(s,3H,-CH3),1.01(t,6H,-N(CH2CH2CH3)2).
PEO123-b-P(MAC-SDBA·HCl)105(PSDBA)1H NMR(400MHz,CDCl3,25℃):δ5.92-5.84(m,1H,-CH=CH2),5.33-5.23(m,2H,-CH=CH2),4.64-4.63(d,2H,-0CH2CH=CH2),4.34-4.28(m,4H,-OCH2-C-CH2O-),4.24(t,2H,-OCH2CH2-),3.64(s,2H,-OCH2CH2),3.38(s,3H,-OCH3),2.92(m,2H,-SCH2CH2N-),2.82(m,2H,-SCH2CH2N-),2.75(m,4H,-N(CH2CH2CH2CH3)2),2.62(t,2H,-OCH2CH2CH2S-),1.98-1.93(m,2H,-OCH2CH2CH2S-),1.60(s,4H,-N(CH2CH2CH2CH3)2),1.39-1.33(m,4H,-N(CH2CH2CH2CH3)2),1.29-1.29(m,6H,-CH3),0.95(t,6H,-N(CH2CH2CH2CH3)2).
由于二丁基的空间位阻,PMAC上的很小百分比的烯丙基与DBA-SH·HCl没有充分反应。
PEO123-b-P(MAC-SC5A·HCl)110(PSC5A)1H NMR(400MHz,CDCl3,25℃):δ4.29(s,4H,-OCH2-C-CH2O-),4.25(t,2H,-OCH2CH2-),3.64(s,2H,-OCH2CH2),3.38(s,3H,-OCH3),3.55-3.29(m,6H,-SCH2CH2N(CH2CH2)2),3.01(m,2H,-SCH2CH2N-),2.66(t,2H,-OCH2CH2CH2S-),2.11(s,4H,-N(CH2CH2)2),2.00-1.95(m,2H,-OCH2CH2CH2S-),1.28(s,3H,-CH3).
PEO123-b-P(MAC-SC6A·HCl)115(PSC6A)1H NMR(400MHz,CDCl3,25℃):δ4.29(s,4H,-OCH2-C-CH2O-),4.25(t,2H,-OCH2CH2-),3.64(s,2H,-OCH2CH2),3.38(s,3H,-OCH3),3.21(br,6H,-SCH2CH2N(CH2CH2)2CH2),3.07(s,2H,-SCH2CH2N-),2.66(t,2H,-OCH2CH2CH2S-),2.00(m,6H,-OCH2CH2CH2S-和-N(CH2CH2)2CH2),1.68(m,2H,-N(CH2CH2)2CH2),1.28(s,3H,-CH3).
PEO123-b-P(MAC-SC7A·HCl)135(PSC7A)1H NMR(400MHz,CDCl3,25℃):δ4.29(s,4H,-OCH2-C-CH2O-),4.25(t,2H,-OCH2CH2-),3.64(s,2H,-OCH2CH2),3.38(s,3H,-OCH3),3.26(s,2H,-SCH2CH2N-),3.23-3.21(m,4H,-N(CH2CH2CH2)2),2.66(t,2H,-OCH2CH2CH2S-),2.00-1.95(m,6H,-OCH2CH2CH2S-和-N(CH2CH2CH2)2),1.74(s,2H,-N(CH2CH2CH2)2),1.28(s,3H,-CH3).
胶束纳米粒的制备
使用PEO-b-P(MAC-SC7A)作为一个实施例。在典型程序中,将10mg PEO123-b-P(MAC-SC7A·HCl)135共聚物溶解在含有150mM NaCl的蒸馏水中。添加NaOH溶液以将最终pH值调节至高于8.0。使用3000Da分子量截止离心管,通过三轮超速离心去除过量的NaOH和盐。向胶束溶液添加蒸馏水,以将聚合物浓度调节至1.0mg/mL。
pH滴定实验
使用PEO-b-P(MAC-SC7A)作为一个实施例。在典型实验中,首先将10mg PEO123-b-P(MAC-SC7A·HCl)135共聚物溶解在10mL蒸馏水中,以使聚合物浓度为1.0mg/mL。添加NaCl以将盐浓度调节至150mM。然后添加NaOH溶液,以使PEO123-b-P(MAC-SC7A·HCl)135共聚物完全脱质子化。通过在搅拌下添加小体积(增量为1μL)0.5M HCl溶液进行pH滴定。通过带有微电极的Mettler Toledo pH计测量pH值。整个范围内的pH降低作为总添加HCl体积的函数进行监测。通过pH滴定曲线一阶导数的两个极值点来确定完全质子化状态(100%质子化度)和脱质子化状态(0%质子化度)。在选定的质子化度下,取出100μL聚合物溶液用于动态光散射测量(DLS,Malvem Nano-ZS模型,He-Ne激光,λ=633nm)。其他PEO-b-P(MAC-SR)共聚物遵循类似的滴定程序。
不同共聚物的TEM图像
首先将PEO123-b-P(MAC-SC7A·HCl)135溶解在蒸馏水中,以使聚合物浓度为1.0mg/mL。添加NaCl以将盐浓度调节至150mM。基于滴定坐标,添加0.5M NaOH的相应体积,以将质子化度调节至95%和85%。将聚合物溶液稀释至0.2mg/mL,并滴在铜网格(copper grid)上。在将网格干燥之后,使用蒸馏水以冲洗网格数秒钟,以去除NaCl,然后添加磷钨酸(phosphotungstic acid,PTA)以用于阴性染色。同样,质子化度为55%和45%的PEO123-b-P(MAC-SDMA)135共聚物通过TEM进行成像。
PEO123-b-P(MAC-SC7A)135在pH 6.5和7.4缓冲液中的降解研究
通过Na2HPO4和NaH2PO4在D2O(50mM)中来制备pH 6.5和7.4的氘化磷酸缓冲溶液。添加NaCl以达到150mM的最终浓度。在pH 6.5溶液中,将5.0mg PEO123-b-P(MAC-SC7A·HCl)135共聚物溶解在1.0mL氘化磷酸缓冲溶液中,以使聚合物浓度达到5.0mg/mL。通过浓缩的NaOD和DCl溶液将聚合物溶液的pH进一步调节至6.5。然后将管密封,并置于具有150rpm的速度的37℃振动器中。在一定时间,将聚合物溶液转移到NMR管以进行1H NMR测量。每隔一天调节聚合物溶液的pH。pH 7.4的溶液研究遵循类似的程序。
等温滴定量热法(ITC)
使用Marvin ITC200微量热计,使用ITC以测量STING二聚体与dUPS共聚物之间的结合亲和力。在20℃下,在含有25mM HEPES的缓冲液(pH 6.5)中进行滴定。滴定迹线通过NITPIC整合,且曲线通过SEDFIT拟合。这些图像是使用GUSSI(biophysics.swmed.edu/MBR/software.html)制备的。
STING报道子实验
将THP1-ISG细胞(5×105个细胞/mL)与佛波醇12-肉豆蔻酸酯13-乙酸酯(PMA)在完全培养基(RPMI-1640、10%胎牛血清、100U/mL青霉素G钠和100μg/mL链霉素)中在37℃下、于5%CO2和正常O2水平下孵育48小时,并补充新鲜培养基再孵育24小时。然后将细胞用含有不同dUPS共聚物(0.5μM)的新鲜培养基孵育48小时。使用萤光素酶检测试剂QUANTI-LucTM评估细胞培养上清液中IRF诱导的Lucia萤光素酶水平。
PSC7A疫苗与肿瘤治疗实验
纳米疫苗通过物理混合肿瘤特异性抗原肽和PSC7A纳米粒来制备。使用基于不可降解PC7A的纳米疫苗进行比较。向6至8周龄C57BL/6小鼠其右大腿皮下接种2×105个TC-1细胞或B16F10黑素瘤细胞。在TC-1肿瘤模型中,在接种之后第8、14、24天向小鼠尾基部皮下注射PBS、仅E7p(0.5μg)、仅PSC7A NP(30μg)、低剂量PSC7A纳米疫苗(6μg PSC7A NP中0.1μgE7p)、高剂量PSC7A纳米疫苗(30μg PSC7A NP中0.5μg E7p)和高剂量PC7A纳米疫苗(30μgPC7A NP中0.5μg E7p)。在B16F10肿瘤模型中,在接种之后第5、10、15天向小鼠尾基部皮下注射PBS、仅Trp1,2(0.5μg Trp1214-237和0.5μg Trp2173-196)、仅PSC7A NP(30μg)、低剂量PSC7A纳米疫苗(6μg PSC7A NP中0.1μg Trp1和0.1μg Trp2)、高剂量PSC7A纳米疫苗(30μgPSC7A NP中0.5μg Trp1和0.5μg Trp2)以及高剂量PC7A纳米疫苗(30μg PC7A NP中0.5μgTrp1和0.5μg Trp2)。随后使用数字卡尺测量肿瘤生长,并以0.5×长度×宽度2计算。当肿瘤体积达到2000mm3时,处死小鼠。
统计学分析
使用Origin和Graphpad Prism进行统计学分析。数据以平均值±s.e.m表示。数据通过t检验进行分析,并且如果P<0.05(***P<0.001,**P<0.01,*P<0.05),则认为是统计学上显著的。
实施例2:pH响应性生物可降解聚合物文库的合成和表征
方案1举例说明了使用开环聚合(ROP)合成生物可降解UPS共聚物。(Chen et al.,1997;Brannigan和Dove,2017;Feng et al.,2012)首先,在二氯甲烷(DCM)中,使用甲氧基封端的聚乙二醇(PEO)(mPEG5k-OH,Mn=5.4×103g/mol,通过1H NMR测量)作为大分子引发剂,以及5-甲基-5-烯丙基氧基羰基-1,3-二氧六环-2-酮(MAC)作为环状单体,合成了烯丙基官能化嵌段共聚物聚(环氧乙烷)-b-聚(5-甲基-5-烯丙基氧基羰基-1,3-二氧六环-2-酮)(PEO-b-PMAC)。使用1-(3,5-双-三氟甲基-苯基)-3-环己基硫脲(TU)和1,8-二氮杂双环[5.4.0]十一-7-烯(DBU)的有机共催化剂。将反应混合物在30℃下加热15小时,以产生PEO-b-PMAC共聚物,其在PMAC链段中有125至140个重复单元,通过1H NMR测量。为了呈现pH敏感性,将PEO-b-PMAC与一系列质子化叔胺(R.HCl)在UV光(365nm,方案1)下通过硫醇-烯反应进一步反应。因此,生物可降解性超pH敏感性共聚物PEO-b-P(MAC-SR·HCl)的文库在质子化状态下合成(表1)。PSR用于指代嵌段共聚物PEO-b-P(MAC-SR·HCl)及其脱质子化状态,如下。
方案1.通过开环聚合和硫醇-烯反应合成PEO-b-P(MAC-SR·HCl)。最终共聚物由亲水性PEO链段、生物可降解的聚碳酸酯骨架和提供pH敏感性的可电离叔胺组成。
在存在模拟生理盐浓度的150mM NaCl的情况下,对新合成的dUPS共聚物(1.0mg/mL)系列进行pH滴定。数据以pH相对于共聚物上叔胺基团质子化度呈现。质子化度作为质子化形式的总胺的摩尔百分比计算。每种共聚物的表观pKa作为当质子化度为50%情况下的pH测量。为了评价pH转变的锐度,测量了每种共聚物的ΔpH10%至90%(质子化度在10%至90%之间的pH范围)。
结果显示,除PEO123-b-P(MAC-SDMA)135(具有二甲胺侧链的共聚物)(PSDMA)之外,所有其他共聚物在大多数pH滴定坐标下显示出超pH敏感行为(图1A)。超敏感pH响应表现为在横跨广泛的质子化度范围(特别是10%到90%)内的显著的pH平稳期(pH plateau),表明在窄pH范围内具有强的pH缓冲效应。令人感兴趣的,PEO123-b-P(MAC-SDMA)135显示出两段式pH响应,质子化度高于50%的宽响应和低于50%的窄响应(参见图4)。对于这些共聚物,ΔpH10%至90%的值处于或低于0.5。对于带有二甲胺侧链的PSDMA,观察到更高的ΔpH10%至90%值(1.2)。常用的多碱(例如聚(乙烯亚胺)、壳聚糖、聚组氨酸、聚赖氨酸)显示出宽pH响应,其ΔpH10%至90%>2(图19)。(Li et al.,2016)此外,具有二甲胺侧链的不可降解PMMA共聚物在整个pH滴定坐标中显示出宽pH响应(Li et al.,2016)。
PEO-b-P(MAC-SR·HCl)共聚物的表观pKa值显示与叔胺取代基的疏水性负相关(图1B)。使用P(MAC-SR)链段(中性/脱质子化状态)重复单元的辛醇-水分配系数(log P)来量化分子疏水性。数据显示对于含有环状或线性胺的共聚物,表观pKa作为log P函数的收敛线性相关性。更具疏水性侧链导致更低的pKa值。这些共聚物的pKa值涵盖了从7.7到5.2的广泛的生理pH范围。
ΔpH10%至90%作为log P的函数的图示出了超pH敏感性响应的疏水性阈值的存在(图1C)。对于log P>2的共聚物,ΔpH10%至90%值处于或低于0.5。对于log P<2时的PEO123-b-P(MAC-SDMA)135,观察到更高的ΔpH10%至90%值(1.2)。对于比较,最常用的多碱(例如聚(乙烯亚胺)、壳聚糖、聚组氨酸、聚赖氨酸)是亲水性的,其log P<2,并显示出广泛的pH响应。聚(乙烯亚胺)具有最高的ΔpH10%至90%值(5.6),这是因为其在质子化过程中具有强亲水性(log P=-3.8)和负协同性。这些结果与不可降解PMMA聚合物一致,表明分子疏水性是两种系统中超pH敏感性的共同驱动者(Li et al.,2016)。
研究了log P值高于和低于疏水性阈值下的两种共聚物PEO123-b-P(MAC-SC7A)135(PSC7A)和PEO123-b-P(MAC-SDMA)135(PSDMA)的疏水性驱动的相变(即胶束化)及其对pH敏感性的影响。对于PEO123-b-P(MAC-SC7A)135,pH滴定期间的动态光散射(DLS)结果(图2A)显示,当质子化度高于90%时,聚合物链作为单聚体存在,其流体动力学直径低于10nm。当质子化度降至90%及以下时,胶束开始形成,如散射计数率提高所表明的。临界胶束化质子化度(CMPD)被定义为这样的质子化度,低于其时聚合物链开始自组装。对于PEO123-b-P(MAC-SC7A)135,CMPD值为90%。PEO123-b-P(MAC-SC7A)135在质子化度为95%和85%时的透射电子显微术(TEM)图像和数加权流体动力学直径分布(图2B)进一步证实了横跨CMPD的相变。胶束直径保持在约45nm,其质子化度低于90%。
PEO123-b-P(MAC-SDMA)135(PSDMA)更能说明胶束化诱导的超pH敏感性。聚合物显示出两段式pH响应,质子化度高于50%的宽响应和低于50%的窄响应(图5)。当质子化度高于50%时,PEO123-b-P(MAC-SDMA)135保持为单聚体,并显示出广泛的pH响应。当质子化低于50%时,观察到显著急剧的pH响应。超pH敏感性响应与CMPD上胶束的形成一致,这提供了相变诱导的超pH敏感性响应的直接证据。令人感兴趣的,具有二甲胺侧链的不可降解PMMA聚合物在整个pH滴定过程期间没有显示出任何相变行为。这些结果显示,聚碳酸酯骨架PMAC比PMMA更具疏水性,并且也有助于胶束的形成。
PEO123-b-P(MAC-SC7A)135被选为代表性的生物可降解共聚物,并研究了其在pH7.4和6.5下的降解特性,所述pH 7.4和6.5分别模拟了正常生理pH和早期内体pH环境。PEO123-b-P(MAC-SC7A)135的表观pKa为6.9,因此共聚物在pH 7.4和6.5下分别以胶束或质子化单聚体状态存在。在含NaCl(150mM)的氘化磷酸缓冲溶液(50mM)中以5.0mg/mL制备共聚物。添加NaOD或DCl溶液以将pH调节至6.5或7.4。图3A示出了PEO123-b-P(MAC-SC7A)135共聚物及其降解产物的结构。在降解过程中,共聚物可降解成寡聚物、单体、PEO链段、二氧化碳,所有都是由于聚碳酸酯骨架的水解裂解(图3A中左侧结构上的圆圈)。侧链上酯基(图3A中右侧结构上的圆圈)的进一步水解可导致另外的降解产物,2,2-双(羟甲基)丙酸(-HPA)和3-(2-氮杂环庚烷-1-基-乙基硫烷基)-丙醇。利用1H NMR以监测两种pH溶液中55天内降解产物的形成。PEO链段的质子信号不随时间变化,并且其峰积分被用作对其他质子峰的内部参考以用于定量。
图3B示出了PEO123-b-P(MAC-SC7A)135在pH 6.5下随时间的降解谱。由于共聚物在溶液中作为质子化单聚体存在,所有质子峰在时间零时都是可见的(例如,对应于c1、d1和e1的质子信号)。在最初数天内,新的峰(c3、c4、d2和d3)形成,且其强度随时间提高。在第25天,显示大多数共聚物降解成单体结构(图3A中的黄色组)和PEO。从第25天到第55天的另外的水解显示出小百分比的双-HPA的进一步降解产物(d4)。通过分析d1和d2(分别来自聚合物和寡聚物状态)峰强度的降低或d3和d4(单体和双-HPA)的提高,对降解动力学进行定量。数据显示,在第12天,两组曲线在50%的相对峰强度处同时相交(图3D)。如本文中所用,t1/2被定义为50%共聚物转变成单体的半衰期。
由于胶束的形成,pH 7.4时的降解谱更加复杂。在时间零时,通过1H NMR仅可看到PEO峰(图3C),因为P(MAC-SC7A)链段的胶束形成导致由于质子信号快速横向弛豫的信号抑制。随着时间的推移,观察到来自降解单体和双-HPA的质子信号,尽管其形成动力学较慢。令人感兴趣的,在第55天,发现双-HPA与MAC单体的比例更高。单体和双-HPA峰(d3+d4)的定量分析显示,在较高pH环境下,t1/2为27天(图3E)。相对于pH 6.5,pH 7.4时的较慢的降解动力学可能是由于数个因素引起的,包括由于疏水性胶束核心导致的水渗透和进入PMAC受限,或pH 7.4时酸催化的碳酸酯键水解降低。
聚碳酸酯骨架具有水解活性,允许聚合物在水性环境中自发降解成生物相容性PEO链段和小分子。降解动力学表明,pH 7.4相比于pH 6.5,水解以更慢的速率发生(t1/2分别为27和12天),这可能是因为在pH 7.4时PSC7A链段的胶束化限制了水进入碳酸酯基团。
实施例3:负载IL-2的胶束的包封
PEG-b-P(MAC-SDPA)(pKa=6.1)胶束被开发用于将T细胞生长因子IL-2递送至肿瘤微环境。在典型程序中,将0.2mg PEG-b-P(MAC-SDPA)溶解在0.05mL甲醇中,并随后将其逐滴添加到0.5mL PBS(pH 7.4)中以形成空胶束。通过超滤(100kDa,5000rpm/15分钟,进行2次)去除甲醇。将胶束重悬在PBS中,并随后与不同量的人重组IL-2蛋白混合。
通过将20μg(10%)、10μg(5%)或1μg(0.5%)IL-2与PEG-b-P(MAC-SDPA)胶束混合来评价IL-2负载效率。通过超滤(100kDa,5000rpm/15分钟,进行2次)从负载IL-2的PEG-b-P(MAC-SDPA)胶束中去除游离IL-2。收集滤液,以通过HPLC确定IL-2浓度。发现在所有情况下,超过90%的IL-2蛋白都被负载在PEG-b-P(MAC-SDPA)胶束内。PEG-b-P(MAC-SDPA)胶束中IL-2的含量分别计算为8.26%、4.31%和0.45%。IL-2-PEG-b-P(MAC-SDPA)的颗粒尺寸为约55nm,如通过动态光散射分析确定的。
A.体外IL-2作用的评价
使用旨在监测由IL-2诱导的JAK-STAT途径的激活的HEK-BlueTM IL-2报道细胞研究IL-2的功能。简言之,将细胞用预先温热的PBS冲洗,并将其从瓶中分离,以制备约280,000个细胞/mL的细胞悬液。然后将20μL游离IL-2或负载IL-2的PEG-b-P(MAC-SDPA)添加到平底96孔板中。将样品与每孔180μL的细胞悬液在37℃下在CO2培养箱中孵育(IL-2浓度:200、50、10、2、0.5、0.2、0.05、0.01ng/mL;PEG-b-P(MAC-SDPA)浓度:40、10、2、0.4、0.1、0.04、0.01、0.002μg/mL)。在24小时之后,将每孔20μL经诱导的HEK-BlueTM IL-2细胞上清液添加到另一个96孔板中,并与100μL QUANTI-BlueTM检测溶液混合。将板在37℃培养箱中孵育1小时,并随后使用分光光度计在630nm处确定SEAP水平。
数据显示,与游离IL-2相比,经PEG-b-P(MAC-SDPA)包封的IL-2的生物作用显著增强(图8)。经PEG-b-P(MAC-SDPA)包封的IL-2和游离IL-2的EC50分别为0.8ng/mL和15ng/mL。胶束递送的IL-2显示出效力是游离IL-2的约20倍高。
B.体内抗肿瘤效力的评价
评价了游离IL-2和PEG-b-P(MAC-SDPA)-IL-2在B16F10黑素瘤肿瘤模型中的肿瘤生长抑制作用。首先向C57b1/6j小鼠接种B16F10细胞(100μL PBS中2.5×105个细胞)。当肿瘤生长到50至80mm3的尺寸时,将小鼠随机分成5组。在第1天和第5天时肿瘤内或静脉内注射游离IL-2或PEG-b-P(MAC-SDPA)-IL-2(IL-2:1μg/次注射;PEG-b-P(MAC-SDPA):200μg/次注射)。
如图9中所示,与i.v.注射相同剂量的游离IL-2相比,在i.v.注射之后PEG-b-P(MAC-SDPA)-IL-2表现出提高的肿瘤生长抑制。与游离IL-2相比,在负载在PEG-b-P(MAC-SDPA)胶束中之后,在i.t注射之后,IL-2抗肿瘤作用也增强。与PBS对照相比,所有经处理组均显示出肿瘤生长抑制。
PBS和游离IL-2i.t组中小鼠的体重在一周之后略有提高,可能是由于肿瘤生长所致。对于PEG-b-P(MAC-SDPA)-IL-2组(i.v和i.t二者),治疗期间未发现明显的重量减轻(weight loss)。然而,在i.v注射之后,游离IL-2在小鼠中造成了一些暂时性的减轻(图10),表明来自全身施用游离IL-2的潜在副作用。
实施例4:cGAMP胶束的包封
cGAMP是内源性的第二信使和高亲和力配体,其通过STING途径触发I型IFN产生。它是阴离子和高度水溶性分子,其活性和治疗效力受到其低生物利用度和差的药物样特性的限制。基于我们的生物可降解PEG-b-P(MAC-SC7A)胶束开发了纳米粒,以用于cGAMP的高效胞质递送。
在典型的配制过程中,首先将PEG-b-P(MAC-SC7A·HCl)溶解在5%葡萄糖水溶液中,以使聚合物浓度为1.0mg/mL。然后添加小体积的HCl,随后添加不同量的cGAMP(聚合物的2%、5%和10%,w/w)。向溶液添加特定体积的NaOH,以将最终pH调节至约7.4。在超滤(10kDa)之后,收集滤液,并通过HPLC测量未负载的cGAMP的量。cGAMP的相应负载效率如下计算:
负载效率(%)=(负载的cGAMP重量/总cGAMP重量)×100%。
结果在图11中示出。cGAMP在PEG-b-P(MAC-SC7A)纳米粒中的负载效率可高达90%(1.0mg/mL PSC7A时2%cGAMP)。另外两种制剂的负载效率也达到高于80%。这对于cGAMP负载纳米粒制剂来说是非常高的。同时,制剂是非常稳定的。即使在24小时之后,负载效率也没有太大变化。
实施例5:STING激活、抗原递送和癌症的T细胞治疗
干扰素基因刺激物(stimulator of interferon genes,STING)是内质网(endoplasmic reticulum,ER)结合的同型二聚体蛋白,其在固有免疫中发挥关键作用(Barber,2015;Ishikawa和Barber,2008)。STING激活导致I型干扰素(IFN)上调,其增强CD8+T细胞针对癌症的应答(Baccala et al.,2007;Fuertes et al.,2013;Zitvogel et al.,2015)。此前,已报道了不可降解的聚合物纳米粒PC7A NP,其允许有效包封肿瘤抗原,并胞质递送至淋巴结驻留的树突细胞。该聚合物还结合并激活STING,并开启共刺激途径(CD80/CD86)以用于产生抗原特异性T细胞(Luo et al.,2017)。
在这项研究中首次评价了一系列dUPS共聚物(PSC7A、PSC6A、PSC5A和PSDEA)与STING的C端结构域(139至397AA)的结合亲和力。选择pH 6.5进行结合研究,其中所有共聚物在溶液中均保持为阳离子单聚体。等温量热法(ITC)结果显示,PSC7A共聚物与STING的结合亲和力最高,解离常数(Kd)为26nM(图12A)。具有环状叔胺的另外两种共聚物PSC6A和PSC5A的结合较低,Kd值分别为43和84nM。具有线性叔胺的共聚物PSEDA与STING的结合可忽略不计。不可降解PC7A对STING的Kd值为72nM,高于通过PSC7A的Kd值。在通过不同共聚物(0.5μM)处理48小时之后,使用THP1-ISG细胞以评价STING激活(图12C)。通过干扰素调节因子诱导型启动子控制下的萤光素酶报道基因转染THP1-ISG细胞。在STING激活之后,I型IFN的分泌将激活萤光素酶表达,以用于发光检测。结果显示,与线性类似物相比,具有环状叔胺的dUPS共聚物提高了IFN诱导。特别地,PSC7A共聚物导致IFN诱导的最大14倍提高,这与通过ITC测量的对STING的最高结合亲和力有关。
基于STING结合和激活测定,选择了PSC7A共聚物用于随后的T细胞疫苗研究(图13)。首先产生PSC7A纳米粒,并随后将其与肿瘤特异性抗原肽混合。使用人乳头瘤病毒(human papilloma virus,HPV)E6/E7转染的TC-1和鼠B16-F10黑素瘤肿瘤模型。首先在6至8周龄C57BL/6小鼠的右大腿接种肿瘤细胞(2×105个)。在TC-1模型中,使用E7肽抗原(E7p,GQAEPDRAHYNIVTFCCKCD(SEQ.No.1))。在肿瘤接种之后第8天、第16天和第24天,对不同组在尾基部皮下注射(在图13A中示出)。PBS、E7p和仅PSC7A NP组用作对照。结果显示,与PBS对照相比,E7p和仅PSC7A NP组具有边缘肿瘤生长抑制响应。大多数动物在肿瘤接种之后30天内损失。相比之下,E7p-PSC7A NP组导致肿瘤生长抑制显著提高和存活延长。低剂量PSC7A疫苗组(6μg PSC7A NP中0.1μg E7p)导致在肿瘤接种之后50天动物存活>50%,而高剂量疫苗组(30μg PSC7A NP中0.5μg E7p)有完全存活结果(图13A)。对于B16-F10黑素瘤肿瘤模型,将肿瘤相关抗原(Trp1214-237和Trp2173-196)的组合负载在PSC7A NP中。与PBS对照和肽或仅PSC7A NP组相比,肽-PSC7A NP组也显示出显著提高的肿瘤生长抑制和延长的存活(图13B)。在这两种模型中,与相同剂量的PC7A纳米疫苗相比,PSC7A纳米疫苗在TC-1模型中显示出轻微提高的肿瘤抑制,并且在B16F10模型中显示出类似的响应(图14)。
结果显示,具有环状胺的dUPS聚合物比具有二烷基胺的聚合物表现出更强的STING结合亲和力和干扰素诱导,其中PSC7A是最佳的。在两种小鼠肿瘤模型中的体内研究显示,负载抗原的PSC7A NP可有效产生抗肿瘤免疫,显著提高肿瘤生长抑制和动物存活。
实施例6:纳米粒的短期和长期安全性评价
特别是对于通过STING途径积极参与固有免疫系统的聚合物,在治疗期间重复施用的安全性指示至关重要。在这项研究中,将用于疫苗接种研究的dUPS PSC7A聚合物与其基于不可降解PMMA的前体PC7A进行了直接比较(图15A)。向6至8周龄的C57BL/6小鼠其右侧胁腹皮下注射高剂量的PSC7A NP或PC7A NP(300μg,疫苗剂量的10倍)。在注射之后24小时收集血清,并确定全身炎性细胞因子浓度。在任一种聚合物处理之后24小时均未观察到明显的急性肾或肝毒性(图15B)。一般来说,相比于通过PSC7A NP,通过PC7A NP将全身细胞因子表达诱导到更高的程度(图15C),表明对PSC7A NP的全身炎性应答更少。与PBS相比,在使用任一种聚合物处理之后,关键器官(心脏、肝、脾和肾)的组织学分析是不显著的(图16)。
生物可降解PSC7A相对于不可降解PC7A的优点在长期安全性研究中更显著。对于该测定,向小鼠皮下注射PBS、300μg PSC7A NP或300μg PC7A NP,并观察60天(图17A)。基于椭圆模型计算产生的皮下结节的表面积,以监测进展(图17B)。在施用之后一天内,在PC7A和PSC7A二者的注射部位均观察到大的急性炎性反应,可能是由于固有免疫刺激引起。组织学上,在注射之后24小时观察到大量嗜中性粒细胞浸润和坏死碎片(第1天时间点,图18)。在该最初的急性炎性反应之后,皮下结节尺寸减小,并逐渐转变成慢性肉芽肿性炎性应答,其中巨噬细胞和淋巴细胞浸润更高(第15天和第30天时间点,图18)。PSC7A诱导的结节尺寸减小,速度快于PC7A诱导的那些,表明PSC7A聚合物在降解,并从注射部位排出,使组织最终愈合。PSC7A结节尺寸减小的半衰期为约13天,支持了以上降解动力学的化学数据。相比之下,直至施用之后45天,PC7A诱导的结节的尺寸随时间减小,在此之后结节的尺寸和外观保持不变。在第60天,收集所有剩余小鼠注射部位的皮肤组织以进行组织学分析(图17C)。大体上,来自PC7A组的6/6皮肤样品含有小、硬、黄色的结节。相比之下,来自PSC7A组中没有一个(0/6)含有结节,并且在外观上与经PBS处理组相似。第60天的H&E染色显示,在用PC7A处理的小鼠中被肉芽肿性炎症围绕的结节,呈“核/壁”外观(图17D)。在此,“壁”主要包含巨噬细胞以及分散的淋巴细胞和嗜中性粒细胞,这是由急性和慢性固有刺激和异物(foreign-body)反应引起的。“核”本质上是坏死的,主要由濒死细胞的蛋白质碎片,以及一些浸润的巨噬细胞、嗜中性粒细胞和淋巴细胞组成。相比之下,来自经PSC7A处理的小鼠的皮肤组织与经PBS处理的那些相比显示出任何结节的完全消失,并恢复至健康状态。
体内安全性研究显示,PSC7A和PC7A二者均在短期内诱导快速、固有炎性应答,其中来自PSC7A NP的全身细胞因子水平低于PC7A NP。长期PSC7A降解允许注射部位完全愈合,而被肉芽肿性炎症围绕的结节在PC7A部位持续存在。总之,这些数据支持PSC7A随时间推移完全降解,以及与PC7A相比其安全性谱显著提高。
*********************
可根据本公开内容在没有过度实验的情况下实施和实践本文中所公开和要求保护的所有组合物和方法。虽然已经根据某些实施方案描述了本公开内容的组合物和方法,但是对于本领域技术人员明显的是,在不脱离本公开内容的理念、精神和范围的情况下可对本文中所述的组合物和方法以及方法的步骤或方法的步骤顺序进行变化。更具体地,将明显的是,在化学和生理学两方面均相关的某些试剂可替代本文中所述的试剂而将实现相同或类似的结果。对于本领域技术人员显而易见的所有这样的类似替代和修改被视为在所附权利要求书限定的本公开内容的精神、范围和概念内。
参考文献
以下参考文献就其提供补充本文中阐述的那些的示例性操作或其他细节而言具体地通过引用并入本文。
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序列表
<110> THE BOARD OF REGENTS OF THE UNIVERSITY OF TEXAS SYSTEM
<120> 生物可降解性超PH敏感性聚合物
<130> UTFD.P3433WO
<140> 未知
<141> 2020-06-22
<150> US 62/865,187
<151> 2019-06-22
<160> 1
<170> PatentIn version 3.5
<210> 1
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<400> 1
Gly Gln Ala Glu Pro Asp Arg Ala His Tyr Asn Ile Val Thr Phe Cys
1 5 10 15
Cys Lys Cys Asp
20
Claims (65)
1.下式聚合物或其可药用盐:
其中:
R1是氢、烷基(C≤8)、经取代烷基(C≤8)或巯基反应性基团;
m是1至8的整数;
p和q各自独立地是1、2或3;
x是10至200的整数;
y是20至200的整数;
z是0至200的整数;
其中y或z的单体随机分布在所述聚合物中;
X1、X2、X1’和X2’各自独立地是O或NRa,其中:
Ra是烷基(C≤6)或经取代烷基(C≤6);
R2和R2’各自独立地是氢、烷基(C≤8)或经取代烷基(C≤8);
R3是氢、烷基(C≤8)或经取代烷基(C≤8);
X3和X3’各自独立地是O或NRb,其中:
Rb是氢、烷基(C≤6)或经取代烷基(C≤6);
L和L’各自独立地是下式基团:
-X4-S(O)n-X5-
其中:
n是0、1或2;并且
X4和X5各自独立地是烷二基(C≤8)或经取代烷二基(C≤8);并且Y1、Y2、Y1’和Y2’各自独立地是烷基(C≤12)、经取代烷基(C≤12)、烯基(C≤12)或经取代烯基(C≤12);或者Y1和Y2或Y1’和Y2’合在一起,并且是烷二基(C≤12)、烯二基(C≤12)或任一基团的经取代形式。
2.权利要求1所述的聚合物,其进一步限定为以下或其可药用盐:
其中:
R1是氢、烷基(C≤8)、经取代烷基(C≤8)或巯基反应性基团;
m是1至8的整数;
p和q各自独立地是1、2或3;
x是10至200的整数;
y是20至200的整数;
X1和X2各自是O或NRa,其中:
Ra是氢、烷基(C≤6)或经取代烷基(C≤6);
R2是氢、烷基(C≤8)或经取代烷基(C≤8);
R3是氢、烷基(C≤8)或经取代烷基(C≤8);
X3是O或NRb,其中:
Rb是氢、烷基(C≤6)或经取代烷基(C≤6);
L是下式基团:
-X4-S(O)n-X5-
其中:
n是0、1或2;并且
X4和X5各自独立地是烷二基(C≤8)或经取代烷二基(C≤8);并且
Y1和Y2各自独立地是烷基(C≤12)、经取代烷基(C≤12)、烯基(C≤12)或经取代烯基(C≤12);或者Y1和Y2合在一起,并且是烷二基(C≤12)、烯二基(C≤12)或任一基团的经取代形式。
3.权利要求1或权利要求2所述的聚合物,其进一步限定为以下或其可药用盐:
其中:
R1是氢、烷基(C≤8)、经取代烷基(C≤8)或巯基反应性基团;
m是1至8的整数;
x是10至200的整数;
y是20至200的整数;
X1和X2各自是O或NRa,其中:
Ra是氢、烷基(C≤6)或经取代烷基(C≤6);
R2是氢、烷基(C≤8)或经取代烷基(C≤8);
R3是氢、烷基(C≤8)或经取代烷基(C≤8);
X3是O或NRb,其中:
Rb是氢、烷基(C≤6)或经取代烷基(C≤6);
L是下式基团:
-X4-S(O)n-X5-
其中:
n是0、1或2;并且
X4和X5各自独立地是烷二基(C≤8)或经取代烷二基(C≤8);并且
Y1和Y2各自独立地是烷基(C≤12)、经取代烷基(C≤12)、烯基(C≤12)或经取代烯基(C≤12);或者Y1和Y2合在一起,并且是烷二基(C≤12)、烯二基(C≤12)或任一基团的经取代形式。
4.根据权利要求1至3中任一项所述的聚合物,其进一步限定为以下或其可药用盐:
其中:
R1是氢、烷基(C≤8)、经取代烷基(C≤8)或巯基反应性基团;
x是10至200的整数;
y是20至200的整数;
X1和X2各自是O或NRa,其中:
Ra是氢、烷基(C≤6)或经取代烷基(C≤6);
R2是氢、烷基(C≤8)或经取代烷基(C≤8);
R3是氢、烷基(C≤8)或经取代烷基(C≤8);
X3是O或NRb,其中:
Rb是氢、烷基(C≤6)或经取代烷基(C≤6);
L是下式基团:
-X4-S(O)n-X5-
其中:
n是0、1或2;并且
X4和X5各自独立地是烷二基(C≤8)或经取代烷二基(C≤8);并且
Y1和Y2各自独立地是烷基(C≤12)、经取代烷基(C≤12)、烯基(C≤12)或经取代烯基(C≤12);或者Y1和Y2合在一起,并且是烷二基(C≤12)、烯二基(C≤12)或任一基团的经取代形式。
5.根据权利要求1至4中任一项所述的聚合物,其进一步限定为以下或其可药用盐:
其中:
R1是氢、烷基(C≤8)、经取代烷基(C≤8)或巯基反应性基团;
x是10至200的整数;
y是20至200的整数;
R2是氢、烷基(C≤8)或经取代烷基(C≤8);
R3是氢、烷基(C≤8)或经取代烷基(C≤8);
L是下式基团:
-X4-S(O)n-X5-
其中:
n是0、1或2;并且
X4和X5各自独立地是烷二基(C≤8)或经取代烷二基(C≤8);并且
Y1和Y2各自独立地是烷基(C≤12)、经取代烷基(C≤12)、烯基(C≤12)或经取代烯基(C≤12);或者Y1和Y2合在一起,并且是烷二基(C≤12)、烯二基(C≤12)或任一基团的经取代形式。
7.权利要求1或权利要求2所述的聚合物,其中p是1。
8.根据权利要求1、2或7中任一项所述的聚合物,其中q是1。
9.根据权利要求1至3、7和8中任一项所述的聚合物,其中m是1、2或3。
10.权利要求9所述的聚合物,其中m是2。
11.根据权利要求1至4和7至10中任一项所述的聚合物,其中X1是O。
12.根据权利要求1至4和7至11中任一项所述的聚合物,其中X2是O。
13.根据权利要求1至4和7至12中任一项所述的聚合物,其中X3是O。
14.根据权利要求1至5和7至13中任一项所述的聚合物,其中R1是烷基(C≤8)或经取代烷基(C≤8)。
15.权利要求14所述的聚合物,其中R1是烷基(C≤8)。
16.权利要求15所述的聚合物,其中R1是甲基。
17.根据权利要求1至5和7至16中任一项所述的聚合物,其中R3是氢。
18.根据权利要求1至17中任一项所述的聚合物,其中R2是烷基(C≤8)或经取代烷基(C≤8)。
19.权利要求18所述的聚合物,其中R2是烷基(C≤8)。
20.权利要求19所述的聚合物,其中R2是甲基。
21.根据权利要求1至20中任一项所述的聚合物,其中L的X4是烷二基(C≤6)或经取代烷二基(C≤6)。
22.权利要求21所述的聚合物,其中L的X4是烷二基(C≤6)。
23.权利要求22所述的聚合物,其中L的X4是-CH2CH2-。
24.根据权利要求1至23中任一项所述的聚合物,其中L的X5是烷二基(C≤6)或经取代烷二基(C≤6)。
25.权利要求24所述的聚合物,其中L的X5是烷二基(C<6)。
26.权利要求25所述的聚合物,其中L的X5是-CH2CH2-。
27.根据权利要求1至26中任一项所述的聚合物,其中n是0。
28.根据权利要求1至27中任一项所述的聚合物,其中Y1是烷基(C≤12)或经取代烷基(C≤12)。
29.权利要求28所述的聚合物,其中Y1是烷基(C2-12)或经取代烷基(C2-12)。
30.权利要求28或权利要求29所述的聚合物,其中Y1是烷基(C2-12)。
31.根据权利要求28至30中任一项所述的聚合物,其中Y1是甲基、乙基、正丙基或正丁基。
32.根据权利要求1至31中任一项所述的聚合物,其中Y2是烷基(C≤12)或经取代烷基(C≤12)。
33.权利要求32所述的聚合物,其中Y2是烷基(C2-12)或经取代烷基(C2-12)。
34.权利要求32或权利要求33所述的聚合物,其中Y2是烷基(C2-12)。
35.根据权利要求32至34中任一项所述的聚合物,其中Y2是甲基、乙基、正丙基或正丁基。
36.根据权利要求1至27中任一项所述的聚合物,其中Y1和Y2合在一起并且是烷二基(C≤12)或经取代烷二基(C≤12)。
37.权利要求36所述的聚合物,其中Y1和Y2合在一起并且是烷二基(C≤8)或经取代烷二基(C≤8)。
38.权利要求37所述的聚合物,其中Y1和Y2合在一起并且是烷二基(C≤8)。
39.权利要求37所述的聚合物,其中Y1和Y2合在一起并且是-CH2CH2CH2CH2-、-CH2CH2CH2CH2CH2-或-CH2CH2CH2CH2CH2CH2-。
41.根据权利要求1至40中任一项所述的聚合物,其中x是40至160的整数。
42.权利要求41所述的聚合物,其中x是80至150的整数。
43.根据权利要求1至42中任一项所述的聚合物,其中y是40至180的整数。
44.权利要求43所述的聚合物,其中y是80至150的整数。
45.胶束,其包含多种根据权利要求1至44中任一项所述的聚合物。
46.组合物,其包含:
(A)根据权利要求1至44中任一项所述的聚合物;以及
(B)治疗剂;
其中所述聚合物包封所述治疗剂。
47.权利要求46所述的组合物,其中所述聚合物形成胶束。
48.权利要求46或权利要求47所述的组合物,其中所述胶束完全包封所述治疗剂。
49.根据权利要求46至48中任一项所述的组合物,其中所述治疗剂是影响免疫系统的药剂。
50.权利要求49所述的组合物,其中所述治疗剂是细胞因子或免疫系统调节剂。
51.权利要求50所述的组合物,其中所述细胞因子是IL-1β、IL-2、IL-12或IL-15。
52.权利要求50所述的组合物,其中所述免疫系统调节剂是cGAMP或1型干扰素。
53.权利要求49所述的组合物,其中所述治疗剂是抗原。
54.权利要求53所述的组合物,其中所述抗原是抗癌抗原。
55.权利要求54所述的组合物,其中所述抗癌抗原是E7肽。
56.根据权利要求46至55中任一项所述的组合物,其中所述组合物被配制为药物组合物,并且还包含赋形剂。
57.权利要求56所述的组合物,其中所述药物组合物被配制用于以下施用:经口、脂肪内、动脉内、关节内、颅内、皮内、病灶内、肌内、鼻内、眼内、心包内、腹膜内、胸膜内、前列腺内、直肠内、鞘内、气管内、肿瘤内、脐带内、阴道内、静脉内、囊内、玻璃体内、经脂质体、局部、经黏膜、肠胃外、经直肠、结膜下、皮下、舌下、表面、经口含化、经皮、阴道、作为乳膏、作为脂质组合物、通过导管、通过灌洗、通过连续输注、通过输注、通过吸入、通过注射、通过局部递送或通过局部灌注。
58.权利要求57所述的组合物,其中所述药物组合物被配制用于通过注射施用。
59.权利要求57所述的组合物,其中所述药物组合物被配制用于动脉内施用、肌内施用、腹膜内施用、肿瘤内施用或静脉内施用。
60.根据权利要求56至59中任一项所述的组合物,其中所述赋形剂是载剂。
61.权利要求60所述的组合物,其中所述载剂是适合于注射的水溶液剂。
62.治疗疾病或病症的方法,其包括向有此需要的患者施用治疗有效量的根据权利要求46至61中任一项所述的组合物,其中所述治疗剂足以治疗所述疾病或病症。
63.权利要求62所述的方法,其中所述疾病或病症是癌症。
64.权利要求62或权利要求63所述的方法,其中所述治疗剂能够调节免疫系统以靶向癌症。
65.根据权利要求62至64中任一项所述的方法,其中所述治疗剂产生针对一种或更多种癌细胞的免疫应答。
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AU2020303968A1 (en) | 2022-01-27 |
EP3986467A4 (en) | 2023-07-19 |
JP2022536993A (ja) | 2022-08-22 |
KR20220024565A (ko) | 2022-03-03 |
IL289196A (en) | 2022-02-01 |
CA3144476A1 (en) | 2020-12-30 |
BR112021026025A2 (pt) | 2022-02-08 |
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